Histone chaperones: assisting histone traffic and nucleosome dynamics.

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Annu. Rev. Biochem. 2014.83:487-517. Downloaded from www.annualreviews.org by Seattle University on 06/08/14. For personal use only.

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Histone Chaperones: Assisting Histone Traffic and Nucleosome Dynamics Zachary A. Gurard-Levin, Jean-Pierre Quivy, and Geneviève Almouzni Institut Curie, Centre de Recherche; CNRS UMR 3664; Equipe Labellisée, Ligue contre le Cancer; and Université Pierre et Marie Curie, Paris F-75248, France; email: [email protected]

Annu. Rev. Biochem. 2014. 83:487–517

Keywords

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

chromatin, epigenetics, cancer, genome function and instability

This article’s doi: 10.1146/annurev-biochem-060713-035536

Abstract

c 2014 by Annual Reviews. Copyright All rights reserved

The functional organization of eukaryotic DNA into chromatin uses histones as components of its building block, the nucleosome. Histone chaperones, which are proteins that escort histones throughout their cellular life, are key actors in all facets of histone metabolism; they regulate the supply and dynamics of histones at chromatin for its assembly and disassembly. Histone chaperones can also participate in the distribution of histone variants, thereby defining distinct chromatin landscapes of importance for genome function, stability, and cell identity. Here, we discuss our current knowledge of the known histone chaperones and their histone partners, focusing on histone H3 and its variants. We then place them into an escort network that distributes these histones in various deposition pathways. Through their distinct interfaces, we show how they affect dynamics during DNA replication, DNA damage, and transcription, and how they maintain genome integrity. Finally, we discuss the importance of histone chaperones during development and describe how misregulation of the histone flow can link to disease.

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Contents


INTRODUCTION . . . . . . . . . . . . . . . . . Discovery and Definition of Histone Chaperones . . . . . . . . . . . Functional Classification of Histone Chaperones . . . . . . . . . . . Histone Chaperones and Their Histone Cargo . . . . . . . . . . . . . . . . Structural Insight into Histone Binding and Variant Selectivity . . . . . . . . . . . . . . . . . . . . . HISTONE CHAPERONES SHUTTLING HISTONES IN VARIOUS PATHWAYS . . . . . . . . . Histone Chaperones Acting on Histones in Transit . . . . . . . . . . . . Protecting H3–H4 from Degradation: NASP . . . . . . . . . . . Directing Histone Traffic: ASF1 . . HISTONE CHAPERONES INVOLVED IN DISTINCT HISTONE DEPOSITION PATHWAYS . . . . . . . . . . . . . . . . . . . . CAF-1 De Novo Deposition of Replicative H3.1–H4 in a DNA Synthesis–Coupled Pathway . . . Histone Chaperone Deposition of Replacement H3.3–H4 in a DNA Synthesis–Independent Pathway . . . . . . . . . . . . . . . . . . . . . .

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INTRODUCTION The nucleosome core is the universal repeat unit of chromatin; it contains 147 bp of DNA wrapped around an octamer comprising two copies of the four core histones H3, H4, H2A, and H2B (1, 2). The addition of linker DNA, along with linker histone, completes the nucleosome (3) and connects adjacent nucleosomes. The linker DNA varies in length depending on the cell type and species. As shown by detailed contacts at 2.8-A˚resolution (4), the basic charge of the histones in the core particle is neutralized by the phosphate backbone of 488

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HJURP Deposits CENP-A in a Cell Cycle–Dependent Manner . . . . . . . . . . . . . . . . . . . . . . . Histone Chaperones Participate in Cross Talk . . . . . . . . . . . . . . . . . . . . HISTONE CHAPERONES OPERATE AS AN ESCORT NETWORK . . . . . . . . . . . . . . . . . . . . . Histone Chaperones’ Interface with Various DNA Processes at the Cellular Level: Adaptor Domains . . . . . . . . . . . . . . . . . . . . . . Histone Chaperones’ Role During Replication: Handling Histones at the Fork . . . . . . . . . . . . . . . . . . . . Histone Chaperones’ Place During DNA Damage Response . . . . . . . Histone Chaperones’ Participation During Transcription. . . . . . . . . . DISCUSSION AND PERSPECTIVES . . . . . . . . . . . . . . . . Histone Chaperone Integration at the Organism Level During Development and Reprogramming . . . . . . . . . . . . . . . Histone Chaperone Misfunction and Disease . . . . . . . . . . . . . . . . . . . Questions About Histone Chaperones for Future Perspectives . . . . . . . . . . . . . . . . . . .

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the DNA. However, before their incorporation into chromatin and after eviction, when histones are soluble, the high basicity may engage promiscuous interactions with any acidic partner in the cell or may form aggregates leading to defects such as those observed when there is an improper histone supply (5–8). Therefore, under most circumstances, dedicated proteins associate with nonnucleosomal histones, some of which directly buffer the positive charge. These factors are known as histone chaperones, a termed coined for nucleoplasmin, the first identified histone chaperone involved


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in the prevention of aberrant histone–DNA aggregation during nucleosome assembly (9). Notably, the use of chaperone was later adopted to describe a class of proteins that help fold others, such as the heat-shock proteins (10). In this review, we examine the functional network of the histone chaperones at the cellular level (Figure 1). Specifically, we discuss (a) the identification and characterization of the known histone chaperones, (b) the role of histone chaperones acting on histones in transit, (c) histone chaperones in the best-characterized nucleosome assembly pathways, (d ) how the histone chaperones operate as an escort network in various DNA metabolic processes, and finally (e) the link between histone chaperones and development and disease.

Histone traffic Histone synthesis Degradation

Nuclear import

Histones in transit

Storage, buffering

Nucleosome assembly

Eviction, nucleosome dynamics

Exchange, recycling

Nucleosomal histones Specific dynamics

Discovery and Definition of Histone Chaperones In vitro the mixing of purified histones and DNA at physiological ionic strength causes aggregation and precipitation. To overcome this problem, reconstitution experiments either exploited slow dialysis from high (2 M NaCl) to physiological salt concentrations (2, 11) or used anionic polymers such as RNA (12) or polyglutamic acid (13, 14). However, these reconstitution experiments, unless positioning sequences are employed, do not generate regular arrays of nucleosomes. In contrast, assembly in crude extracts provided additional components, including chaperones and remodelers. The large maternal store of histones in Xenopus laevis eggs (15) that enable multiple rounds of cell division prior to the onset of transcription provided a major source of chaperone proteins. Indeed, cell-free extracts generated initially from unfertilized X. laevis eggs (16) or Drosophila embryos (17) efficiently formed nucleosomes by using the histones present in these extracts (18) on exogenously added DNA without noticeable histone–DNA aggregation. The first histone chaperone was thereby purified from X. laevis oocytes in 1978 (9) and named nucleoplasmin (19). In X. laevis eggs, nucleoplasmin has a major storage function for the ma-

Genomic regions Centromere

DNA processes Replication

Telomere

Repair

Genes ...

