BI85CH02-Ahel

ARI

V I E W

19:21

Review in Advance first posted online on January 29, 2016. (Changes may still occur before final publication online and in print.)

A

N

I N

C E

S

R

E

Annu. Rev. Biochem. 2016.85. Downloaded from www.annualreviews.org Access provided by Gazi Universities Main Library (D-S) on 02/04/16. For personal use only.

21 January 2016

D V A

Macrodomains: Structure, Function, Evolution, and Catalytic Activities Johannes Gregor Matthias Rack,1 Dragutin Perina,2 and Ivan Ahel1,∗ 1

Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom; email: [email protected], [email protected]

2 Division of Molecular Biology, Ruder ¯ Boˇskovi´c Institute, Zagreb 10002, Croatia; email: [email protected]

Annu. Rev. Biochem. 2016. 85:2.1–2.24

Keywords

The Annual Review of Biochemistry is online at biochem.annualreviews.org

ADP-ribose, PARP family, PARG, NAD, posttranslational modifications

This article’s doi: 10.1146/annurev-biochem-060815-014935

Abstract

c 2016 by Annual Reviews. Copyright  All rights reserved ∗

Corresponding author

Recent developments indicate that macrodomains, an ancient and diverse protein domain family, are key players in the recognition, interpretation, and turnover of ADP-ribose (ADPr) signaling. Crucial to this is the ability of macrodomains to recognize ADPr either directly, in the form of a derived metabolite, or as a modification covalently bound to proteins. Thus, macrodomains regulate a wide variety of cellular and organismal processes, including DNA damage repair, signal transduction, and immune response. Their importance is further indicated by the fact that dysregulation or mutation of a macrodomain is associated with several diseases, including cancer, developmental defects, and neurodegeneration. In this review, we summarize the current insights into macrodomain evolution and how this evolution influenced their structural and functional diversification. We highlight some aspects of macrodomain roles in pathobiology as well as their emerging potential as therapeutic targets.

2.1

Changes may still occur before final publication online and in print

BI85CH02-Ahel

ARI

21 January 2016

19:21

Contents

Annu. Rev. Biochem. 2016.85. Downloaded from www.annualreviews.org Access provided by Gazi Universities Main Library (D-S) on 02/04/16. For personal use only.

INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 EVOLUTION AND DIVERSIFICATION OF MACRODOMAINS . . . . . . . . . . . . . . . 2.3 STRUCTURAL AND CATALYTIC FEATURES OF MACRODOMAINS . . . . . . . . 2.5 Mono(ADP-Ribosyl) Hydrolases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.9 Poly(ADP-Ribosyl) Glycohydrolases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.10 THE FUNCTION OF MACRODOMAINS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.10 Macrodomains as Readers of Protein ADP-Ribosylation and Sensors of Metabolites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.11 Macrodomains as Erasers of Protein ADP-Ribosylation. . . . . . . . . . . . . . . . . . . . . . . . . . . 2.13 Macrodomains in Microorganisms and Pathogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.14 THE THERAPEUTIC POTENTIAL OF MACRODOMAIN INHIBITORS . . . . . . 2.16 Viral Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.16 Macrodomains in Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.17 OUTLOOK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.17

INTRODUCTION Macrodomains are evolutionarily conserved structural modules of 130–190 amino acids that are found in proteins with diverse cellular functions from all domains of life as well as in some viruses (1). Genomic sequencing identified the first macrodomains (initially termed X domain), as “a domain of considerable conservation” within the genomes of the murine hepatitis virus (MHV) and infectious bronchitis virus (2, p. 579). Shortly thereafter, a homologous domain was identified as part of the rat MacroH2A protein, a histone variant that consists of a fusion between histone H2A and a domain of then unknown function (3). Because MacroH2A was the largest histone variant, the novel domain was dubbed macrodomain. In contrast to many other modification recognition domains, which are adapted to recognize a single or small number of modification types (4), macrodomains can recognize ADP-ribose (ADPr) both in its free and protein-linked forms, in related ligands, such as O-acyl-ADP-ribose (AAR, also called OAADPr), and even in ligands unrelated to ADPr (5–10). They exert regulatory influence on inter- and intracellular signaling, transcription, DNA repair pathways, maintenance of genomic stability, telomere dynamics, cell differentiation and proliferation, as well as on necrosis and apoptosis (5, 11–19). Two factors further highlight the importance of macrodomains in controlling various cellular processes: First, the number of macrodomain-containing proteins correlates well with the complexity of the organism, and second, the macrodomains coevolved most notably with two important NAD+ -utilizing protein families, poly(ADP-ribose) polymerases (PARPs) and sirtuins (20–22). The majority of sirtuins use NAD+ as a cosubstrate for protein deacylation, releasing AAR as a by-product in the reaction (23, 24), but in some instances, sirtuins also catalyze protein ADP-ribosylation (25, 26). PARPs catalyze the transfer of single or multiple ADPr unit(s) from NAD+ onto an acceptor site, usually a glutamate or aspartate residue, thus resulting in mono- or poly(ADP-ribosylation) of the target proteins (20–22, 27, 28). Note that only some members of the PARP family can catalyze the formation of the O-glycosidic ribose-ribose bond and synthesize linear or branched chains of ADPr polymers (27, 29–31). In addition to the ability of macrodomains to bind ADPr derivatives, an early biochemical genomics study identified the yeast macrodomain Poa1 as a phosphatase of ADP-ribose-1 phosphate, a by-product of tRNA splicing (32, 33). Since then it has become apparent that the 2.2

Rack

·

Perina

·

Ahel

Changes may still occur before final publication online and in print

Annu. Rev. Biochem. 2016.85. Downloaded from www.annualreviews.org Access provided by Gazi Universities Main Library (D-S) on 02/04/16. For personal use only.

BI85CH02-Ahel

ARI

21 January 2016

19:21

processing of ADPr derivatives is common among certain types of macrodomains. The catalyzed reactions include the hydrolysis of the 2 ,1 -O-glycosidic ribose-ribose bond in poly(ADP-ribose) (PAR), the protein-ADPr ester bond, or the acyl-ADPr ester (8, 27, 34–40), as detailed below. Thus, macrodomains represent a rare example of a protein fold that is utilized to directly modulate multiple aspects of posttranslational protein modifications, i.e., signal reading, erasing, and interpreting. The ADPr released in some macrodomain reactions acts both as a precursor for the regeneration of NAD+ as well as an important secondary messenger (41). Moreover, reports on human GDAP2 (ganglioside-induced differentiation-associated protein 2) and SUD-M-like macrodomains suggest that additional ADPr-unrelated binding partners, including nucleic acids, may exist for macrodomains (9, 10, 42). In this review, we highlight some aspects of the evolution of macrodomains and their resulting functional and structural diversification. In addition, we discuss the role of macrodomains in pathobiology, including the causes of disease via mutation and dysregulation, as well as the potential of macrodomains as therapeutic targets.

EVOLUTION AND DIVERSIFICATION OF MACRODOMAINS The intricate connection between macrodomains and NAD+ -utilizing pathways suggests that by studying their coevolution one could infer the functions and regulation of specific proteins involved in these processes. Macrodomains can be phylogenetically subdivided into six distinct classes (Figure 1). Probably the most diverged classes are poly(ADP-ribose) glycohydrolase (PARG)-like and SUD-M-like because they were recognized as macrodomains only after the first three-dimensional structure of their representatives had been determined (10, 40, 43). The identification of the latter as macrodomains has two direct consequences: First, the original definition of macrodomains requires rephrasing, emphasizing structural rather than sequential conservation. Second, the lack of a conserved sequence motif opens up the possibility that further, as yet unidentified, classes of macrodomains may exist. Among all macrodomain classes, the Macro2-type remains the least understood branch with almost no functional data available today. Although macrodomains appear less regularly in archaea, most bacteria contain at least one type of macrodomain (Table 1). In eukaryotes, the number of macrodomain-containing proteins generally increases with the complexity of the organism. Among vertebrata, Actinopterygii (a class of bony fishes) possesses the highest number of macrodomain proteins owing to a fish-specific third-genome duplication event. A discrepancy is also observed in some animals with accelerated evolution (e.g., the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster), which possess fewer macrodomain representatives than simple nonbilaterian animals, and this correlates well with the reduced number of PARPs in these organisms (20). Saccharomyces cerevisiae has lost all obvious PARP homologs as well as macrodomains that were present in the common ancestor of Opisthokonta and as a result possesses only two macrodomain proteins (20). In humans, there are at least 12 different proteins containing 16 macrodomains distributed over four branches: MacroD-type, MacroH2A-like, ALC1-like, and PARG-like (Figures 1 and 2 and Table 1) (8, 11). The phylogenetic classification of macrodomains correlates noticeably with their functional diversification; for example, members of the MacroH2A-like class show strong binding to ADPribosylated proteins but possess no catalytic activity, whereas degradation of PAR is specifically associated with the PARG-like class (27, 36, 40) and removal of mono(ADP-ribosylation) with the MacroD-type class (34, 38). However, these associations are not exclusive as TARG1, a member of the ALC1-like class, also possesses mono(ADP-ribosyl) hydrolase activity, albeit utilizing a different reaction mechanism (39). The emergence of the same molecular function within two distinct www.annualreviews.org • Macrodomains

Changes may still occur before final publication online and in print

Reading: the recognition of a posttranslational modification by a protein domain Erasing: the removal of a posttranslational modification from a protein Interpreting: the spatial/temporal recognition of a posttranslational modification, which triggers a series of downstream events by effector proteins

2.3

BI85CH02-Ahel

ARI

21 January 2016

19:21

MacroH2A-like

) 24 79 60 67) 1 40

NP _0 (NP 010 0 _ um d 2 (N 0601 456 iscoid P_ 5 3 eum Staphyloco Macro 564966) ) ccus aure 0 us SauMac D ro (WP_00 (XP_642) 0449060) 223) 44) (WP_0109223 SpyMacro Streptococcus pyogenes

osteli

Ara

6)

Dicty

5) MERS-CoV nsp3 protein (YP_00904721

PA

-t

aG

lian

tha

bido

psis

sap

DAP

2(

P2

AP

DA

GD

sG

io

ien

er

or ni

mo

Da

Ho

ab polyprotein (AHY6133

4)

BtVs-BetaCoV/SC2013 ORF1

e

13

02

pe

2 20 64 P_ (X RG PA 2) 62 um 03 _0 ide co (NP dis ARG 541) ium s P _687 tel ien os sap ARG (XP P cty mo Di Honio rerio Da

-t y

) 5) 930 949 380 001 _01 (YP_ NP ein W( prot 087 like MR blyeY sem 38) 2 isia il as 35982 0 rev e ta (WP_ hag s ce in p yce SL1 . prote ge R r-1'’-p proc rom 08) pha cha (XP_0033883 .DP C100640713 tonia m sp Rals rhizobiu imedon queenslandica LO Amph Brady

Sac

roD

Ma

cr o

2

li k

e

1

RG -li k

00

_0

2 (N

nsp

(N

e

P_

U1

1 LC

yp

(X

HK

fulg id

b

bus

(XP

oglo

P9

dura

Bb

hae

adio

5) 78 ) 00 025 93 182 0 A NP_ _0 s C1 ( L (XP en i 031) A 1 AS56 ap LC haliana 2W (A t os oA 858) BR02 m o reri idopsis Y e o 007004 ia H ani Arab 58 (YP_ erevis D 12 gp1 ces c 4 y F 7 m V age w haro hia ph 86606) Sacc 1 (XP_0033 Escheric dica TARG queenslan on ed im Amph Homo sapiens TARG1 (NP_659500) Danio re rio TAR G1 (NP_0 Mycob 010185 acteri 91) um tu bercu losis R v0060 (WP_0 03400 551) Ther mom Pa Mono onosp ora c nd siga ora urva bre ta PA vir vico RG (W us llis sal P_04 PAR inu 1439 G (X sP 432) P_0 AR G( 017 YP 4 464 _0 0) 08 43 87 Ar Ar Mon 21 ab ab osig ) ab id ido op ps rev ico sis is th llis th ali PA an al RG ia aP (XP na AR _00 PA G2 174 RG (N 885 P 1 _8 7) (N 50 P_ 17 5) 00 10 77 98 9)

14

cus r

M ac

Annu. Rev. Biochem. 2016.85. Downloaded from www.annualreviews.org Access provided by Gazi Universities Main Library (D-S) on 02/04/16. For personal use only.

PR

10 P_ 206 061 73 119 ) 3 (Y ns m Therm us A ) acro P_ odesulf dom 460 F15 obacte 2 a in 0 1 rium g -con 24) (WP eofonti tg. p s ADPrrote _0108 in (W 1'’-p p 7 roc. p P_01 9018) rotein (WP_0 088891 Escherichia co 13910 6) li YmdB (WP_ 000857399) 118) Arabidopsis thaliana MacroD (NP_030605) 7) 01091697 43) 719 (WP_ 9568 um TVN0 _(NP 2407)96) 3) 2 a volcani D sm la ro op ac Therm _54 39 7 rerio M (NP 527 045 Danio oD2 P_00 010 acr 0 X M ( s 1 P_ pien roD 1 (N o sa ac D M Hom s ro ien ac M sap rio mo e o r H o ni Da ococ

00

P_

RP

2A

00

io

P_

PA

us

oH

(N

er

vir

acr

) 65

32

4 12

io

na

H2

A2

sm

or

ro

sap

ien

oro

rer

ac

ni

nc

m

nio

io

Da

Arc

er

e -lik C1 AL

mo

ma

Dein

or

Ho

Da

s mo ni

Hu

Da nio r e r io Ho PA mo RP sap 14 i e A n b sP Hom (X AR o sap P_ P14 iens 0 0 b P 2 A ( RP9b NP _ 06 6635 (XP_ 002 80 005 Da n 2 io 4 re 7 rio P 877) 4) ) A R P 1 4Bc (XP _00260 7924) Danio rerio PARP14Ac (XP_ 002663580) 06995) 4) b (NP_0011 2 ns PARP15 0600 Homo sapie (NP_ 29) 5 P14c 347 1) PAR 004 iens (XP_ 03545 o sap H2 A 1 ) Hom a c ro _ 00 2 5 8 aki m (N P 3 zar z A1 61 owc H2 P_ or a cro (N sasp ma A1 o Cap reri H2 ro nio Da ac sm ien ap

Ho Da

S U D- M-

Figure 1 Phylogenetic representation of evolutionary relationships between different macrodomain sequences. The phylogram shows the six major macrodomain branches and includes eukaryotic (black), archaeal (blue), bacterial ( green), and viral (red ) representatives. The scale bar indicates the genetic distance of the branch lengths, and the accession numbers of sequences used are given after the species and protein names.

2.4

Rack

·

Perina

·

Ahel

Changes may still occur before final publication online and in print

BI85CH02-Ahel

ARI

21 January 2016

19:21

1

120

216

120

3

216

H2A 9

228

277

136

255

335

Macro 230 293

RRM

820

1032

937

Macro

Macro

1245

Macro

650

446

823

PARP cat 1532 1597 1618

1347

Macro 107

759

Macro

Macro

1148

330

616

359

HELICc

SNF2_N

330

Macro

H2A

WWE

223

322

Macro

424

185

678 H. sapiens PARP15 (NP_001106995)

481

SEC14 283

Annu. Rev. Biochem. 2016.85. Downloaded from www.annualreviews.org Access provided by Gazi Universities Main Library (D-S) on 02/04/16. For personal use only.

Macro Macro 31

136

Macro 461 476

716

922

Accessory domain

286

587

229

92

HLH

337

145 546

630

235

HIT 293

Macro

4

398

195

309

NUDIX

Vmethyltransf

Peptidase_C41

686

798 817

Duf3729

915

Macro

984

112

NUDIX

Macro 1198

Viral_helicase1

1351

152 H. sapiens TARG1 (NP_659500)

448 A. suum Dtx3l (ERG82446) 912 A. thaliana Aprataxin (NP_195751) 564 C. albicans Mfs1 (XP_714874)

266 273

Macro2

592

ZnF

476

Sir2

1

409 432

838 824 892

726

425 H. sapiens MacroD2 (NP_542407)

776 A. queenslandica STE20-like (XP_011409012) 436

Ring Deltex_C

Macro

AAA 110

34

705

Macro 251 295304

Macro 53

325 H. sapiens MacroD1 (XP_005273996)

976 H. sapiens PARG (NP_003622)

Macro

Pkinase 35

497 H. sapiens GDAP2 (NP_060156)

201

88

14

854 H. sapiens PARP9 (XP_005247877)

PARP cat 333 170

Regulatory domain

797 H. sapiens ALC1 (NP_001243265)

1801 H. sapiens PARP14 (NP_060024)

Macro

1

372 H. sapiens MacroH2A2 (NP_061119)

PARP cat 493

Macro 72

372 H. sapiens MacroH2A1 (NP_613258)

1689

RdRP_2

447 C. maltosa G210_2818 (EMG46915) 358 O. trichoides OSCT_2070 (EFO80079) 1706 Hepatitis E virus nsP3 (ABK80468)

Figure 2 Schematic architecture of domains present in macrodomain representatives. The schematic representation depicts the domain organization of macrodomain-containing proteins from human (Homo sapiens) as well as from several other interesting organisms’ domain architectures (Amphimedon queenslandica, Arabidopsis thaliana, Ascaris suum, Candida albicans, Candida maltosa, Oscillochloris trichoides). The protein length (in amino acids) is given on the right, and domain boundaries are shown on top of the corresponding scheme and correspond to the SMART/Pfam database. Domain abbreviations: AAA, ATPase associated with diverse cellular activities; Deltex_C, Deltex C-terminal domain; Duf3729, domain of unknown function 3729; H2A, core histone H2A-like domain; HELICc, helicase conserved C-terminal domain; HIT, histidine tirade domain; HLH, helix-loop-helix DNA-binding domain; Macro, macrodomain; NUDIX, nucleoside diphosphate-linked moiety X; PARP cat, poly(ADP-ribose) polymerase catalytic domain; RdRP_2, RNA-dependent RNA polymerase; Ring, really interesting new gene finger domain; Peptidase_C41, hepatitis E cysteine protease; Pkinase, protein kinase domain; RRM, RNA recognition motif; SEC14, named after yeast SECretory protein 14 (Sec14p); Sir2, sirtuin domain; SNF2_N, SNF2 helicase family N-terminal domain; Vmethytransf, viral methyltransferase; WWE, domain is named after a conserved tryptophan/glutamate-containing motif; ZnF, zinc finger.

phylogenetic branches stresses the importance of ADP-ribosylation reversal and demonstrates the adaptability of the macrodomain fold to exert regulatory functions.

STRUCTURAL AND CATALYTIC FEATURES OF MACRODOMAINS As revealed by structure determination, macrodomains adopt a globular α/β/α sandwich fold composed of a central six-stranded mixed β-sheet flanked by five α-helices (Figure 3a) (6, 44–46). Substrate binding occurs via a deep cleft on the crest of the domain. The macrodomain www.annualreviews.org • Macrodomains

Changes may still occur before final publication online and in print

2.5

2.6

Rack

·

Perina

·

Ahel

Changes may still occur before final publication online and in print Branchiostoma floridae Strongylocentrotus purpuratus Aplysia californica Drosophila melanogaster Caenorhabditis elegans Hydra vulgaris Trichoplax adhaerens Amphimedon queenslandica Monosiga brevicollis Capsaspora owczarzaki Saccharomyces cerevisiae

Lancelet Sea urchin Sea slug Fruit fly Roundworm Cnidarian Placozoan Sponge Choanoflagellate Filose amoeboid Yeast

African trypanosome

Danio rerio

Fish

Excavata

Xenopus tropicalis

Frog

Trypanosoma brucei

Dictyostelium discoideum

Anolis carolinensis

Slime mold

Gallus gallus

Lizard

Mus musculus

Chicken

Homo sapiens

Human Mouse

1

2



6

1

2

2

3

1

1

2

2

2

3

3

3

2

3

3

MacroD-type 9 (5)



1



1



20 (9)

10 (9)

1





5 (3)

1

16 (10)

23 (10)

22 (10)

7 (4)

10 (4)

8 (4)



1

1

2



3

1

2



3

1

2

1

2

1

2

2

2

2

ALC1-like





1





1









2

1















Macro2-type

1

1



3

2

3

1

1

2

1

2

2

2

2

1

1

1

1

1

PARGlike







































SUD-M-like

21 January 2016

Amoebozoa

Opisthokonta

Species

MacroH2A-like (number of proteins)

Macrodomain classesa,b

ARI

Eukaryotes

Phylogenetic classification

Table 1 Distribution of macrodomains among different taxa

Annu. Rev. Biochem. 2016.85. Downloaded from www.annualreviews.org Access provided by Gazi Universities Main Library (D-S) on 02/04/16. For personal use only.

BI85CH02-Ahel 19:21

Chlorarachniophyte alga

Rhizaria

Semliki Forest virus (SFV)

Togaviridae

b

1

1 —











1







1

1

Owing to the limitations of available annotation data, the table does not consider protein isoforms derived from alternative splicing. Dashes indicate the absence of an identifiable member of the corresponding macrodomain class from the organism.

Hepatitis E virus (HEV)

Hepeviridae

a

Severe acute respiratory syndrome coronavirus (SARS-CoV)

Coronaviridae

1



1

Escherichia coli Streptomyces coelicolor

Bacteria

Viruses



1

Archaeoglobus fulgidus









Archaea

1

2

2

3

















2







1





5

2

1





1













21 January 2016

Prokaryotes

Arabidopsis thaliana

Mouse-ear cress

Plantae Bigelowiella natans

Phytophthora nicotianae

ARI

Chromalveolata

Annu. Rev. Biochem. 2016.85. Downloaded from www.annualreviews.org Access provided by Gazi Universities Main Library (D-S) on 02/04/16. For personal use only.

BI85CH02-Ahel 19:21

www.annualreviews.org • Macrodomains

Changes may still occur before final publication online and in print

2.7

BI85CH02-Ahel

ARI

21 January 2016

a

19:21

b

c

d

Annu. Rev. Biochem. 2016.85. Downloaded from www.annualreviews.org Access provided by Gazi Universities Main Library (D-S) on 02/04/16. For personal use only.

C

N

MacroH2A1.1

MacroD2 D102

D202

Loop 1

TARG1 D78

D20

S35

N92 F351

F224

K84

Y190

Loop 2

D125

e

PARG F902

Loop 1

N756

F877

Figure 3 Structure and reaction mechanism of the human hydrolytic macrodomain classes. (a) Topological representation of the macrodomain shows the organization of the central six-stranded β-sheet (red ) flanked on both sides by five α-helices ( green). Note that several macrodomains can contain additional α-helices and/or β-sheets. (b–e) The ribbon and surface representations of four human macrodomains illustrate (b,c) the binding of ADPr, (d ) the lysyl-ADPr intermediate, or (e) dimeric ADPr ( yellow). The coordination of the adenosine moiety by a conserved phenylalanine and/or asparagine residue as well as by the substrate-binding loops 1 and 2 (red ) is depicted in the magnifications. (b) MacroH2A1.1, Protein Data Bank (PDB) identification number 3IID, (blue) as a reader macrodomain coordinates ADPr in a relaxed conformation. (c) MacroD2, PDB 4IQY, ( green) coordinates ADPr in a strained conformation owing to the presence of a structural water molecule (dark blue) and Tyr190 (loop 2). The catalytic residues Asn92 and Asp102 (loop 1) interact electrostatically with the distal ribose. (d ) The catalytic Asp125 residue of TARG1, PDB 4J5S, (orange) resides, in contrast to MacroD1/2 and PARG, in substrate loop 2. The structure contains the lysyl-ADPr intermediate formed with the catalytic Lys84. (e) The domain organization of PARG, PDB 5A7R, shows the macrodomain (blue), the accessory domain (orange), and the short, unassigned C terminus ( green). The crystal structure was obtained using a catalytic mutant (E756N) to stabilize the dimeric ADPr substrate. All structures were generated with PyMol (Molecular Graphics System, Version 1.3 Schrodinger, LLC). ¨

2.8

Rack

·

Perina

·

Ahel

Changes may still occur before final publication online and in print

Annu. Rev. Biochem. 2016.85. Downloaded from www.annualreviews.org Access provided by Gazi Universities Main Library (D-S) on 02/04/16. For personal use only.