Transcription

Cellular level

Tissue

Organism and development

Normal Pathological

Figure 1 Histones are escorted by histone chaperones throughout their cellular life and are shuttled into various pathways for their nuclear import, storage, degradation, assembly, and dynamics at chromatin. Together, these processes participate in several DNA metabolic processes that regulate cellular function, which ultimately affects the entire organism.

ternal pool of H2A–H2B dimers, and similarly, the N1 and N2 proteins are in charge of H3–H4 dimers (20, 21). This histone selectivity is consistent with the proposed two-step nucleosome formation in vitro, wherein one chaperone first promotes the deposition of an H3–H4 tetramer [herein noted (H3–H4)2 ] and a different chaperone then deposits H2A–H2B dimers [for a review, see Kaufman & Almouzni (22)]. In this review, we focus on histone chaperones for histone H3 and its variants. For more information about H2A–H2B, please see References 23–26. In somatic cells, which are largely studied in culture, the soluble pool of histones is limited, and other chaperones were identified. The www.annualreviews.org • Histone Chaperones

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use of an in vitro SV40 DNA replication assay with a cytosolic extract (27) complemented with a salt-extracted nuclear fraction from the same cells (28) revealed an activity that promotes nucleosome formation on newly replicated DNA. Furthermore, fractionation of the nuclear extract demonstrated that a three-subunit protein complex termed chromatin assembly factor 1 (CAF-1) is responsible for this activity (29). Also identified in Xenopus (30), this key H3–H4 histone chaperone factor couples DNA replication to chromatin assembly and is essential for early development in Xenopus. We discuss its function in more detail below in the section titled CAF-1 De Novo Deposition of Replicative H3.1–H4 in a DNA Synthesis–Coupled Pathway. These two examples (nucleoplasmin and CAF-1) illustrate two important concepts for histone chaperones: (a) with nucleoplasmin, a storage function and some degree of histone specificity (H2A–H2B), and (b) with CAF-1, a deposition factor and the concept of coupling with one particular aspect of DNA metabolism, such as replication. Thus, in addition to the interaction with histones, one must also consider the interface aspect. We discuss these factors in conjunction with other chaperones throughout this review.


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Functional Classification of Histone Chaperones The current definition of a histone chaperone is a protein that associates with histones and is involved in their transfer but is not necessarily part of the final product (31). In vitro, all histone chaperones share the fundamental ability to promote a progressive transfer of purified histones onto naked DNA at physiological ionic strength to reconstitute nucleosomes from purified components (32). However, not all histone chaperones promote nucleosome assembly in vivo. Investigators developed an assay that used X. laevis egg extracts that enabled them to follow chromatin assembly either coupled or uncoupled from DNA synthesis (33–35) to further classify histone chaperones. 490

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By depleting chaperones from these extracts, in combination with add-back experiments using wild-type or mutant forms, the experiments helped define the histone chaperones’ role in particular pathways (36). This strategy revealed that CAF-1 and the histone regulator A (HIRA) chaperone are bona fide histone deposition factors that promote assembly that is dependent on and independent of DNA synthesis, respectively (30, 37). The assay also demonstrated that the histone chaperone antisilencing function 1 (ASF1), which directly interacts with histones H3–H4 and can promote nucleosome reconstitution in vitro (38, 39), does not necessarily have a direct role in nucleosome assembly in vivo (39). Rather, current data point to a model in which ASF1 can relay histones to either CAF-1 or HIRA for subsequent deposition, processes that we discuss below in the section titled Histone Chaperones Involved in Distinct Histone Deposition Pathways (reviewed in References 31 and 40). These observations underscore the importance of choosing assay conditions—specifically, nucleosome reconstitution from purified components and assembly using extracts—in a complementary fashion so as to formulate a hypothesis concerning their histone chaperone functions. On this basis, in vivo experiments can then be designed to test and strengthen these hypotheses.

Histone Chaperones and Their Histone Cargo Histone chaperones can be classified according to their selectivity for cognate histones. First, we consider H3–H4 or H2A–H2B chaperones (Table 1). However, because H3, H2A, and H2B can exist as several variants (41–44), their specificity can be further refined. The use of stable cell lines expressing epitope-tagged histone variants, combined with biochemical isolation from soluble extracts of the corresponding histone complexes, proved to be critical to identify associated histone chaperones (45, 46). This approach identified CAF-1 with the replicative H3.1 variant (45); HIRA (45) and death domain–associated protein (DAXX) (47)

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Table 1 Histone chaperones in multiple organisms Classification of histone chaperones


H3–H4

Histone chaperonea

Variant selectivity

Conservation

Main function(s)

Reference(s)

ASF1 (Drosophila melanogaster)

H3.1–H4, H3.3–H4

Asf1 (Saccharomyces cerevisiae, Xenopus laevis); Cia1 (Saccharomyces pombe); Sga1, Sga2 (Arabidopsis thaliana); ASF1a, ASF1b (Mus musculus, Homo sapiens)

Histone donor for CAF-1 and HIRA

97–99

CAF-1 complex (H. sapiens)

H3.1–H4

—

Deposition factor coupled to DNA synthesis: replication, DNA repair

29

p150

H3.1–H4

Rif2/Cac1 (S. cerevisiae), SPBC29A10.03C (S. pombe), Fas1 (A. thaliana), p180 (D. melanogaster), p150 (X. laevis, M. musculus)

p60

H3.1–H4

Cac2 (S. cerevisiae), SPAC26H5.03 (S. pombe), Fas2 (A. thaliana), p150 (D. melanogaster), p60 (X. laevis, M. musculus)

RbAp48b

H3–H4

Msi1/Cac3 (S. cerevisiae), Msi16 (S. pombe), Msi1 (A. thaliana), p55 (D. melanogaster), p48 (X. laevis), RbAp48 (M. musculus)

DAXX (with ATRX)

H3.3–H4

—

Deposition factor independent of DNA synthesis: telomere maintenance, ribosomal DNA, pericentric heterochromatin

DEK (D. melanogaster)

H3.3–H4

DEK (H. sapiens)

Transcriptional coactivator

Hif1 (S. cerevisiae)

H3–H4

—

Assists HAT

93

HIRA complex

H3.3–H4

—

Deposition factor independent of DNA synthesis

37

HIRA

H3.3–H4

HIR1/HIR2 (S. cerevisiae); Hip1, Sim2 (S. pombe), HIRA (A. thaliana, D. melanogaster, H. sapiens, M. musculus, X. laevis

Cabin1

H3.3–H4

Hir3 (S. cerevisiae), Hip3 (S. pombe), Cabin1 (M. musculus), AT4G32820 (A. thaliana)

129, 131

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Table 1 (Continued) Classification of histone chaperones

Variant selectivity

Histone chaperonea


UBN1

H2A–H2B

Conservation

Main function(s)

Reference(s)

H3.3–H4

Hpc4 (S. cerevisiae), Hip4 (S. pombe), yemanuclein-A (D. melanogaster), T14N5.16 (A. thaliana), mCG.1031012 (M. musculus)

HJURP (H. sapiens)