BI85CH02-Ahel

ARI

21 January 2016

19:21

fold shares some resemblance to the DNA-binding domain of leucine aminopeptidases as well as the P-loop nucleotide hydrolase fold, and therefore a nucleotide-binding or processing activity was originally suggested (44). Indeed, further structural and biochemical characterization showed that ADPr and its derivatives can be accommodated within the cleft (Figure 3b) (6, 45, 46). The interaction between ligand and macrodomain is stabilized by several conserved interactions within the binding pocket: (a) The adenosine moiety readily undergoes π-π stacking with a conserved aromatic residue, whereas its N6 nitrogen is further coordinated by an aspartate residue (Figure 3b–e) (5, 6, 8, 47). Mutagenesis analysis showed that the aspartate residue is crucial for ADPr binding by the macrodomains of human ALC1 (amplified in liver cancer 1) and Archaeoglobus fulgidus, Af1521. (b) The central part of the cleft stabilizes substrate binding by several side-chain/backbone-pyrophosphate contacts, which induce a more closed conformation of the macrodomain (6, 48). (c) The pyrophosphate and distal ribose are accommodated between two substrate-binding loops (termed loop 1 and 2). Although both loops contribute to substrate specificity, loop 1 harbors the catalytic residues of most macrodomains exhibiting hydrolase activity (for this reason it has been also termed catalytic loop). Loop 2 provides further coordination of the pyrophosphate; hence, it is also called the diphosphate-binding loop (Figure 3b–e) (15, 37, 40, 49). The stable interaction between the ligand and the macrodomain can trigger a variety of downstream effects, including recruitment to DNA damage sites (hot spots of PAR generation) or formation of protein complexes (50).

Mono(ADP-Ribosyl) Hydrolases Thus far, two classes of macrodomains have been shown to contain mono(ADP-ribosyl) hydrolases as members: the MacroD-type class and ALC1-like class. Biochemical and structural work on MacroD1, MacroD2, and TARG1, the human representatives of the classes, revealed that these classes utilize fundamentally different catalytic mechanisms. In MacroD1/2, the distal ribose is bound in a constrained conformation, bending it toward the ADPr α-phosphate group (Figure 3c) (8, 34). This orientation is forced through the presence of a highly conserved aromatic residue that is part of the bipartite, MacroD-type signature motif Nx(6)GG[V/L/I] and G[V/I/A][Y/F]G located in loops 1 and 2, respectively (34). A major difference between the reading and erasing macrodomains is the presence of a groove in the pyrophosphate-binding site in which a structural water molecule is coordinated. The exact mechanism of catalysis is as yet undetermined, but two possible reaction sequences were put forward: First, a substrate-assisted mechanism in which the structural water molecule, positioned between the α-phosphate and distal ribose, becomes activated through the α-phosphate group and carries out a nucleophilic attack on the protein-ADPr ester bond (34, 35). Although the constrained conformation of the substrate appears to be crucial for the catalysis, there is controversy over whether the low pKa of the α-phosphate is sufficient to activate the water molecule (34, 35). Second, a conserved aspartate residue in the active site acts as general base for the activation of a water molecule, which in turn carries out a nucleophilic attack on the C1 atom of the distal ribose (8, 38). Recent quantum mechanics simulation and kinetic isotope effect measurements of the hydrolysis of AAR by MacroD1 support the latter mechanism and suggest a concerted mechanism involving simultaneous nucleophile attack and ester bond breakage (51). However, it is important to point out, although it is conserved in MacroD1 and MacroD2, not all catalytically active MacroD-type enzymes possess an isostructural aspartate residue (34). In contrast to the MacroD-type enzymes, the reaction catalyzed by TARG1 progresses via a conserved lysine residue (Lys84 in human TARG1) (Figure 3d ). The lysine nucleophilically attacks the C1 atom of the distal ribose, leading to the formation of a lysyl-ADPr intermediate www.annualreviews.org • Macrodomains

Changes may still occur before final publication online and in print

2.9

BI85CH02-Ahel

ARI

21 January 2016

19:21

and release of the demodified glutamate/aspartate residue (39). The lysine residue is restored by resolving the intermediate via a proximal catalytic aspartate residue (Asp125 in human TARG1), thus releasing ADPr from TARG1. A second difference that sets TARG1 apart from MacroD1/2 is higher solvent accessibility at the adenosine ribose 2 -OH position, which suggests that TARG1 can bind to the poly(ADP-ribosylated) target protein and release PAR from its substrates. This possibility was experimentally demonstrated in vitro, but whether it occurs in vivo remains an open question (35, 39).

Poly(ADP-Ribosyl) Glycohydrolases

Annu. Rev. Biochem. 2016.85. Downloaded from www.annualreviews.org Access provided by Gazi Universities Main Library (D-S) on 02/04/16. For personal use only.

In mammals, PARG is composed of three domains: an N-terminal putative regulatory region, the PARG accessory domain, and the macrodomain (Figures 2 and 3e) (40, 52–54). Together, the latter two form the catalytic core found in all canonical PARG homologs. The PARG macrodomain is composed of a seven-stranded mixed β-sheet accompanied by five α-helices and contains the PARG-specific GGGx(6–8)QEE catalytic motif within loop 1 (40, 52, 54–56). Most of the PARGsubstrate contacts are established via the macrodomain, and the function of the accessory domain is less well understood. It was proposed that the latter acts indirectly by stabilizing the macrodomain fold (19). Structural insights from bacterial and mammalian PARGs show the positioning of the 2 ,1 -O-glycosidic ribose-ribose bond in immediate spatial proximity to the second catalytic glutamate (Glu756 in human). The catalytic mechanism is distinct from both MacroD1/2 and TARG1 (reviewed in detail in 19, 27, 49) and is initiated through an acid/base protonation of the ribose 2 -OH in the proximal ADPr unit. The resulting oxocarbenium intermediate is stabilized by spatial constraints imposed by a phenylalanine (Phe875 in human PARG) present in loop 2 (PARG contains the same signature motif as MacroD1/2 in loop 2, see above). The intermediate is resolved through a nucleophilic attack onto the oxocarbenium ion by a water molecule, followed by the release of ADPr and the remaining PAR chain (40, 52, 54, 55). In vitro data show that PARG has a preference for chain termini; hence, it is predominantly an exoglycohydrolase with only minor contributions of endocleavage. In addition, structural constraints limit the possibility that PARG can cleave at PAR branch points (40, 54, 55). Because endocleavage remains a possibility under condition of extreme cellular stress and PARP1 overactivation, PARG could, similarly to TARG1, release oligo- or poly(ADPr) fragments, which in turn are proposed to induce apoptotic cell death (19, 35, 57).

THE FUNCTION OF MACRODOMAINS A driving factor for the evolution of macrodomains may lie in the increasing complexity of NAD+ signaling/consumption processes, regulating DNA repair, redox defense, chromatin architecture, protein acylation, and response to viral infection among others (58, 59). Support for the latter idea comes from studies of the evolution of PARP genes as well as vertebrate NAD metabolism (20, 60, 61), which suggest that the macrodomain evolution, at least in MacroPARPs, is still ongoing (58, 61). Although the majority of identified macrodomains, especially in bacteria and archaea, are single-domain proteins, the protein families database (Pfam) lists more than 180 different domain architectures containing at least one macrodomain (http://pfam.xfam.org). Among these are homologs of human macrodomain-containing proteins as well as distinct domain combinations in lower organisms (Figure 2). The presence of these proteins suggests a complex interplay between ADPr signaling and a large number of different cellular processes. For example, in plants, a distinct macrodomain type is fused to the DNA-processing enzymes polynucleotide kinase and Aprataxin, suggesting a role in DNA repair (Figure 2) (62). Furthermore, association of macrodomains with NUDIX (nucleoside diphosphate-linked moiety X) domains is commonly observed, suggesting 2.10

Rack

·

Perina

·

Ahel

Changes may still occur before final publication online and in print

BI85CH02-Ahel

ARI

21 January 2016

19:21

involvement in the ADPr recycling pathways. NUDIX pyrophosphatases can cleave ADPr into AMP and ribose-5-phosphate for resynthesis of NAD (63, 64) as well as for other nucleotides, and the human family member NUDT16 was recently shown to act on ADP-ribosylated proteins in vitro (65). Additional domain compositions suggest the cross talk of macrodomains with other posttranslational modifications, including methylation, phosphorylation, and ubiquitination (Figure 2).

Annu. Rev. Biochem. 2016.85. Downloaded from www.annualreviews.org Access provided by Gazi Universities Main Library (D-S) on 02/04/16. For personal use only.

Macrodomains as Readers of Protein ADP-Ribosylation and Sensors of Metabolites Macrodomains are key players in the complex network of NAD-dependent signaling. This is a consequence of their ability to interpret not only protein ADP-ribosylation and PARP-dependent signaling but also second messengers such as ADPr and its derivates, which can be released independently of PARP activity (e.g., through sirtuin activation). It is noteworthy that in humans reader macrodomains only occur in multidomain proteins, thus combining signal recognition and effactor domains in a single polypeptide, as discussed below. MacroH2A. MacroH2A contains an N-terminal histone fold, allowing integration into chromatin, as well as a C-terminal macrodomain (Figure 2) (66). Capsaspora owczarzaki, a Filasterea, occupies one of several unicellular sister groups to Metazoa and is the simplest organism in which MacroH2A can be identified. As a consequence of a whole genome duplication event in the early vertebrate lineage, two MacroH2A genes, MacroH2A1 and MacroH2A2, can be identified (Figure 1). Verified in mammals is the further functional diversification of MacroH2A1 by alternative splicing (into isoforms MacroH2A1.1 and MacroH2A1.2). This splice event leads to the exchange of a short stretch of amino acids within the macrodomain and alters the topology of the ADPr binding pocket (67). Binding studies show that MacroH2A1.1 interacts with ADPr, AAR, and PAR, although neither MacroH2A1.2 nor MacroH2A2 can do so (46). Because the latter two MacroH2A variants contain a binding cleft, albeit altered, it is intriguing to speculate whether these proteins have developed an unknown specificity beyond the usual ADPr metabolites. MacroH2A has been associated with several cellular processes, including cell differentiation and proliferation, transcription repression, and DNA repair (66, 68, 69). Studies investigating the function of MacroH2A during embryonic stem cell development indicate that MacroH2A1 plays an important role during the early stages of differentiation by repressing pluripotency genes and facilitating activation of developmental genes, whereas MacroH2A2 stabilizes the cell fate by locking down genes of a different cell fate (70, 71). In vitro studies on reconstituted nucleosomes suggest that MacroH2A1.2 facilitates gene repression by suppression of p300-mediated histone acetylation and blockage of nucleosome sliding and chromatin remodeling (72). In vivo MacroH2A1.1 was shown to localize to sites of PARP1 activation in a PAR-dependent manner and to facilitate chromatin compaction (15). The authors hypothesize that PARP activation induces transient MacroH2A1.1-dependent chromatin changes. Reduced MacroH2A expression was observed in several cancer types, including breast and lung cancer, and has been associated with increased tumor proliferation and metastatic potential (reviewed in 73). The underlying mechanism is complex and involves loss of transcriptional control over cancer genes (e.g., CDK8 and c-Fos), a dysregulation of the cell cycle, and promotion of differentiation. Taken together the available data support a role of MacroH2A as epigenetic tumor suppressor. ALC1. ALC1 (also known as CHD1L) homologs are present in representatives from three eukaryotic supergroups and were probably also present in last eukaryotic common ancestor. They www.annualreviews.org • Macrodomains