CENP-A–H4

Scm3 (S. cerevisiae), HJURP (M. musculus, X. laevis), CAL1 (D. melanogaster)f

Deposition factor, centromere maintenance

N1/N2 (X. laevis)

H3–H4

tNASP, sNASP (M. musculus, H. sapiens)

H3–H4 storage in X. laevis oocytes; NASP protects H3–H4 from degradation in human cells

Rsf-1 (H. sapiens)

H3–H4

Rsf-1 (M. musculus)

Assists RC

214

Rtt106 (S. cerevisiae)

H3–H4

SPAC6G9.03c (S. pombe)

Heterochromatic silencing

204

Spt6 (S. cerevisiae)

H3–H4

Spt6 (S. pombe, D. melanogaster, X. laevis, M. musculus, H. sapiens)

Transcription initiation and elongation

205

SSRP1c (FACT complex)

H3–H4

Pob3 (S. cerevisiae), Pob3 (S. pombe), SSRP (A. thaliana), SSRP1 (D. melanogaster, X. laevis, M. musculus)

Transcription elongation, assistance in chromatin remodeling

58

Chz1 (S. cerevisiae)

H2A.Z–H2B

HIRIP3? (H. sapiens)

H2AZ incorporation by SWR1

206

Nap1d (X. laevis); Nap1-related proteins: Nap1L2 (M. musculus), SET/TAF1b (H. sapiens), CINAP (H. sapiens, M. musculus), Vps75 (S. cerevisiae)

H2A–H2B

Nap1 (S. cerevisiae, D. melanogaster, M. musculus, H. sapiens); NRP1, NRP2 (A. thaliana); Nap1, Nap1.2 (S. pombe)

Cytosolic-nuclear transport, replication, transcription

9, 210–213

Nucleoline (H. sapiens)

macroH2A– H2B

NSR1 (S. cerevisiae), nucleolin (A. thaliana, X. laevis, M. musculus)


Nucleoplasmin (X. laevis), nucleophosmin 1 (NPM1) (H. sapiens)

H2A–H2B

Nip (D. melanogaster); NPM1, NPM2, NPM3 (M. musculus, H. sapiens)

Storage in X. laevis oocytes, cytosolicnuclear transport, replication, transcription

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48, 49

21, 51, 52

26

9, 209

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Table 1 (Continued) Classification of histone chaperones


Not determined or multiple

Histone chaperonea

Variant selectivity

Conservation

Main function(s)

Reference(s)

Spt16 (FACT complex)

H2A–H2B

Spt16 (S. cerevisiae, S. pombe, A. thaliana, D. melanogaster, X. laevis, M. musculus)


58

Arp4 (S. cerevisiae)

Not determined

Alp5 (S. pombe), Arp4 (A. thaliana), BAP55 (D. melanogaster), BAF53 (M. musculus, H. sapiens)

Assists RC

207

Arp7, Arp9 (S. cerevisiae)

Not determined

Arp7, Arp9 (A. thaliana); BAP55 (D. melanogaster); BAF53 (M. musculus, H. sapiens)

Assists RC

215

Arp8 (S. cerevisiae)

H3–H4

BAP55 (D. melanogaster), BAF53 (M. musculus, H. sapiens)

Assists RC

208

Acf1 (D. melanogaster)

H2A–H2B, H3–H4

Itc1 (S. cerevisiae), Acf1 (M. musculus, H. sapiens)

Assists RC

216

a

Histone chaperones are classified as H3–H4, H2A–H2B, or not determined/multiple histone chaperones, and then listed alphabetically. Specifically preferred histone variants, when known, are in bold. b RbAp48 (also known as Rbbp4) and its homologs can act as single chaperones, as part of the multichaperone complex CAF-1, or within other complexes (RC, HAT, HDAC, or PC). c SSRP1, through its interaction with H3–H4, may assist Spt16 in nucleosome binding. d Both Nap1 and sNASP also interact with linker histones. e Nucleolin facilitates remodeling of nucleosomes containing macroH2A, suggesting specificity for this variant. f Proposed to be a functional homolog. Abbreviations: ATRX, α-thalassemia/mental retardation X-linked; CENP-A, centromere protein A; DAXX, death domain–associated protein; FACT, facilitates chromatin transcription; HAT, histone acetyltransferase; HDAC, histone deacetylase complex; HIRA, histone regulator A; HJURP, Holliday junction recognition protein; PC, Polycomb complex; PHC, pericentric heterochromatin; RC, remodeling complex; sNASP, somatic nuclear autoantigenic sperm protein (NASP); SSRP1, structure-specific recognition protein 1; tNASP, testicular NASP; UBN1, ubinuclein 1.

with the replacement variant H3.3; and Holliday junction recognition protein (HJURP) with the human centromeric H3 variant centromere protein A (CENP-A) (48, 49). In contrast to this selective behavior, the histone chaperones ASF1 and nuclear autoantigenic sperm protein (NASP) are present in both H3.1 and H3.3 soluble complexes (45). This finding shows that histone chaperone–histone interactions are not necessarily strict. That the histone chaperone NASP associates with H1 in mammals (50) and is also an H3–H4 chaperone also illustrates this point (45, 51, 52). Furthermore, immunoprecipitation experiments showed that Nap1, an H2A–H2B chaperone, binds the B4 linker his-

tone in X. laevis eggs (53). Thus, the selectivity of histone chaperone–histone interactions should be considered with caution and in a context-dependent manner, given that changes (including alterations of histone provision or histone chaperone expression) can affect these interactions. As stated above, beyond in vitro assays the ability to test chaperone activity in vivo is critical. In cell culture, the use of a system that allows expression of histone variants fused with a DNA alkyltransferase hAGT mutant is a powerful in vivo tool for histone deposition. In this assay, referred to as SNAP-tag technology, the DNA alkyltransferase protein reacts rapidly www.annualreviews.org • Histone Chaperones

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and specifically in cell culture with exogenously added benzylguanine derivatives. This process enables covalent labeling of the histone variant fusion molecule with a synthetic probe (54) that may or may not be fluorescent, thus enabling pulse-chase experiments. The first application of quench-chase-pulse protocols allowed investigators to distinguish newly synthesized CENP-A from parental CENP-A and to determine the timing of new CENP-A deposition during the cell cycle (55); this approach later enabled the discovery that new CENP-A deposition is HJURP dependent (48, 49). Subsequent adaptations of this assay with other histone variants are described below.


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Structural Insight into Histone Binding and Variant Selectivity The identification of acidic patches on several histone chaperones accords with the idea that histone chaperones play a general role in neutralizing the basicity of histones (56–58). Posttranslational modifications (PTMs) can also alter the electrostatic potential of the chaperone and affect histone binding, as exemplified by polyglutamylation of Nap1 in Drosophila melanogaster (59). However, in some cases charge neutralization alone is dispensable for some histone chaperone functions (60–62). Beyond these general charge properties, a characteristic histone-binding motif can be found as a signature on several H3–H4 and H2A–H2B chaperones (56, 60, 62–67). These shared features may relate to common proper-

ties, yet they do not necessarily imply that all histone chaperones have the same partners, so a refined analysis is required. High-resolution structures aid in identifying key domains and determining how histones may interact with their cognate partners. For example, the structure of ASF1 with a dimer of histones H3–H4 shows that it occludes the tetramerization of H3–H4 by binding critical residues at the H3–H3 interface (Figure 2a). This finding accords with results from in vitro experiments, in which ASF1 acts to promote the disruption of (H3–H4)2 tetramers (68). A current model for ASF1 function at the replication fork proposes that (a) ahead of the fork, ASF1 handles histones from disrupted nucleosomes and (b) behind the fork it delivers dimers to other deposition factors involved in assembly for both recycling and de novo deposition (69). Furthermore, the structure shows that the divergent residues between histones H3.1 and H3.3 (41) remain exposed to the solvent (68, 70, 71), enabling other chaperones to differentiate the variants bound to ASF1 and target them to particular deposition pathways, such as HIRA and CAF-1. The solved structure of ASF1 bound to a small peptide corresponding to the HIRA B domain shows that a region within the N-terminal 156 residues of ASF1 mediates the interaction (72). CAF-1 p60 also contains B-domain motifs that recognize the same ASF1-binding site, a finding that explains why ASF1 binds these proteins in a mutually exclusive manner (72). These structural observations help illustrate a scheme in which ASF1

−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−→ Figure 2 Structural insights into histone chaperone–histone binding, variant selectivity, and in vivo function. (a) (Left) A soluble H3–H4 dimer bound to ASF1 [Protein Data Bank (PDB) identifier 2I05] (68). (Right) A nucleosomal (H3–H4)2 tetramer (PDB 1AOI) (4). Common H3 residues that bind antisilencing function 1 (ASF1) and mediate the (H3–H4)2 tetramer are colored red. The H4 C terminus (brown) undergoes a conformational change following binding to ASF1. Divergent residues between H3.1 and H3.3 ( purple) remain exposed to the solvent in the ASF1 complex. (b) (Left) Death domain–associated protein (DAXX) in complex with H3.3–H4. (Right) Holliday junction recognition protein (HJURP) in complex with centromere protein A (CENP-A)–H4. Red boxes indicate critical residues for variant selectivity. Similar binding motifs are depicted (bottom), and conserved residues are indicated with side chains and labels. DAXX, PDB 4H9N (74); HJURP, PDB 3R45 (75). Abbreviations: aa, amino acids; CAF-1, chromatin assembly factor 1; CBD, CENP-A-binding domain; HIRA, histone regulator A; HBD, histone-binding domain. 494

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can act as a histone donor that functions with CAF-1 and HIRA (22). Interestingly, this binding site for the B domain is conserved between human ASF1a and ASF1b, suggesting possible redundancy (73). However, as discussed below, this is not necessarily the case.

a

The solved structures of DAXX and HJURP (Scm3 in yeast) with H3.3–H4 and CENP-A–H4 (Cse4 in yeast), respectively, revealed additional histone chaperones that bind dimers (74–76), although not all chaperones share this property (60, 77). The DAXX

ASF1 binds a dimer of H3–H4 Nucleosomal (H3–H4)2

Soluble H3–H4 dimer


ASF1 (aa1–156)

H3–H3’ interface

H4 HIRA/CAF-1binding site H3 H4 C terminus

H3–H3’ interface

b

H4 C terminus

H3 aa 87, 89–90

H3 aa 87, 89–90

Similar binding motifs: DAXX with H3.3–H4 and HJURP with CENP-A–H4 DAXX (HBD)

HJURP (CBD)

H3.3

CENP-A Ser68 H4 H3.3 Gly90 CENP-A

H4

CENP-A

H4

Y

DAXX

K

L

L

L

Y

K

L

L

L

HJURP

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structure demonstrates an interaction with a region of H3.3 that is also recognized by ASF1 (Figure 2b). This finding suggests that the formation of DAXX and ASF1 complexes with H3.3 represent concurrent events in vivo, a hypothesis supported by pull-down experiments in vitro and in vivo (74). The HJURP structure underscores the importance of the CENP-A targeting domain and CENP-A Ser68 to distinguish this variant from canonical H3 (Figure 2b, right) (75). Interestingly, the structures of DAXX with H3.3– H4 and HJURP with CENP-A–H4 reveal a striking similarity in terms of how they associate with their respective histone partners (Figure 2b). Therefore, cross talk may play a role in the ability of these chaperones to bind different variants, particularly in the case of an imbalance in histone provision (78). Therefore, how cross talk could lead to errors in the timing and/or placement of these variants throughout the genome that affect cell function is important to consider. The association of the FACT (facilitates chromatin transcription) subunit Spt16 with an H2A–H2B dimer provides evidence for the first chaperone that interacts through H2B (79), which may explain its broad association with various H2A variants. For a comprehensive review of histone chaperone structures, see Reference 80. Together with the examples discussed above, this section illustrates how structural analyses help explain how different chaperones bind histones and their potential selectivity for histone variants, thereby providing an entry point to investigate the effect of mutations on histone chaperone– histone interactions and gain insight into chaperone function in vivo.


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HISTONE CHAPERONES SHUTTLING HISTONES IN VARIOUS PATHWAYS In this section, we discuss histone chaperones that act on histones in transit (Figure 1). We focus on the best-characterized histones, H3 and H4 (for reviews on H2A–H2B chaperones, see References 81–83). We begin by describing the 496

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presence of histone chaperones in histone complexes following their synthesis; we then discuss how the chaperones NASP and ASF1 shuttle histones into pathways for nucleosome assembly, storage, and degradation in response to cellular needs.

Histone Chaperones Acting on Histones in Transit Soluble histone complexes from cell lines that stably express epitope-tagged histones (45, 46) were purified to characterize subcomplexes of histones H3 and H4 in transit. A series of complexes, along with histone PTMs, were characterized (Figure 3a) (46, 51, 52, 84). Notably, these complexes are dynamic. Thus, additional transient or low-abundance subcomplexes and PTMs that are not detectable under the conditions of the complex purification and/or characterization may exist. Histone chaperones may aid nuclear import; some may increase the affinity for karyopherins that are responsible for transport (85; for a review, see Reference 81). Once in the nucleus, histone chaperones do not necessarily distribute histones to deposition factors for immediate incorporation into chromatin. Histones may persist in a soluble state depending on the variant and cell-cycle phase. In the next two sections, we describe the roles of the chaperones NASP and ASF1 in regulating histone provision and the storing and buffering of soluble histones H3.1–H4 and H3.3–H4.