Changes may still occur before final publication online and in print

2.11

ARI

21 January 2016

19:21

belong to the SNF2 family of ATP-dependent DNA translocases and possess a SNF2-like ATPase domain followed by a nuclear localization sequence and a distinct type of macrodomain at the C terminus (Figures 1 and 2) (5, 47, 74). In mammals, ALC1 is involved in DNA damage repair, gene regulation, cell proliferation, embryonal development and p53-indepentent apoptosis (5, 17, 75– 77). ALC1 is recruited to sites of DNA damage via its macrodomain by sensing PARP1-generated PAR (5, 47). Recognition of PAR leads both to the formation of a stable ALC1-nucleosomepoly(ADP-ribosylated) PARP1 complex and an increase in the chromatin-remodeling activity of ALC1 (5, 47, 78). The function of ALC1 as an oncogene came into focus through several studies reporting on its involvement in tumorigenesis. ALC1 is frequently amplified in certain cancer types, including hepatocellular carcinoma and bladder cancer (79). Ectopic expression of ALC1 in mice increased the rate of spontaneous tumor formation and promoted tumor susceptibility in response to a model of inducible hepatocyte lesion (80). Its overexpression was shown to sensitize cells to DNA damage, most likely owing to its increased chromatin retention at the damage site (5). In addition, missense mutations near or proximal to the macrodomain, which reduce its affinity for PAR, were identified in patients with congenital anomalies of the kidney and urinal tract (81). On the basis of correlation between immunohistology and gene expression analysis, it seems that ALC1 plays an important role in kidney development, most likely by impairment of its chromatin-remodeling function.

Annu. Rev. Biochem. 2016.85. Downloaded from www.annualreviews.org Access provided by Gazi Universities Main Library (D-S) on 02/04/16. For personal use only.

BI85CH02-Ahel

MacroPARPs. Three human members of the PARP family (9, 14, and 15) contain multiple macrodomains in addition to their PARP catalytic domain (Figure 2) (11, 27). The MacroPARP ancestor probably arose early in Unikonts’ (predecessors of Amoebozoa, Opisthokonta, and Apusozoa) evolution and was most similar to the recent PARP14 homologs (Figure 1) (20). Although no PARP activity has as yet been detected for PARP9, both PARP14 and PARP15 show robust autoADP-ribosylation activities (82). All of the MacroPARPs in humans are encoded within ∼200 kb in the chromosomal 3q20 region that is associated with multiple hematological malignancies (82– 84). Likewise, the highest expression of PARP9 and PARP14 was found in lymphatic tissue (85). In response to DNA damage, PARP9 (also called BAL1) and its binding partner BBAP are recruited to the damage site via the PARP9 macrodomain 2 in a PARP1/PAR-dependent manner. Subsequent, BBAP-mediated histone ubiquitinylation serves to recruit additional repair factors, including 53BP1 and BRCA1 (86). Experimental data show that PARP14 localizes to the end of actin stress fibers (28). Loss-of-function experiments showed that, although the focal adhesion assembly appeared to be normal, the fiber turnover was reduced, resulting in elongated cellular protrusions and increased adherence. Hence, PARP14 appears to have an important function in cell morphology and motility. Dysregulation of both PARP9 and PARP14 are often associated with lymphoma. For example, amplification of PARP9 in diffuse large B cell lymphomas is associated with increased cell migration and a poor prognosis (83, 84). The increase in PARP9 leads to the formation of an ADP-ribosylation/macrodomain-dependent complex between PARP9 and the transcription repressor STAT1β, followed by translocation into the nucleus and inhibition of the expression of the tumor suppressor IRF1 (87). Even though no functional data relating to PARP15 cellular activity are available, it is interesting to note that a recent high-throughput genomic study investigating cancer-related gene inactivation identified PARP15 as novel tumor suppressor in head and neck squamous cell carcinoma (88). GDAP2, a macrodomain protein of unknown function. GDAP2 is a highly conserved protein of unknown function found from plants to humans. Although its macrodomain is similar to human 2.12

Rack

·

Perina

·

Ahel

Changes may still occur before final publication online and in print

BI85CH02-Ahel

ARI

21 January 2016

19:21

MacroD1/2 proteins (Figure 1), it does not bind to derivatives of ADPr, but instead, it appears to have specificity for poly(A) (42). In addition, GDAP2 proteins possess a lipid-binding SEC14 domain at the C terminus (Figure 2), which is known to act in signal transduction, transport, and organelle biology (89). Thus a function in the integration of ADPr- and lipid-mediated signaling appears possible.

Annu. Rev. Biochem. 2016.85. Downloaded from www.annualreviews.org Access provided by Gazi Universities Main Library (D-S) on 02/04/16. For personal use only.

Macrodomains as Erasers of Protein ADP-Ribosylation Like other signal transduction pathways, ADPr-dependent signaling requires both recognition and removal of the signal. Therefore, it may not be surprising that macrodomains, in addition to their binding ability, have evolved to reverse cellular ADP-ribosylation. The catalyzed signal termination reactions include hydrolysis of mono- and poly(ADP-ribosylation) as well as degradation of NAD+ -derived second messengers, such as AAR (8, 11, 19, 90). MacroD1 and MacroD2. Orthologs of MacroD-type proteins can be found in all kingdoms of life. In vertebrates, a duplication of the ancestral MacroD-type gene gave rise to MacroD1 and MacroD2 proteins (Figure 1) (20). MacroD1 and MacroD2 act as mono(ADP-ribosyl) hydrolases that reverse protein mono(ADP-ribosylation) and catalyze the cleavage of the terminal ADPr moiety, e.g., from proteins after PARG-mediated polymer degradation (19, 34, 35). In addition, both enzymes can hydrolyze AAR (8). Although their catalytic activities were established in vitro, their exact protein targets and biological roles remain largely unknown. There is a high degree of sequence similarity between the catalytic domains of MacroD1 and MacroD2; however, their primary subcellular localizations are different (MacroD1 in mitochondria and MacroD2 in the cytoplasm), implying distinct functions (42). MacroD1 (also called LRP16) was reported to act as a cofactor, modulating estrogen and androgen receptor signaling, and its overexpression was associated with proliferation and invasive growth of cancer cells (91, 92). A recent study showed that MacroD2 reverses the PARP10-mediated mono(ADP-ribosylation) and thereby inhibition of GSK3β kinase, thus restoring its catalytic activity (38). MacroD2 is found amplified in a subset of breast cancers. Interestingly, transgenic overexpression of MacroD2 in breast cancer cell lines results in tamoxifen resistance and estrogen-independent growth (93). By contrast, it has been suggested that MacroD2 may be a cancer-specific fragile site and function as a tumor suppressor (94, 95). TARG1. The TARG1 gene (the terminal ADPr protein glycohydrolase 1, also known as OARD1 or C6orf130) is present in different Metazoans, and scattered examples are present in bacteria (Figure 1) (20). Evolutionary analysis suggests that TARG1 may have arisen from ALC1 as a consequence of a partial duplication event. As yet, only limited data are available on the function of TARG1. Biochemical characterization showed that TARG1 can hydrolyze protein ADPribosylation (38, 39). In addition, it can also hydrolyze the sirtuin reaction product AAR, including its acetyl, propionyl, and butyryl derivatives, thus yielding ADPr and a corresponding carboxylic acid (37). Homozygous mutation of the TARG1 gene in patients with severe neurodegeneration was observed, and depletion of the TARG1 protein in cells leads to proliferation, DNA repair defects, and cellular senescence (39). PARG. Although a simple single-domain type of PARG (called bacterial-type PARG) is found in some bacteria, viruses, and sporadically in representatives from all eukaryotic supergroups (except Plantae) (Figure 1), the vertebrate PARGs contain a more complex structure with regulatory and accessory domains that precede the PARG catalytic macrodomain (Figure 2) (49, 52). In mammals, a single gene encodes PARG, and additional diversity is achieved through alternative splicing. As a www.annualreviews.org • Macrodomains

Changes may still occur before final publication online and in print

2.13

ARI

21 January 2016

19:21

consequence, PARG isoforms can be identified in several subcellular compartments: PARG111 is in the nucleus, PARG102 and PARG99 are predominantly in the cytoplasm, and the PAR degradationdeficient PARG55 variant localizes to the mitochondrial matrix (the subscript numbers indicate the molecular weight of the corresponding human isoforms) (96, 97). During DNA damage, PARG hydrolyzes PAR generated by DNA damage-inducible PARPs, thereby allowing regulation of the later repair events and recycling of NAD+ (98, 99). Because PARG is unable to remove the terminal ADPr moiety from proteins (40), TARG1, MacroD1, and/or MacroD2 are suggested to catalyze this reaction (34, 38, 39). The knockout of all PARG isoforms leads to increased apoptosis and embryonic lethality in mouse and fruit fly (100, 101). However, mice lacking the longest isoform, PARG110 , are viable, most likely due to nucleocytoplasmic shuttling of the smaller cytoplasmic isoforms during DNA damage (102, 103). Nevertheless, PARG110 −/− mice show hypersensitivity to genotoxic stress induced by ionizing radiation or alkylating agents (101, 104). In addition, PARG was implicated as a modulator of the inflammatory response, and PARG inactivation (either in PARG110 −/− mice or by inhibition) had protective effects in models of dinitrobenzene sulfonic acid–induced colitis, splanchnic artery occlusion shock, ischemia and reperfusion, as well as the associated injuries (105–109).

Annu. Rev. Biochem. 2016.85. Downloaded from www.annualreviews.org Access provided by Gazi Universities Main Library (D-S) on 02/04/16. For personal use only.

BI85CH02-Ahel

Generation of ADPr, a second messenger in calcium signaling. In the context of erasing cellular ADP-ribosylation, it is worth noting that overactivation of PARP1 has long been associated with cell death (110–112). Though the underlying mechanism is still elusive, an enticing hypothesis can be raised from several observations regarding macrodomain- and PARG-derived ADPr. During oxidative stress, the activation of the TRMP2 (transient receptor potential melastatin 2), a calcium-permeable cation channel, appears to be PARP1 dependent (113), but the high PAR-degrading activity of PARG localized to nucleus and cytoplasm suggests an indirect mechanism via ADPr (114). Indeed, it has been shown that ADPr is specific activator of TRPM2 via binding to its cytosolic NUDIX9-homology domain (41, 115, 116). As a result, the concentration of free intracellular calcium is increased and cell death is induced (41). A second, potentially synergetic, pathway requires further degradation of ADPr to AMP and ribose-5-phosphate, a reaction efficiently catalyzed by the pyrophosphatases NUDT5 and NUDT9 (117, 118). The resulting accumulation of AMP acts as an inhibitor of the mitochondrial ADP/ATP translocase, thus preventing the nucleotide exchange with the cytoplasm and resulting in mitochondrial energy failure (117). In addition, the sirtuin reaction product AAR has also been suggested to function as a second messenger by direct interaction with macrodomain-containing proteins, and both MacroD1/2 and TARG1 have been implicated in signal clearance through AAR hydrolysis (8, 37, 68, 90).

Macrodomains in Microorganisms and Pathogens Macrodomain homologs can be identified in most microbes as well as several viruses. Although less information is available on these macrodomains, the crucial role in maintenance of cellular homoestasis in higher organisms together with the high degree of evolutionary conversation, argues for a similar importance in microorgansims. If this assumption would hold up, macrodomains could emerge as new targets for microbial and viral infections. The latter notion is supported by the identification of pathogen-specific macrodomain-containing systems in bacteria (25) as well as by the importance of viral macrodomains during infection (18, 26). Bacterial macrodomains. Macrodomain-containing proteins are found in most of the sequenced bacterial species and are most commonly of the MacroD-type (Figure 1). Overall, very little is known about intracellular ADP-ribosylation in bacteria. The first described example came from the 2.14

Rack

·

Perina

·

Ahel

Changes may still occur before final publication online and in print

Annu. Rev. Biochem. 2016.85. Downloaded from www.annualreviews.org Access provided by Gazi Universities Main Library (D-S) on 02/04/16. For personal use only.

BI85CH02-Ahel

ARI

21 January 2016

19:21

bacterial and archaeal nitrogen fixation pathway. This highly energy-demanding reaction sequence is regulated via reversible ADP-ribosylation of an arginine residue in the key enzyme nitrogenase (119). ADP-ribosylation has also been detected in species of the bacterial genera Streptomyces and Myxococcus; however, the corresponding protein ADP-ribosyltransferases are still unknown (120, 121). More recently an analysis of the sequences, structures, and genomic contexts of NADutilizing enzymes predicted novel classes of ADP-ribosyltransferases (59). Some of these exhibit genomic associations with macrodomain or PARG homologs, thus implying the wider presence of pathways regulated by ADP-ribosylation in bacteria. If present in pathogens, such macrodomaincontaining operons could be of additional interest as they may be linked to virulence. Recently, we characterized a new system for reversible protein ADP-ribosylation present in pathogens, such as Staphylococcus aureus and Streptococcus pyogenes (25). Central to this system is a macrodomain/sirtuin pair in which the sirtuin component (termed macrodomain-linked sirtuin or SirTM) can ADP-ribosylate a target protein derived from the same operon, whereas the MacroD-type macrodomain reverses the modification. Interestingly, the ADP-ribosylation activity of SirTM is dependent on another protein modification, lipoylation. The latter is involved in the regulation of energy metabolism and detoxification of reactive oxygen species, thereby contributing to bacterial pathogenesis (reviewed in 122). Current data indicate that the macrodomain/SirTM pair modulates the response to oxidative stress both in bacteria and in fungi possessing a homologous system, such as Candida albicans (Figure 2) (25, 123, 124). Genomic evidence suggests that the association of macrodomains and pathogenesis may be quite common. For example, a putative macrodomain-involving toxin/antitoxin system has been recently discovered in Pseudomonas mendocina by a large-scale cloning approach (125). The system is composed of a toxin of unknown function and a bipartite antitoxin containing an N-terminal macrodomain. The macrodomain is a diverged representative within the ALC1-like class, and its orthologs can be identified in other pathogens, such as Mycobacterium tuberculosis as well as in Vibrio and Xanthomonas species (Figure 1). These examples suggest that the bacterial macrodomains may influence processes that have been shown to be crucial for the survival and virulence of bacteria in the host environment, thus promoting the study of these macrodomains to further our understanding of host-pathogen interactions and explore novel therapeutic routes. Viral macrodomains. Similarly, evidence is emerging that targeting viral macrodomains could be a promising therapeutic approach to promote recovery and reduce infection severity (18, 126, 127). Viral macrodomains appear to have undergone a peculiar evolution; structural as well as phylogenetic evidence indicates that viral and cellular macrodomains are strongly related (Figure 1) (42). Several different types of macrodomains are found in different virus genomes, and it has been suggested that this is because of repeated, independent host acquisition of macrodomains (42, 128, 129). Together this argues for specific and different functions in virushost coevolution. Macrodomain proteins were identified in more than 150 viruses, most belonging to family Myoviridae (which includes various phages) and are also present in other virus families: Coronaviridae, Togaviridae, Iridoviridae, Poxviridae, and Hepeviridae (present in only one species, hepatitis E virus) (45, 130, 131). Heretofore, no studies have been conducted on phage macrodomains, and the macrodomains of RNA viruses are being investigated for their potential as druggable targets. Both in corona- and alphaviruses, the MacroD-type macrodomain is encoded as part of the multidomain nonstructural protein 3 (nsP3), which is implicated in host protein recruitment and viral replication (132, 133). However, beyond this broad classification, the nsP3 proteins of Togaviridae and Coronaviridae are distinct in their domain makeup and, consequently, have only limited overlapping functions (134, 135). www.annualreviews.org • Macrodomains

Changes may still occur before final publication online and in print

2.15

ARI

21 January 2016

19:21

In vitro studies showed that macrodomains from both origins can hydrolyze ADPr-1 phosphate and bind to PAR (45, 129, 136, 137), but whether this reflects their endogenous functions remains elusive. By contrast, sequential and structural similarity to human MacroD1 and MacroD2 strongly indicate that MacroD-type viral proteins might exhibit mono(ADP-ribosyl) hydrolase activity (34). This is particularly exciting as the expression of the so-called antiviral PARPs (PARP7, PARP10, and PARP12) is triggered via the type I interferon response (138, 139). The activity of the antiviral PARPs decreases the rate of cellular translation and viral replication, thus counteracting the production of viral particles. Because PARP7, PARP10, and PARP12 are mono(ADP-ribosyl) transferases (28) and their antiviral function is dependent on their catalytic activity (139), it is intriguing to speculate that the viral macrodomains have evolved to counteract this host defense. The macrodomains appear, however, to fulfill additional functions within the viruses. In a study of the Sindbis virus nsP3 macrodomain, mutagenesis had a complex phenotype. Although replication in cultured, mature neurons was macrodomain dependent, titer levels in mice were not affected 24 h postinfection (136). This indicates that the macrodomain, which possibly influences replication, is not crucial for its success. Similarly, the coronavirus macrodomain appears to be dispensable for replication in interferon-deficient cells (137). However, mouse MHV infection models, using a virus strain that carried a catalytic null mutation of the macrodomain, led to reduction of viral virulence (18, 126). It was suggested that the milder course of infection was caused by a reduction in the proinflammatory immune response, which is associated with server tissue damage in certain viral infections (140, 141).

Annu. Rev. Biochem. 2016.85. Downloaded from www.annualreviews.org Access provided by Gazi Universities Main Library (D-S) on 02/04/16. For personal use only.

BI85CH02-Ahel

SARS-unique domain, an RNA-binding macrodomain. In addition to MacroD-type macrodomains, the nsP3 proteins of SARS coronavirus (SARS-CoV) and other β-coronaviruses contain a highly diverged macrodomain found in the SARS-unique domains (SUDs) (Figure 1). Analysis of the structure of SUD from SARS-CoV revealed that this domain consists of two macrodomains (SUD-N and SUD-M, respectively) and a C-terminal frataxin-fold domain (SUD-C) (9, 10). However, it is worth noting that the sequence comparison data indicate that most SUD-containing viruses carry only one of the macrodomains, a SUD-M homolog. In vitro studies have demonstrated that the SARS-CoV macrodomains bind nucleic acids with a preference for purine-rich RNA sequences, such as RNA G-quadruplexes, and that SUD-C increases the target specificity (9, 10). The importance of this interaction was recently highlighted by demonstrating that the binding of RNA by SUD-M is required for viral replication (142).

THE THERAPEUTIC POTENTIAL OF MACRODOMAIN INHIBITORS The study of macrodomains in their cellular context gave the first insight into their pathobiological importance. Consequently, new strategies are being explored to target macrodomains to treat or relieve the burden of diseases.

Viral Infections In several viral systems, intricate connections between the nsP3 macrodomain function and the host immune system were described (18, 126, 127, 140, 141). MHV (an α-coronavirus) infection models showed that a catalytic mutation within the macrodomain attenuated the infection severity by preventing overactivation of the immune response (18, 126). In contrast, mutation of the same catalytic residue in β-coronaviruses prevented the suppression of the type I interferon response and increased the viral susceptibility to the innate immune response (127). Despite the differences in 2.16

Rack

·

Perina

·

Ahel

Changes may still occur before final publication online and in print

BI85CH02-Ahel

ARI

21 January 2016

19:21

the underlying mechanisms, these results encourage further investigation into viral macrodomains as their inhibition may help to reduce disease burden and assist recovery.

Annu. Rev. Biochem. 2016.85. Downloaded from www.annualreviews.org Access provided by Gazi Universities Main Library (D-S) on 02/04/16. For personal use only.

Macrodomains in Cancer Next in importance to studying the relationship of macrodomains to viral infections is investigation of the involvement of macrodomains in tumorigenesis. It has been shown that several macrodomain-containing proteins are amplified in different cancer types, which correlates with a poor prognosis and/or drug resistance. Examples of a direct link between macrodomain amplification and tumor biology include ALC1, which can inhibit apoptosis (5, 79); MacroD2, which can induce tamoxifen resistance in estrogen receptor-positive breast cancer cells (93); and PARP9, which can increase tumor cell migration (83, 84). Altogether these observations promote the idea that macrodomain targeting could slow tumor progression and support therapy. A second strategy for a cancer therapy, based on synthetic lethality, involves inhibition of PARG. This approach exploits the reduced DNA repair capability of BRCA1- or BRCA2-deficient tumors similar to those of PARP inhibitors (143–145).

Synthetic lethality: two mutations, which occurring alone have a viable but synergistically a lethal phenotype

OUTLOOK Notwithstanding ongoing efforts (52, 146, 147), so far no soluble, efficient, bioavailable inhibitor against a macrodomain has been developed. However, the increasing numbers of available macrodomain structures, together with advancements in structure-guided drug design, have the potential to accelerate the process. The emergence of rhodamine and phenolic hydrazide hydrazone-based compounds, which exhibit PARG inhibition in vitro, is a further reason for optimism. However, one of the greatest remaining challenges is the limited availability of data on the biological function of macrodomains. This is true for virtually all of the macrodomains studied so far, as most of the data regarding binding or catalysis have been derived from in vitro observations. In this context, potent inhibitors would be a valuable tool for the in vivo characterization of macrodomains. The specificity of macrodomains has been extensively studied; however, only a limited number of ADP-ribosylated metabolites have been tested as ligands/substrates for most of the macrodomains. One example of an untested compound is diadenosine 5 ,5 -P1 ,P4 -tetraphosphate (Ap4 A) (a ubiquitous second messenger synthesized from ATP during cellular stress), which was shown as ADP-ribosylated over three decades ago (148). Although Ap4 A ADP-ribosylation was believed to occur only under nonphysiological conditions (149), a recent study demonstrated that the concentration of both Ap4 A and its ADP-ribosylated form increase under conditions of sublethal stress and may act in the DNA damage response (150). Investigation of ADP-ribosylated Ap4 A and other metabolites as potential substrates for macrodomains will further our understanding of their diverse functions and physiological importance.

DISCLOSURE STATEMENT The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS We apologize to all colleagues whose work could not be included because of space restrictions. We are grateful to Gytis Jankevicius and Kerryanne Crawford for critical comments on the manuscript. www.annualreviews.org • Macrodomains

Changes may still occur before final publication online and in print

2.17

BI85CH02-Ahel

ARI

21 January 2016

19:21

Work in the I.A. laboratory is supported by the Wellcome Trust and the European Research Council.

LITERATURE CITED

Annu. Rev. Biochem. 2016.85. Downloaded from www.annualreviews.org Access provided by Gazi Universities Main Library (D-S) on 02/04/16. For personal use only.