Protecting H3–H4 from Degradation: NASP NASP was identified in a screen for histone binding proteins in testes. It exists in two isoforms: somatic NASP, which is ubiquitously expressed, and testicular NASP, which is highly expressed in testes and ovaries, as well as in transformed cells (50, 86). Although originally considered a chaperone for the linker histone H1 (50, 87–89), NASP has H3–H4 chaperone activity in vitro (90, 91) and its homologs in Saccharomyces cerevisiae (Hif1p) and in Saccharomyces pombe (Sim3) have H3–H4 chaperone activity in vivo (92, 93). The high sequence

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Figure 3 Histone chaperones acting on histones in transit. (a) Histone subcomplexes in transit following their synthesis. (i ) H3 with Hsc70. H3 is monomethylated at Lys9; H4 is with Hsc70 and Hsp90. (ii ) An H3–H4 dimer with Hsp90 and testicular nuclear autoantigenic sperm protein (tNASP). H3 is still monomethylated; a small fraction of H4 is acetylated at Lys12. (iii ) An H3–H4 dimer with somatic NASP (sNASP), histone acetyltransferase 1 (HAT1), antisilencing function 1 (ASF1), and RbAp48. H4 is acetylated at Lys5 and Lys12, but H3K9me1 has decreased. (iv) An H3–H4 dimer with Importin-4 and ASF1; H4 displays the Lys5 and Lys12 diacetylation pattern commonly associated with newly synthesized H4 (203). Note that these subcomplexes are dynamic and may not be unidirectional. (b) NASP maintains a soluble H3–H4 pool by protecting them from degradation by chaperone-mediated autophagy involving Hsc70 and Hsp90. Dispensable for normal proliferation, NASP is important for S-phase progression when H3–H4 provision is impaired, deals with an overload of new H3–H4, and deals with H3–H4 that suddenly accumulates during replication stress. The fine-tuning of the soluble reservoir of H3–H4 by NASP therefore integrates contingency into the histone supply network to cope with unanticipated changes in demand or provision. Modified from Reference 52.

identity between NASP and the H3–H4 chaperones N1/N2 in X. laevis, implicated in histone storage in oocytes (21), may provide a clue about its function in other species. Depletion

or overexpression of NASP in human cells does not yield a strong change to the cell cycle or perturb histone deposition. Only during acute replication stress in human cells, when new www.annualreviews.org • Histone Chaperones

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soluble histones cannot be deposited onto DNA, does NASP become critical through a storage function (52). Indeed, the storage of histones via NASP and their transfer to a multichaperone complex containing NASP, ASF1, and RbAp48 (8) allow deposition to restart once replication resumes. This reservoir of H3–H4 (51, 52), although dispensable during normal proliferative conditions, is needed to cope with unanticipated changes in demand or impaired histone production (52). NASP fine-tunes the capacity of this reservoir through a mechanism that involves a dynamic balance between histone protection and degradation by chaperonemediated autophagy (Figure 3b) (52). Intriguingly, this degradation pathway in mammals differs from that in yeast, in which histones in excess of cellular requirements are degraded in a Rad53- and proteasome-dependent pathway (94, 95). Thus, although some general principles may broadly apply in various species, the details of the mechanisms can differ and depend on the variant.


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Directing Histone Traffic: ASF1 ASF1 (also known as CIA-1), originally identified as a transcriptional derepressor in a yeast genetic screen (96), was later described as an H3–H4 histone chaperone (61, 97, 98). ASF1 is the most conserved eukaryotic H3–H4 chaperone. In yeast, ASF1 exists as a single protein, whereas most vertebrates have two ASF1 paralogs, termed ASF1a and ASF1b in mammals. Among its conserved functions, ASF1 synergizes with CAF-1 and HIRA to channel H3.1 and H3.3 histones into distinct deposition pathways. Even though a high sequence identity and a conserved binding domain for histones and CAF-1/HIRA suggest common properties, ASF1a and ASF1b are not functionally equivalent, as evidenced by different gene-expression patterns (73, 99, 100), different protein–protein interactions (73, 101), and the finding that the human paralogs rescue different defects in yeast depleted of yASF1 (102). Comparative genomics approaches provided interesting clues about how the human paralogs evolved distinct functions. The phylogeny suggested that ASF1 498

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experienced subfunctionalization, where ancestral functions are distributed between the two gene duplicates. Furthermore, the different genomic contexts allowed optimization of distinct functions (73). In support of subfunctionalization, biochemical approaches revealed that human ASF1a interacts selectively with HIRA in vitro and in vivo (65, 73, 101, 103) and that ASF1b has a preferential interaction for CAF-1 p60 in vivo (73). The productive combination of multiple approaches to elucidate the function of this histone chaperone could apply to various chaperones and even other protein families. As mentioned above, replication is one instance in which ASF1 is in the middle of heavy histone traffic, as we discuss below in more detail in the section titled Histone Chaperones’ Role During Replication: Handling Histones at the Fork. Importantly, by interfacing with the replication machinery (104) and associating with newly synthesized and parental histones (105), ASF1 may coordinate de novo histone deposition and histone recycling. These actions make ASF1 a critical factor in the regulation of chromatin inheritance, which can affect genome function and cell fate. This observation emphasizes the importance of histone chaperones acting on histones in transit.

HISTONE CHAPERONES INVOLVED IN DISTINCT HISTONE DEPOSITION PATHWAYS Several histone chaperones play a role in nucleosome dynamics at or near chromatin. In this section, we consider each histone chaperone individually and discuss the role of each in different deposition pathways for distinct H3 variants (Figure 4).

CAF-1 De Novo Deposition of Replicative H3.1–H4 in a DNA Synthesis–Coupled Pathway CAF-1 is a key factor that deposits histones in a manner coupled to DNA replication (28) and in DNA repair (106). CAF-1 is a complex comprising three subunits, termed p150, p60, and

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Figure 4 Histone chaperones involved in histone deposition pathways. (a) The chromatin assembly factor 1 (CAF-1) complex deposits the replicative H3.1 variant in a DNA synthesis–coupled (DSC) pathway during replication and repair. (b) The histone regulator A (HIRA) complex deposits the replacement variant H3.3 in a DNA synthesis–independent (DSI) pathway, particularly at transient nucleosome-free regions and at transcribed genes and regulatory elements. Death domain–associated protein (DAXX) may participate in the deposition of H3.3 at telomeres. (c) Holliday junction recognition protein (HJURP) deposits centromere protein A (CENP-A) in a DSI pathway. Abbreviations: ATRX, α-thalassemia/mental retardation X-linked; UBN1, ubinuclein 1.

RbAp48 (or simply p48) in human cells (66). The large subunit, p150, is crucial for coupling to DNA synthesis through an interaction with the proliferating cell nuclear antigen (PCNA) protein (106–109). This interaction is promoted by the phosphorylation of CAF1 p150 by Cdc7/Dbf4 (110). The p60 subunit is also a substrate for phosphorylation by Cdk in vitro, which may represent another mechanism by which CAF-1 deposition activity is regulated (111). Interestingly, chromatin assembly coupled to DNA synthesis is more efficient than assembly independent of DNA synthesis (33– 35), indicating that an advantage is conferred by this coupling. This finding accords with the fact that CAF-1 prominently deposits the replicative variant H3.1–H4 histones onto DNA at DNA synthesis sites; this deposition has been observed through the colocalization of CAF-1 with new H3.1, as detected with the SNAP assay (112). CAF-1 receives histone dimers provided by ASF1, as discussed above. A possible way for CAF-1 to then promote tetramer formation may be its capacity to dimerize through the p150 subunit, as determined in both human

and X. laevis CAF-1 orthologs (30). Interestingly, yeast CAF-1 can bind two H3–H4 dimers or a cross-linked (H3–H4)2 tetramer. This finding suggests that yeast CAF-1 may even assemble (H3–H4)2 tetramers prior to deposition (114). Finally, although CAF-1 function is conserved across several species, including Drosophila (115–117), Xenopus (30), Arabidopsis (118), and yeast (119, 120), its sequence has diverged, and the exact mechanisms of de novo deposition and/or their interfaces with various partners may differ accordingly and should be considered species specific. This general principle also applies to other histone deposition pathways.