1. Till S, Ladurner AG. 2009. Sensing NAD metabolites through macro domains. Front. Biosci. 14:3246–58 2. Lee HJ, Shieh CK, Gorbalenya AE, Koonin EV, La Monica N, et al. 1991. The complete sequence (22 kilobases) of murine coronavirus gene 1 encoding the putative proteases and RNA polymerase. Virology 180:567–82 3. Pehrson JR, Fried VA. 1992. MacroH2A, a core histone containing a large nonhistone region. Science 257:1398–400 4. Taverna SD, Li H, Ruthenburg AJ, Allis CD, Patel DJ. 2007. How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. Nat. Struct. Mol. Biol. 14:1025–40 5. Ahel D, Horejsi Z, Wiechens N, Polo SE, Garcia-Wilson E, et al. 2009. Poly(ADP-ribose)-dependent regulation of DNA repair by the chromatin remodeling enzyme ALC1. Science 325:1240–43 6. Karras GI, Kustatscher G, Buhecha HR, Allen MD, Pugieux C, et al. 2005. The macro domain is an ADP-ribose binding module. EMBO J. 24:1911–20 7. Kraus WL. 2009. New functions for an ancient domain. Nat. Struct. Mol. Biol. 16:904–7 8. Chen D, Vollmar M, Rossi MN, Phillips C, Kraehenbuehl R, et al. 2011. Identification of macrodomain proteins as novel O-acetyl-ADP-ribose deacetylases. J. Biol. Chem. 286:13261–71 9. Johnson MA, Chatterjee A, Neuman BW, Wuthrich K. 2010. SARS coronavirus unique domain: threedomain molecular architecture in solution and RNA binding. J. Mol. Biol. 400:724–42 10. Tan J, Vonrhein C, Smart OS, Bricogne G, Bollati M, et al. 2009. The SARS-unique domain (SUD) of SARS coronavirus contains two macrodomains that bind G-quadruplexes. PLOS Pathog. 5:e1000428 11. Feijs KL, Forst AH, Verheugd P, Luscher B. 2013. Macrodomain-containing proteins: regulating new intracellular functions of mono(ADP-ribosyl)ation. Nat. Rev. Mol. Cell. Biol. 14:443–51 12. Han W, Li X, Fu X. 2011. The macro domain protein family: structure, functions, and their potential therapeutic implications. Mutat. Res. 727:86–103 13. Maas NM, Van de Putte T, Melotte C, Francis A, Schrander-Stumpel CT, et al. 2007. The C20orf133 gene is disrupted in a patient with Kabuki syndrome. J. Med. Genet. 44:562–69 14. Buschbeck M, Uribesalgo I, Wibowo I, Rue P, Martin D, et al. 2009. The histone variant macroH2A is an epigenetic regulator of key developmental genes. Nat. Struct. Mol. Biol. 16:1074–79 15. Timinszky G, Till S, Hassa PO, Hothorn M, Kustatscher G, et al. 2009. A macrodomain-containing histone rearranges chromatin upon sensing PARP1 activation. Nat. Struct. Mol. Biol. 16:923–29 16. Kim W, Chakraborty G, Kim S, Shin J, Park CH, et al. 2012. Macro histone H2A1.2 (macroH2A1) protein suppresses mitotic kinase VRK1 during interphase. J. Biol. Chem. 287:5278–89 17. Chen L, Hu L, Chan TH, Tsao GS, Xie D, et al. 2009. Chromodomain helicase/adenosine triphosphatase DNA binding protein 1-like (CHD1l ) gene suppresses the nucleus-to-mitochondria translocation of nur77 to sustain hepatocellular carcinoma cell survival. Hepatology 50:122–29 18. Eriksson KK, Cervantes-Barragan L, Ludewig B, Thiel V. 2008. Mouse hepatitis virus liver pathology is dependent on ADP-ribose-1 -phosphatase, a viral function conserved in the alpha-like supergroup. J. Virol. 82:12325–34 19. Barkauskaite E, Jankevicius G, Ladurner AG, Ahel I, Timinszky G. 2013. The recognition and removal of cellular poly(ADP-ribose) signals. FEBS J. 280:3491–507 ´ ˇ 20. Perina D, Mikoˇc A, Ahel J, Cetkovi´ c H, Zaja R, Ahel I. 2014. Distribution of protein poly(ADPribosyl)ation systems across all domains of life. DNA Repair 23:4–16 21. Feijs KL, Verheugd P, Luscher B. 2013. Expanding functions of intracellular resident mono-ADPribosylation in cell physiology. FEBS J. 280:3519–29 22. Gibson BA, Kraus WL. 2012. New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. Nat. Rev. Mol. Cell. Biol. 13:411–24 23. Denu JM. 2005. The Sir 2 family of protein deacetylases. Curr. Opin. Chem. Biol. 9:431–40 2.18

Rack

·

Perina

·

Ahel

Changes may still occur before final publication online and in print

Annu. Rev. Biochem. 2016.85. Downloaded from www.annualreviews.org Access provided by Gazi Universities Main Library (D-S) on 02/04/16. For personal use only.

BI85CH02-Ahel

ARI

21 January 2016

19:21

24. Sauve AA, Youn DY. 2012. Sirtuins: NAD+ -dependent deacetylase mechanism and regulation. Curr. Opin. Chem. Biol. 16:535–43 25. Rack JG, Morra R, Barkauskaite E, Kraehenbuehl R, Ariza A, et al. 2015. Identification of a class of protein ADP-ribosylating sirtuins in microbial pathogens. Mol. Cell 59:309–20 26. Kowieski TM, Lee S, Denu JM. 2008. Acetylation-dependent ADP-ribosylation by Trypanosoma brucei Sir2. J. Biol. Chem. 283:5317–26 27. Barkauskaite E, Jankevicius G, Ahel I. 2015. Structures and mechanisms of enzymes employed in the synthesis and degradation of PARP-dependent protein ADP-ribosylation. Mol. Cell 58:935–46 28. Vyas S, Matic I, Uchima L, Rood J, Zaja R, et al. 2014. Family-wide analysis of poly(ADP-ribose) polymerase activity. Nat. Commun. 5:4426 29. Kleine H, Poreba E, Lesniewicz K, Hassa PO, Hottiger MO, et al. 2008. Substrate-assisted catalysis by PARP10 limits its activity to mono-ADP-ribosylation. Mol. Cell 32:57–69 30. Langelier MF, Pascal JM. 2013. PARP-1 mechanism for coupling DNA damage detection to poly(ADPribose) synthesis. Curr. Opin. Struct. Biol. 23:134–43 31. Miwa M, Ishihara M, Takishima S, Takasuka N, Maeda M, et al. 1981. The branching and linear portions of poly(adenosine diphosphate ribose) have the same α(1→2) ribose-ribose linkage. J. Biol. Chem. 256:2916–21 32. Martzen MR, McCraith SM, Spinelli SL, Torres FM, Fields S, et al. 1999. A biochemical genomics approach for identifying genes by the activity of their products. Science 286:1153–55 33. Shull NP, Spinelli SL, Phizicky EM. 2005. A highly specific phosphatase that acts on ADP-ribose 1 phosphate, a metabolite of tRNA splicing in Saccharomyces cerevisiae. Nucleic Acids Res. 33:650–60 34. Jankevicius G, Hassler M, Golia B, Rybin V, Zacharias M, et al. 2013. A family of macrodomain proteins reverses cellular mono-ADP-ribosylation. Nat. Struct. Mol. Biol. 20:508–14 35. Barkauskaite E, Brassington A, Tan ES, Warwicker J, Dunstan MS, et al. 2013. Visualization of poly(ADP-ribose) bound to PARG reveals inherent balance between exo- and endo-glycohydrolase activities. Nat. Commun. 4:2164 36. Miwa M, Sugimura T. 1971. Splitting of the ribose-ribose linkage of poly(adenosine diphosphate-ribose) by a calf thymus extract. J. Biol. Chem. 246:6362–64 37. Peterson FC, Chen D, Lytle BL, Rossi MN, Ahel I, et al. 2011. Orphan macrodomain protein (human C6orf130) is an O-acyl-ADP-ribose deacylase: solution structure and catalytic properties. J. Biol. Chem. 286:35955–65 38. Rosenthal F, Feijs KL, Frugier E, Bonalli M, Forst AH, et al. 2013. Macrodomain-containing proteins are new mono-ADP-ribosylhydrolases. Nat. Struct. Mol. Biol. 20:502–7 39. Sharifi R, Morra R, Appel CD, Tallis M, Chioza B, et al. 2013. Deficiency of terminal ADP-ribose protein glycohydrolase TARG1/C6orf130 in neurodegenerative disease. EMBO J. 32:1225–37 40. Slade D, Dunstan MS, Barkauskaite E, Weston R, Lafite P, et al. 2011. The structure and catalytic mechanism of a poly(ADP-ribose) glycohydrolase. Nature 477:616–20 41. Fliegert R, Gasser A, Guse AH. 2007. Regulation of calcium signalling by adenine-based second messengers. Biochem. Soc. Trans. 35:109–14 42. Neuvonen M, Ahola T. 2009. Differential activities of cellular and viral macro domain proteins in binding of ADP-ribose metabolites. J. Mol. Biol. 385:212–25 43. Chatterjee A, Johnson MA, Serrano P, Pedrini B, Joseph JS, et al. 2009. Nuclear magnetic resonance structure shows that the severe acute respiratory syndrome coronavirus-unique domain contains a macrodomain fold. J. Virol. 83:1823–36 44. Allen MD, Buckle AM, Cordell SC, Lowe J, Bycroft M. 2003. The crystal structure of AF1521 a protein from Archaeoglobus fulgidus with homology to the non-histone domain of macroH2A. J. Mol. Biol. 330:503–11 45. Egloff MP, Malet H, Putics A, Heinonen M, Dutartre H, et al. 2006. Structural and functional basis for ADP-ribose and poly(ADP-ribose) binding by viral macro domains. J. Virol. 80:8493–502 46. Kustatscher G, Hothorn M, Pugieux C, Scheffzek K, Ladurner AG. 2005. Splicing regulates NAD metabolite binding to histone macroH2A. Nat. Struct. Mol. Biol. 12:624–25 47. Gottschalk AJ, Timinszky G, Kong SE, Jin J, Cai Y, et al. 2009. Poly(ADP-ribosyl)ation directs recruitment and activation of an ATP-dependent chromatin remodeler. PNAS 106:13770–74 www.annualreviews.org • Macrodomains