Histone Chaperone Deposition of Replacement H3.3–H4 in a DNA Synthesis–Independent Pathway HIRA is a H3.3 chaperone that deposits this variant throughout interphase, independently of DNA synthesis (37, 45, 112). Although HIRA-mediated H3.3 deposition may potentially address all the needs for dynamics outside www.annualreviews.org • Histone Chaperones

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S phase, during S phase it can be considered a backup plan for faulty H3.1 deposition under CAF-1 guidance. In yeast, HIRA is a complex composed of Hir1p, Hir2p, Asf1p, Hir3p, and Hpc2p (103, 121–124). Interestingly, the sequence of human HIRA resembles that of Hir1p and Hir2p, suggesting that orthologs for the other components may also exist in human cells. Bioinformatics approaches have been critical for the identification of ubinuclein 1 (UBN1) (125) and calcineurin-binding protein 1 (CABIN1) (126, 127), the human orthologs of Hpc2p and Hir3p. Notably, UBN1 and CABIN1 had previously been identified in the soluble H3.3 complex by mass spectrometry (45), but their placement as members of the HIRA complex was not known. Thus, this strategy underscores the ability of bioinformatics and phylogenetic techniques to gain insights into histone chaperone function. Bioinformatics has also been critical in analyses of genome-wide data from chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) experiments (128). This technique provides an enrichment profile of a particular chromatin-bound factor from a mixed population of cells, and it was used to map the H3.3 enrichment profile in the presence of and following depletion of HIRA (112, 129). The HIRA binding sites were further confirmed by a HIRA ChIP-seq experiment (130). Notably, for proper enrichment profiles to be detected via these methods, the populations of cells being analyzed should display homogeneous behavior. Single cell–level analyses enable the detection of events that may escape genome-wide analyses. Thus, the combination of genome-wide approaches with individual cell analyses is essential. Moreover, enrichment data provide an end point and do not address the time frame of in vivo deposition assays, such as SNAP technology (112), that distinguish new and old histones and can provide further insight into histone chaperone function. ChIP-seq experiments have also generated a DAXX-dependent H3.3 enrichment profile that is distinct from HIRA (129, 131). Interestingly, when the SNAP assay is used, DAXX


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depletion does not affect global H3.3 deposition in human HeLa cells (112). Whether DAXX-dependent H3.3 deposition plays a role at particular genomic loci in other cell types or is beyond the detection limits of the assay remains to be considered. Indeed, following neuronal activation, DAXX mediates H3.3 loading at regulatory regions of select genes in which calcium- and calcineurindependent phosphorylation dynamics regulate DAXX chaperone activity (132). DAXX can associate with the α-thalassemia/mental retardation X-linked (ATRX) protein, which is also found in the soluble H3.3 complex (45). A member of the Swi2/Snf2 family of chromatin remodelers (133), ATRX may recruit DAXX activity to specific genomic loci (129, 131). Together, HIRA and DAXX are representative chaperones that bind the same histone variant but demonstrate distinct cellular roles by interfacing with different cellular machinery.

HJURP Deposits CENP-A in a Cell Cycle–Dependent Manner HJURP represents a prototype of a histone chaperone that can define a chromatin landmark by depositing a particular histone variant at a specific locus (e.g., the centromere). Indeed, the centromere marks the site of kinetochore formation, which drives chromosome segregation. Except in budding yeast, in which the centromere is dictated by the underlying DNA sequence (134), the centromere is defined epigenetically by the presence of the H3 centromeric variant CENP-A in human and mouse (135). HJURP, initially characterized as a protein that binds to Holliday junctions (recombination intermediates) in vitro (136), was later described as a histone chaperone for human CENP-A after being purified from soluble CENP-A complexes (48, 49). Using the SNAP-tag approach, Jansen et al. (55) observed that newly synthesized CENP-A is deposited during late telophase and early G1 in human cells. This deposition timing coincided with the localization of HJURP at centromeres (48). Thus, during replication, new CENP-A


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is not deposited and the concentration of CENP-A is halved in each daughter cell, giving rise to questions about the composition of the centromeric particle post-replication. Experiments using chromatin fibers to locate the presence of H3.3 during replication at centromeric regions suggested that H3.3 may act as a placeholder and is later replaced by CENP-A in an HJURP-dependent manner (137). Interestingly, a recent report showed that HJURP dimerization is required for CENP-A deposition (138); this property may ensure that centromeric nucleosome particles contain two copies of CENP-A (homotypic nucleosome), thereby contributing to the maintenance of this chromatin landmark during the dilution that eventually occurs during replication. A related HJURP in X. laevis (139) deposits CENP-A during early interphase. Finally, dedicated centromeric histone chaperones are also found in more distant species, including yeast (140). In Drosophila, an evolutionarily distinct protein, CAL1, has been proposed to be a functional homolog (141). Together, these data suggest that HJURP and its functional homologs are key factors for CENP-A deposition and the maintenance of centromere identity.

Histone Chaperones Participate in Cross Talk In S. cerevisiae, which has a single H3 that bears the strongest relationship to H3.3, deletion of either the CAF-1 or HIRA ortholog causes minor defects, whereas the double mutant is severely compromised (142, 143). These findings suggest that CAF-1 or HIRA may compensate for the loss of the other. When double mutants are robust, triple-mutant analyses provide a model system enabling the identification of cross talk. Indeed, this approach determined that the Swi/Snf component RdH54 can compensate for the loss of Cac1 (CAF-1 p150 ortholog) and Asf1 (144). In mammals, the H3.1 and H3.3 deposition pathways described above act in concert in vivo, and cross-talk mechanisms have been reported in different species. In mouse NIH3T3 cells depleted of CAF-1

subunits p150 and p60, nucleosomes are still detected, indicating that there are in vivo compensation mechanisms (113). Indeed, the SNAP assay revealed possible cross talk between the HIRA and CAF-1 deposition pathways in human cells. CAF-1 p60 depletion allows HIRA to place H3.3 at replication foci where it does not normally go (112). However, the converse is not true, and CAF-1 does not compensate for the depletion of HIRA (112). Interestingly, despite the common property to associate with H3.3, no evidence has demonstrated cross-talk mechanisms for HIRA and DAXX. Thus, when considering possible crosstalk mechanisms, it is important to question (a) how relaxed selectivity for histones can permit cross talk, particularly during stress conditions or following a change in histone provision, and (b) whether cross talk can cause pathological situations due to improper histone placement. The latter issue stresses that although histone chaperones may compensate for histone binding, they do not demonstrate perfect redundancy because they also interface with distinct partners. To further illustrate this point, in the following section we discuss how histone chaperones operate as an escort network in different DNA metabolic pathways.

HISTONE CHAPERONES OPERATE AS AN ESCORT NETWORK In this section, we discuss how histone chaperones act in concert in vivo. We begin by observing that histone chaperones exploit adapter domains that interface with several partners to regulate the handling of histones. We then consider these actions in the context of DNA replication, in response to DNA damage, and in the setting of DNA transcription.

Histone Chaperones’ Interface with Various DNA Processes at the Cellular Level: Adaptor Domains The presence of so-called adapter domains can help recruit or localize histone chaperones to www.annualreviews.org • Histone Chaperones

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Figure 5 Histone chaperones interface with several partners to link histone metabolism to specific genomic regions or particular functions. Representative H3–H4 histone chaperones and several other binding partners broadly link the chaperones to various cellular processes. Note that antisilencing function 1a (ASF1a) specifically interacts with histone regulator A (HIRA), and ASF1b preferentially binds chromatin assembly factor 1 (CAF-1) p60. Abbreviations: ATRX, α-thalassemia/mental retardation X-linked; CENP-A, centromere protein A; HJURP, Holliday junction recognition protein; HP1, heterochromatin protein 1; NASP, nuclear autoantigenic sperm protein; MCM2-7, minichromosome maintenance protein 2-7; PCNA, proliferating cell nuclear antigen; Pol II, polymerase II; SetDB1, a histone lysine N-methyltransferase; Tlk-1/2, tousled-like kinases 1/2; UBN1, ubinuclein 1.

particular genomic loci or regulate chaperone activity for specific biological functions (Figure 5). A prime example is the coupling of CAF-1 to sites of DNA synthesis, mediated 502

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by the interaction between p150 and PCNA (107, 108). Additionally, p150 interacts with heterochromatin protein 1 alpha (HP1α) (145) and the histone lysine N-methyltransferase


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SetDB1 (146). Here, CAF-1 recruits these partners to defined chromosomal regions. The ability of HIRA to bind naked DNA (112) suggests that HIRA may deposit H3.3 at transiently nucleosome-depleted regions, possibly to maintain genome integrity. Also, the presence of HIRA in a complex with RNA polymerase II (Pol II) supports its recruitment to transcription sites, a finding supported by ChIP-seq data showing a correlation between HIRA-dependent H3.3 accumulation and RNA Pol II at transcript sites and specific regulatory elements (112). DAXX, through its interaction with ATRX, is implicated in the enrichment of H3.3 at telomeres, in ribosomal DNA, and in embryonic stem cells (129, 147). ATRX also recruits DAXX to pericentric heterochromatin in mouse embryonic fibroblasts (MEFs) (131). These examples demonstrate that adapter domains can yield histone chaperones that bind the same histone variant but carry out different functions. The use of adaptor domains can also regulate histone handling away from chromatin. ASF1 interacts with Codanin-1 through the same region that interacts with the B domain of HIRA and CAF-1. Codanin-1 is proposed to sequester ASF1 with histones in the cytoplasm, which would prevent ASF1 from donating histones to CAF-1 and HIRA for subsequent deposition (148). Furthermore, ASF1 interacts with several other partners, either directly or through histones, revealing a complex network with various functional outcomes that may differ between organisms. Thus, the use of adapter domains expands the interaction network and plays an integral role in dictating histone chaperone function.

Histone Chaperones’ Role During Replication: Handling Histones at the Fork Histone chaperones play a critical role in the transient disruption of chromatin organization during replication and its restoration after fork passage (Figure 6) (22, 149, 150). Ahead of the replication fork, a tetramer of (H3–H4)2

and two H2A–H2B dimers are evicted. Here, ASF1 may act as a histone acceptor, potentially disrupting the (H3–H4)2 tetramer (68, 70). Analyses of bulk histones demonstrated that an entire parental (H3–H4)2 tetramer can be recycled (151–157). SILAC (stable isotope labeling of amino acids in cell culture)-based mass spectrometry experiments designed to visualize whether endogenous and tagged histone dimers mix after replication demonstrated that (H3.1–H4)2 tetramers rarely mix, whereas approximately 10–20% of (H3.3–H4)2 tetramers do mix (158, 159). Importantly, this finding does not rule out the possibility that the parental tetramers experience a transient dimeric state and reassociate prior to deposition. Mixing requires splitting, but splitting does not necessarily lead to mixing. In addition to recycling parental histones, newly synthesized histones are deposited during replication, which accounts for the doubling of nucleosomes required to package the duplicated genome (Figure 6). Recycling and de novo deposition must be coordinated because the inheritance of chromatin marks can dictate cell fate (reviewed in Reference 160). ASF1, in escorting both parental and newly synthesized histones, may help coordinate these processes (for a review, see Reference 150). During de novo assembly, newly synthesized H3.1–H4 histones associated with ASF1 can be handed off to CAF-1 for subsequent deposition (39, 117). For recycling, ASF1 complexed with the MCM2-7 helicase may handle evicted parental histones and direct their distribution onto the daughter strands. Once the (H3–H4)2 tetramer is deposited onto DNA, H2A–H2B dimers rapidly associate to form the complete nucleosome. Although the dynamic nature of H2A–H2B has limited our understanding of this process, the FACT complex is possibly involved (161, 162), FACT binds several components of the replisome (163–166), it is required for replication in several organisms, and DT40 chicken cells lacking the FACT subunit structure-specific recognition protein 1 (SSRP1) experience reduced fork progression speed (167). Thus, replication represents a www.annualreviews.org • Histone Chaperones

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De novo assembly Figure 6 Histone chaperones during replication: escorting histones at the fork. Nucleosomes are disrupted ahead of the replication fork, and parental histones are escorted by antisilencing function 1 (ASF1) (for H3–H4) and possibly FACT (facilitates chromatin transcription) (for H2A–H2B). Evicted (H3–H4)2 tetramers may proceed through a transient dimeric state. During recycling, ASF1 complexes with the minichromosome maintenance protein 2-7 (MCM2-7) helicase, an interaction mediated by histones. During de novo assembly, ASF1 donates newly synthesized H3.1–H4 dimers to chromatin assembly factor 1 (CAF-1), which is coupled to synthesis sites through an interaction with proliferating cell nuclear antigen (PCNA). After (H3–H4)2 tetramers are loaded onto DNA, H2A–H2B dimers rapidly associate, potentially aided by the FACT or Nap1 chaperones. In case of faulty CAF-1 deposition of H3.1–H4 at the fork (right), histone regulator A (HIRA) may deposit H3.3, away from the replication fork, in transiently nucleosome-depleted regions as a way to maintain genome integrity. Abbreviation: PTM, posttranslational modification.

critical time window in which the histone chaperone network is paramount, ensuring that the overall chromatin organization is properly duplicated to maintain genome integrity. Notably, histone chaperones are also vital in stress conditions, such as problems encountered during replication. As described above, ASF1 buffers histones that accumulate upon replication stress (104). Interestingly, if there are problems in the deposition of histones at the fork, HIRA may act away from the fork to fill in gaps (Figure 6), exploiting its DNA binding ability to deposit H3.3 at these transiently nucleosome-free regions (112). In the next section, we consider the role of chaperones in the 504

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response to DNA damage, another type of cellular stress.