Changes may still occur before final publication online and in print

2.19

ARI

21 January 2016

19:21

48. Forst AH, Karlberg T, Herzog N, Thorsell AG, Gross A, et al. 2013. Recognition of mono-ADPribosylated ARTD10 substrates by ARTD8 macrodomains. Structure 21:462–75 49. Zaja R, Mikoc A, Barkauskaite E, Ahel I. 2012. Molecular insights into poly(ADP-ribose) recognition and processing. Biomolecules 3:1–17 50. Tallis M, Morra R, Barkauskaite E, Ahel I. 2014. Poly(ADP-ribosyl)ation in regulation of chromatin structure and the DNA damage response. Chromosoma 123:79–90 51. Hirsch BM, Burgos ES, Schramm VL. 2014. Transition-state analysis of 2-O-acetyl-ADP-ribose hydrolysis by human macrodomain 1. ACS Chem. Biol. 9:2255–62 52. Dunstan MS, Barkauskaite E, Lafite P, Knezevic CE, Brassington A, et al. 2012. Structure and mechanism of a canonical poly(ADP-ribose) glycohydrolase. Nat. Commun. 3:878 53. Patel CN, Koh DW, Jacobson MK, Oliveira MA. 2005. Identification of three critical acidic residues of poly(ADP-ribose) glycohydrolase involved in catalysis: determining the PARG catalytic domain. Biochem. J. 388:493–500 54. Tucker JA, Bennett N, Brassington C, Durant ST, Hassall G, et al. 2012. Structures of the human poly (ADP-ribose) glycohydrolase catalytic domain confirm catalytic mechanism and explain inhibition by ADP-HPD derivatives. PLOS ONE 7:e50889 55. Kim IK, Kiefer JR, Ho CM, Stegeman RA, Classen S, et al. 2012. Structure of mammalian poly(ADPribose) glycohydrolase reveals a flexible tyrosine clasp as a substrate-binding element. Nat. Struct. Mol. Biol. 19:653–56 56. Lambrecht MJ, Brichacek M, Barkauskaite E, Ariza A, Ahel I, Hergenrother PJ. 2015. Synthesis of dimeric ADP-ribose and its structure with human poly(ADP-ribose) glycohydrolase. J. Am. Chem. Soc. 137:3558–64 57. Andrabi SA, Kim NS, Yu SW, Wang H, Koh DW, et al. 2006. Poly(ADP-ribose) (PAR) polymer is a death signal. PNAS 103:18308–13 58. Daugherty MD, Young JM, Kerns JA, Malik HS. 2014. Rapid evolution of PARP genes suggests a broad role for ADP-ribosylation in host-virus conflicts. PLOS Genet. 10:e1004403 59. de Souza RF, Aravind L. 2012. Identification of novel components of NAD-utilizing metabolic pathways and prediction of their biochemical functions. Mol. BioSyst. 8:1661–77 60. Citarelli M, Teotia S, Lamb RS. 2010. Evolutionary history of the poly(ADP-ribose) polymerase gene family in eukaryotes. BMC Evol. Biol. 10:308 61. Gossmann TI, Ziegler M. 2014. Sequence divergence and diversity suggests ongoing functional diversification of vertebrate NAD metabolism. DNA Repair 23:39–48 62. Rass U, Ahel I, West SC. 2008. Molecular mechanism of DNA deadenylation by the neurological disease protein Aprataxin. J. Biol. Chem. 283:33994–4001 63. McLennan AG. 2006. The Nudix hydrolase superfamily. Cell. Mol. Life Sci. 63:123–43 64. Tong L, Lee S, Denu JM. 2009. Hydrolase regulates NAD+ metabolites and modulates cellular redox. J. Biol. Chem. 284:11256–66 65. Palazzo L, Thomas B, Jemth AS, Colby T, Leidecker O, et al. 2015. Processing of protein ADPribosylation by Nudix hydrolases. Biochem. J. 468:293–301 66. Buschbeck M, Di Croce L. 2010. Approaching the molecular and physiological function of macroH2A variants. Epigenetics 5:118–23 67. Rasmussen TP, Huang T, Mastrangelo MA, Loring J, Panning B, Jaenisch R. 1999. Messenger RNAs encoding mouse histone macroH2A1 isoforms are expressed at similar levels in male and female cells and result from alternative splicing. Nucleic Acids Res. 27:3685–89 68. Posavec M, Timinszky G, Buschbeck M. 2013. Macro domains as metabolite sensors on chromatin. Cell. Mol. Life Sci. 70:1509–24 69. Turinetto V, Giachino C. 2015. Histone variants as emerging regulators of embryonic stem cell identity. Epigenetics 10:563–73 70. Creppe C, Janich P, Cantarino N, Noguera M, Valero V, et al. 2012. MacroH2A1 regulates the balance between self-renewal and differentiation commitment in embryonic and adult stem cells. Mol. Cell. Biol. 32:1442–52

Annu. Rev. Biochem. 2016.85. Downloaded from www.annualreviews.org Access provided by Gazi Universities Main Library (D-S) on 02/04/16. For personal use only.

BI85CH02-Ahel

2.20

Rack

·

Perina

·

Ahel

Changes may still occur before final publication online and in print

Annu. Rev. Biochem. 2016.85. Downloaded from www.annualreviews.org Access provided by Gazi Universities Main Library (D-S) on 02/04/16. For personal use only.

BI85CH02-Ahel

ARI

21 January 2016

19:21

71. Yildirim O, Hung JH, Cedeno RJ, Weng Z, Lengner CJ, Rando OJ. 2014. A system for genome-wide histone variant dynamics in ES cells reveals dynamic MacroH2A2 replacement at promoters. PLOS Genet. 10:e1004515 72. Doyen CM, An W, Angelov D, Bondarenko V, Mietton F, et al. 2006. Mechanism of polymerase II transcription repression by the histone variant macroH2A. Mol. Cell. Biol. 26:1156–64 73. Cantarino N, Douet J, Buschbeck M. 2013. MacroH2A—an epigenetic regulator of cancer. Cancer Lett. 336:247–52 74. Ryan DP, Owen-Hughes T. 2011. Snf2-family proteins: chromatin remodellers for any occasion. Curr. Opin. Chem. Biol. 15:649–56 75. Chen L, Chan TH, Yuan YF, Hu L, Huang J, et al. 2010. CHD1L promotes hepatocellular carcinoma progression and metastasis in mice and is associated with these processes in human patients. J. Clin. Investig. 120:1178–91 76. Ji X, Li J, Zhu L, Cai J, Zhang J, et al. 2013. CHD1L promotes tumor progression and predicts survival in colorectal carcinoma. J. Surg. Res. 185:84–91 77. Snider AC, Leong D, Wang QT, Wysocka J, Yao MW, Scott MP. 2013. The chromatin remodeling factor Chd1l is required in the preimplantation embryo. Biol. Open 2:121–31 78. Gottschalk AJ, Trivedi RD, Conaway JW, Conaway RC. 2012. Activation of the SNF2 family ATPase ALC1 by poly(ADP-ribose) in a stable ALC1·PARP1·nucleosome intermediate. J. Biol. Chem. 287:43527–32 79. Cheng W, Su Y, Xu F. 2013. CHD1L: a novel oncogene. Mol. Cancer 12:170 80. Chen M, Huang JD, Hu L, Zheng BJ, Chen L, et al. 2009. Transgenic CHD1L expression in mouse induces spontaneous tumors. PLOS ONE 4:e6727 81. Brockschmidt A, Chung B, Weber S, Fischer DC, Kolatsi-Joannou M, et al. 2012. CHD1L: a new candidate gene for congenital anomalies of the kidneys and urinary tract (CAKUT). Nephrol. Dial. Transplant. 27:2355–64 82. Aguiar RC, Takeyama K, He C, Kreinbrink K, Shipp MA. 2005. B-aggressive lymphoma family proteins have unique domains that modulate transcription and exhibit poly(ADP-ribose) polymerase activity. J. Biol. Chem. 280:33756–65 83. Aguiar RC, Yakushijin Y, Kharbanda S, Salgia R, Fletcher JA, Shipp MA. 2000. BAL is a novel risk-related gene in diffuse large B-cell lymphomas that enhances cellular migration. Blood 96:4328–34 84. Juszczynski P, Kutok JL, Li C, Mitra J, Aguiar RC, Shipp MA. 2006. BAL1 and BBAP are regulated by a gamma interferon-responsive bidirectional promoter and are overexpressed in diffuse large B-cell lymphomas with a prominent inflammatory infiltrate. Mol. Cell. Biol. 26:5348–59 85. Hakm´e A, Huber A, Doll´e P, Schreiber V. 2008. The macroPARP genes parp-9 and parp-14 are developmentally and differentially regulated in mouse tissues. Dev. Dyn. 237:209–15 86. Yan Q, Xu R, Zhu L, Cheng X, Wang Z, et al. 2013. BAL1 and its partner E3 ligase, BBAP, link Poly(ADP-ribose) activation, ubiquitylation, and double-strand DNA repair independent of ATM, MDC1, and RNF8. Mol. Cell. Biol. 33:845–57 87. Camicia R, Bachmann SB, Winkler HC, Beer M, Tinguely M, et al. 2013. BAL1/ARTD9 represses the anti-proliferative and pro-apoptotic IFNγ-STAT1-IRF1-p53 axis in diffuse large B-cell lymphoma. J. Cell Sci. 126:1969–80 88. Guerrero-Preston R, Michailidi C, Marchionni L, Pickering CR, Frederick MJ, et al. 2014. Key tumor suppressor genes inactivated by “greater promoter” methylation and somatic mutations in head and neck cancer. Epigenetics 9:1031–46 89. Saito K, Tautz L, Mustelin T. 2007. The lipid-binding SEC14 domain. Biochim. Biophys. Acta 1771:719– 26 90. Tong L, Denu JM. 2010. Function and metabolism of sirtuin metabolite O-acetyl-ADP-ribose. Biochim. Biophys. Acta 1804:1617–25 91. Han WD, Zhao YL, Meng YG, Zang L, Wu ZQ, et al. 2007. Estrogenically regulated LRP16 interacts with estrogen receptor α and enhances the receptor’s transcriptional activity. Endocr. Relat. Cancer 14:741–53 92. Yang J, Zhao YL, Wu ZQ, Si YL, Meng YG, et al. 2009. The single-macro domain protein LRP16 is an essential cofactor of androgen receptor. Endocr. Relat. Cancer 16:139–53 www.annualreviews.org • Macrodomains

Changes may still occur before final publication online and in print

2.21

ARI

21 January 2016

19:21

93. Mohseni M, Cidado J, Croessmann S, Cravero K, Cimino-Mathews A, et al. 2014. MACROD2 overexpression mediates estrogen independent growth and tamoxifen resistance in breast cancers. PNAS 111:17606–11 94. Rajaram M, Zhang J, Wang T, Li J, Kuscu C, et al. 2013. Two distinct categories of focal deletions in cancer genomes. PLOS ONE 8:e66264 95. Yao F, Kausalya JP, Sia YY, Teo AS, Lee WH, et al. 2015. Recurrent fusion genes in gastric cancer: CLDN18-ARHGAP26 induces loss of epithelial integrity. Cell Rep. 12:272–85 96. Meyer-Ficca ML, Meyer RG, Coyle DL, Jacobson EL, Jacobson MK. 2004. Human poly(ADP-ribose) glycohydrolase is expressed in alternative splice variants yielding isoforms that localize to different cell compartments. Exp. Cell Res. 297:521–32 97. Niere M, Mashimo M, Agledal L, Dolle ¨ C, Kasamatsu A, et al. 2012. ADP-ribosylhydrolase 3 (ARH3), not poly(ADP-ribose) glycohydrolase (PARG) isoforms, is responsible for degradation of mitochondrial matrix-associated poly(ADP-ribose). J. Biol. Chem. 287:16088–102 98. Feng X, Koh DW. 2013. Roles of poly(ADP-ribose) glycohydrolase in DNA damage and apoptosis. Int. Rev. Cell Mol. Biol. 304:227–81 99. Nikiforov A, Kulikova V, Ziegler M. 2015. The human NAD metabolome: functions, metabolism and compartmentalization. Crit. Rev. Biochem. Mol. Biol. 50:284–97 100. Hanai S, Kanai M, Ohashi S, Okamoto K, Yamada M, et al. 2004. Loss of poly(ADP-ribose) glycohydrolase causes progressive neurodegeneration in Drosophila melanogaster. PNAS 101:82–86 101. Koh DW, Lawler AM, Poitras MF, Sasaki M, Wattler S, et al. 2004. Failure to degrade poly(ADP-ribose) causes increased sensitivity to cytotoxicity and early embryonic lethality. PNAS 101:17699–704 102. Haince JF, Ouellet ME, McDonald D, Hendzel MJ, Poirier GG. 2006. Dynamic relocation of poly(ADPribose) glycohydrolase isoforms during radiation-induced DNA damage. Biochim. Biophys. Acta 1763:226– 37 103. Mortusewicz O, Fouquerel E, Ame JC, Leonhardt H, Schreiber V. 2011. PARG is recruited to DNA damage sites through poly(ADP-ribose)- and PCNA-dependent mechanisms. Nucleic Acids Res. 39:5045– 56 104. Cortes U, Tong WM, Coyle DL, Meyer-Ficca ML, Meyer RG, et al. 2004. Depletion of the 110-kilodalton isoform of poly(ADP-ribose) glycohydrolase increases sensitivity to genotoxic and endotoxic stress in mice. Mol. Cell. Biol. 24:7163–78 105. Burkle A, Virag L. 2013. Poly(ADP-ribose): PARadigms and PARadoxes. Mol. Aspects Med. 34:1046–65 106. Cuzzocrea S, Di Paola R, Mazzon E, Cortes U, Genovese T, et al. 2005. PARG activity mediates intestinal injury induced by splanchnic artery occlusion and reperfusion. FASEB J. 19:558–66 107. Cuzzocrea S, Wang ZQ. 2005. Role of poly(ADP-ribose) glycohydrolase (PARG) in shock, ischemia and reperfusion. Pharmacol. Res. 52:100–8 108. Genovese T, Di Paola R, Catalano P, Li JH, Xu W, et al. 2004. Treatment with a novel poly(ADPribose) glycohydrolase inhibitor reduces development of septic shock-like syndrome induced by zymosan in mice. Crit. Care Med. 32:1365–74 109. Patel NS, Cortes U, Di Poala R, Mazzon E, Mota-Filipe H, et al. 2005. Mice lacking the 110-kD isoform of poly(ADP-ribose) glycohydrolase are protected against renal ischemia/reperfusion injury. J. Am. Soc. Nephrol. 16:712–19 110. Burkle A. 2001. Physiology and pathophysiology of poly(ADP-ribosyl)ation. BioEssays 23:795–806 111. Chiarugi A. 2002. Poly(ADP-ribose) polymerase: Killer or conspirator? The ‘suicide hypothesis’ revisited. Trends Pharmacol. Sci. 23:122–29 112. Ha HC, Snyder SH. 1999. Poly(ADP-ribose) polymerase is a mediator of necrotic cell death by ATP depletion. PNAS 96:13978–82 113. Fonfria E, Marshall IC, Benham CD, Boyfield I, Brown JD, et al. 2004. TRPM2 channel opening in response to oxidative stress is dependent on activation of poly(ADP-ribose) polymerase. Br. J. Pharmacol. 143:186–92 114. Dolle C, Niere M, Lohndal E, Ziegler M. 2010. Visualization of subcellular NAD pools and intraorganellar protein localization by poly-ADP-ribose formation. Cell. Mol. Life Sci. 67:433–43 115. Perraud AL, Fleig A, Dunn CA, Bagley LA, Launay P, et al. 2001. ADP-ribose gating of the calciumpermeable LTRPC2 channel revealed by Nudix motif homology. Nature 411:595–99

Annu. Rev. Biochem. 2016.85. Downloaded from www.annualreviews.org Access provided by Gazi Universities Main Library (D-S) on 02/04/16. For personal use only.

BI85CH02-Ahel

2.22

Rack

·

Perina

·

Ahel

Changes may still occur before final publication online and in print

Annu. Rev. Biochem. 2016.85. Downloaded from www.annualreviews.org Access provided by Gazi Universities Main Library (D-S) on 02/04/16. For personal use only.

BI85CH02-Ahel

ARI

21 January 2016

19:21

116. Toth ´ B, Iordanov I, Csan´ady L. 2015. Ruling out pyridine dinucleotides as true TRPM2 channel activators reveals novel direct agonist ADP-ribose-2 -phosphate. J. Gen. Physiol. 145:419–30 117. Formentini L, Macchiarulo A, Cipriani G, Camaioni E, Rapizzi E, et al. 2009. Poly(ADP-ribose) catabolism triggers AMP-dependent mitochondrial energy failure. J. Biol. Chem. 284:17668–76 118. Lin S, Gasmi L, Xie Y, Ying K, Gu S, et al. 2002. Cloning, expression and characterisation of a human Nudix hydrolase specific for adenosine 5 -diphosphoribose (ADP-ribose). Biochim. Biophys. Acta 1594:127–35 119. Nordlund S, Hogbom M. 2013. ADP-ribosylation, a mechanism regulating nitrogenase activity. FEBS J. 280:3484–90 120. Eastman D, Dworkin M. 1994. Endogenous ADP-ribosylation during development of the prokaryote Myxococcus xanthus. Microbiology 140(Pt 11):3167–76 121. Penyige A, Keseru J, Fazakas F, Schmelczer I, Szirak K, et al. 2009. Analysis and identification of ADPribosylated proteins of Streptomyces coelicolor M145. J. Microbiol. 47:549–56 122. Spalding MD, Prigge ST. 2010. Lipoic acid metabolism in microbial pathogens. Microbiol. Mol. Biol. Rev. 74:200–28 123. Enjalbert B, Rachini A, Vediyappan G, Pietrella D, Spaccapelo R, et al. 2009. A multifunctional, synthetic Gaussia princeps luciferase reporter for live imaging of Candida albicans infections. Infect. Immun. 77:4847– 58 124. Surmann K, Michalik S, Hildebrandt P, Gierok P, Depke M, et al. 2014. Comparative proteome analysis reveals conserved and specific adaptation patterns of Staphylococcus aureus after internalization by different types of human non-professional phagocytic host cells. Front. Microbiol. 5:392 125. Sberro H, Leavitt A, Kiro R, Koh E, Peleg Y, et al. 2013. Discovery of functional toxin/antitoxin systems in bacteria by shotgun cloning. Mol. Cell 50:136–48 126. Fehr AR, Athmer J, Channappanavar R, Phillips JM, Meyerholz DK, Perlman S. 2015. The nsp3 macrodomain promotes virulence in mice with coronavirus-induced encephalitis. J. Virol. 89:1523–36 127. Kuri T, Eriksson KK, Putics A, Zust R, Snijder EJ, et al. 2011. The ADP-ribose-1 -monophosphatase domains of severe acute respiratory syndrome coronavirus and human coronavirus 229E mediate resistance to antiviral interferon responses. J. Gen. Virol. 92:1899–905 128. Basta HA, Cleveland SB, Clinton RA, Dimitrov AG, McClure MA. 2009. Evolution of teleost fish retroviruses: characterization of new retroviruses with cellular genes. J. Virol. 83:10152–62 129. Malet H, Coutard B, Jamal S, Dutartre H, Papageorgiou N, et al. 2009. The crystal structures of Chikungunya and Venezuelan equine encephalitis virus nsP3 macro domains define a conserved adenosine binding pocket. J. Virol. 83:6534–45 130. Malet H, Dalle K, Bremond N, Tocque F, Blangy S, et al. 2006. Expression, purification and crystallization of the SARS-CoV macro domain. Acta Crystallogr. Sect. F 62:405–8 131. Putics A, Slaby J, Filipowicz W, Gorbalenya AE, Ziebuhr J. 2006. ADP-ribose-1 phosphatase activities of the human coronavirus 229E and SARS coronavirus X domains. Adv. Exp. Med. Biol. 581:93–96 132. Gorbalenya AE, Enjuanes L, Ziebuhr J, Snijder EJ. 2006. Nidovirales: evolving the largest RNA virus genome. Virus Res. 117:17–37 133. LaStarza MW, Lemm JA, Rice CM. 1994. Genetic analysis of the nsP3 region of Sindbis virus: evidence for roles in minus-strand and subgenomic RNA synthesis. J. Virol. 68:5781–91 134. Neuman BW, Joseph JS, Saikatendu KS, Serrano P, Chatterjee A, et al. 2008. Proteomics analysis unravels the functional repertoire of coronavirus nonstructural protein 3. J. Virol. 82:5279–94 135. Neuvonen M, Kazlauskas A, Martikainen M, Hinkkanen A, Ahola T, Saksela K. 2011. SH3 domain– mediated recruitment of host cell amphiphysins by alphavirus nsP3 promotes viral RNA replication. PLOS Pathog. 7:e1002383 136. Park E, Griffin DE. 2009. The nsP3 macro domain is important for Sindbis virus replication in neurons and neurovirulence in mice. Virology 388:305–14 137. Putics A, Filipowicz W, Hall J, Gorbalenya AE, Ziebuhr J. 2005. ADP-ribose-1 -monophosphatase: a conserved coronavirus enzyme that is dispensable for viral replication in tissue culture. J. Virol. 79:12721– 31 138. Atasheva S, Akhrymuk M, Frolova EI, Frolov I. 2012. New PARP gene with an anti-alphavirus function. J. Virol. 86:8147–60 www.annualreviews.org • Macrodomains

Changes may still occur before final publication online and in print

2.23

ARI

21 January 2016

19:21

139. Atasheva S, Frolova EI, Frolov I. 2014. Interferon-stimulated poly(ADP-Ribose) polymerases are potent inhibitors of cellular translation and virus replication. J. Virol. 88:2116–30 140. Bertoletti A, Maini MK. 2000. Protection or damage: A dual role for the virus-specific cytotoxic T lymphocyte response in hepatitis B and C infection? Curr. Opin. Microbiol. 3:387–92 141. Gu J, Korteweg C. 2007. Pathology and pathogenesis of severe acute respiratory syndrome. Am. J. Pathol. 170:1136–47 142. Kusov Y, Tan J, Alvarez E, Enjuanes L, Hilgenfeld R. 2015. A G-quadruplex-binding macrodomain within the “SARS-unique domain” is essential for the activity of the SARS-coronavirus replicationtranscription complex. Virology 484:313–22 143. Fathers C, Drayton RM, Solovieva S, Bryant HE. 2012. Inhibition of poly(ADP-ribose) glycohydrolase (PARG) specifically kills BRCA2-deficient tumor cells. Cell Cycle 11:990–97 144. Feng FY, de Bono JS, Rubin MA, Knudsen KE. 2015. Chromatin to clinic: the molecular rationale for PARP1 inhibitor function. Mol. Cell 58:925–34 145. Min W, Wang ZQ. 2009. Poly (ADP-ribose) glycohydrolase (PARG) and its therapeutic potential. Front. Biosci. 14:1619–26 146. Finch KE, Knezevic CE, Nottbohm AC, Partlow KC, Hergenrother PJ. 2012. Selective small molecule inhibition of poly(ADP-ribose) glycohydrolase (PARG). ACS Chem. Biol. 7:563–70 147. Islam R, Koizumi F, Kodera Y, Inoue K, Okawara T, Masutani M. 2014. Design and synthesis of phenolic hydrazide hydrazones as potent poly(ADP-ribose) glycohydrolase (PARG) inhibitors. Bioorg. Med. Chem. Lett. 24:3802–6 148. Tanaka Y, Matsunami N, Itaya A, Yoshihara K. 1981. Histone-dependent ADP-ribosylation of low molecular nucleotide by poly(ADP-ribose) polymerase. J. Biochem. 90:1131–39 149. Baltzinger M, Ebel JP, Remy P. 1986. Accumulation of dinucleoside polyphosphates in Saccharomyces cerevisiae under stress conditions. High levels are associated with cell death. Biochimie 68:1231–36 150. Marriott AS, Copeland NA, Cunningham R, Wilkinson MC, McLennan AG, Jones NJ. 2015. Diadenosine 5 , 5 -P1 ,P4 -tetraphosphate (Ap4 A) is synthesized in response to DNA damage and inhibits the initiation of DNA replication. DNA Repair 33:90–100

Annu. Rev. Biochem. 2016.85. Downloaded from www.annualreviews.org Access provided by Gazi Universities Main Library (D-S) on 02/04/16. For personal use only.

BI85CH02-Ahel

2.24

Rack

·

Perina

·

Ahel

Changes may still occur before final publication online and in print

Macrodomains: Structure, Function, Evolution, and Catalytic Activities.

Recent developments indicate that macrodomains, an ancient and diverse protein domain family, are key players in the recognition, interpretation, and ...
564B Sizes 1 Downloads 11 Views