Histone Chaperones’ Place During DNA Damage Response Histone chaperones play key roles in responding to various types of DNA damage (31, 168– 172). In this section, we describe the role of histone chaperones in the response to DNA damage, with a particular focus on UV-C damage. The DNA damage response may be divided into three nonexclusive events: detection, processing, and restoration (Figure 7). During

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Figure 7 Histone chaperones in response to UV-C DNA damage. During the detection and priming steps, H2A.X phosphorylation initiates the signaling cascade and inhibits the H2A.X/H2A exchange mediated by FACT (facilitates chromatin transcription) (in mammals). Additionally, Arp8 recruits the INO80 complex to damage sites (218). Histone regulator A (HIRA) is recruited early, perhaps in a ubiquitin-dependent manner. Other histone modifying enzymes are important in the response to DNA damage, and histone chaperones may be present in these complexes. During the processing and handling steps, parental histones are displaced from the damage site to provide access and may be buffered by antisilencing function 1 (ASF1). HIRA then promotes the deposition of H3.3 and exits. During restoration and assembly, the chromatin assembly factor 1 (CAF-1) complex and FACT are involved in the deposition of newly synthesized H3.1–H4 and H2A–H2B, respectively. Finally, nucleosome restoration and γH2A.X exchange, aided by the INO80 complex, contribute to turn off DNA damage signaling. Modified from Reference 168.

detection, the presence of phosphorylated H2A.X, termed γH2A.X in mammals (173), is an early marker for DNA damage (174). To provide access for the DNA repair machinery, the parental histones flanking the DNA damage site are transiently displaced and thus escorted by histone chaperones during the processing event. ASF1 may handle evicted H3–H4 dimers, similarly to the way in which it buffers histones that accumulate in response to

a DNA replication fork block (104). The HIRA complex is recruited very early to UV-C damage regions at the detection step, potentially through a ubiquitin-dependent mechanism in which ubiquitylated proteins, including histones, may be displaced and transient access to DNA is provided. HIRA uses its DNA binding property to promote H3.3 deposition at damage sites and then leaves. This transient action of HIRA, which leads to new H3.3 deposition, www.annualreviews.org • Histone Chaperones

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acts as a marking system, licensing transcription restart following DNA damage repair (175). During the later steps of this process, the CAF1 complex is recruited to the DNA synthesis repair site for the restoration event. CAF-1 recruitment can occur through the interaction with PCNA (107), and de novo H3.1–H4 histones are deposited (40). CAF-1-mediated H3.1–H4 deposition participates to reassemble nucleosomal organization and may provide a signal to terminate the DNA damage response (168). For H2A–H2B, the FACT complex facilitates accelerated exchange of H2A–H2B that is also important for transcription restart (176). The link between the DNA damage response to UV-C and transcription demonstrates that DNA metabolic processes are interdependent and that the cellular response to one process can affect the other and, therefore, cell fate.


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Histone Chaperones’ Participation During Transcription During transcription, changes to the chromatin structure accompany the progression of the RNA Pol II machinery (177–179). The recruitment of several classes of chromatin regulators, including histone chaperones, to transcription sites can facilitate a local rearrangement of the chromatin structure to permit the passage of RNA Pol II (for reviews, see References 31 and 180). Additionally, these factors can help regulate histone exchange to maintain chromatin integrity during transcription elongation (181, 182). One mechanism by which this process occurs is that histone chaperones can handle and buffer histones displaced ahead of the polymerase, thereby functioning as a so-called histone sink (183). Indeed, several histone chaperones have been implicated in accepting H2A–H2B dimers to facilitate transcription factor binding; these include yeast Nap1 and nucleoplasmin (184, 185), human FACT (58), and nucleolin (26). Following the passage of RNA Pol II, the reassembly of nucleosomes restores the chromatin structure, preventing cryptic transcription; ASF1, FACT, and Spt6 may facilitate this process (58, 186, 187). 506

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The targeting of histone chaperones to transcription sites may occur through interactions with the transcriptional machinery or transcription-associated chromatin marks by the use of the adapter domains described above. For example, human Spt6 and HIRA have been found in complex with RNA Pol II (112, 188), and ASF1 associates with TAFII250, the largest subunit of the TFIID transcription factor (189). Finally, interactions between histone chaperones and chromatin remodelers may recruit histone chaperones to transcription sites, as demonstrated by FACT and the CHD1 chromatin remodeler (190). Thus, similarly to replication and repair, transcription represents another transient disruption to the chromatin organization and another window of opportunity to either maintain or alter the chromatin landscape. Here we consider the role of histone chaperones in facilitating these processes, including the reassembly of nucleosomes via a combination of evicted parental and newly synthesized histones to restore the chromatin organization. This balance, if perturbed, may slow down processes that reestablish chromatin marks at transcription sites that dictate genome function. This possibility suggests that regulation of histone chaperone function, to achieve timely and efficient handling of histones, in conjunction with histone-modifying enzymes may help control and maintain the timely execution of the specific expression profile that dictates cell identity.

DISCUSSION AND PERSPECTIVES This review addresses the definition of histone chaperones and their selectivity for cognate histones. Along with structural data and evolutionary studies, the use of complementary in vitro and in vivo assays enabled the elucidation of several functional aspects of histone chaperones, including their roles in histone metabolism, namely storage, buffering, nuclear import, deposition, and degradation. By interfacing with additional partners, adapter

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domains can regulate histone chaperone activity through recruitment to particular genomic loci or during specific biological processes. Together, these observations at the molecular and cellular levels enabled the placement of various histone chaperones in an escort network that shuttles histones throughout their cellular life and affects all aspects of histone dynamics.


Histone Chaperone Integration at the Organism Level During Development and Reprogramming The role of histone chaperones in the disruption of the chromatin organization intimately links these proteins with development and reprogramming (for a review, see Reference 42). The role in development is illustrated by evidence that knockout mice for several histone chaperones, including HIRA, DAXX, ASF1a, and CAF-1 p150, are embryonic lethal (Table 2) (191–195; for ASF1b, see http://www.informatics.jax.org). This effect may arise from improper placement of particular histone variants over space and time, at either a defined developmental stage or a specific genomic location. Indeed, in Drosophila and in mice, after fertilization but before the first round of replication, H3.3 is deposited globally in the paternal chromatin (196), a process that requires HIRA (197). Furthermore, in the early development of X. laevis, H3.3 expression peaks at gastrulation and HIRA promotes its deposition. Interfering with morpholinos to titrate out either HIRA or H3.3 impairs normal development by impeding progression through late gastrulation and affecting mesoderm induction. Interestingly, the morpholino titration of all H3 causes defects at a very early gastrulation stage (198). The most dramatic effect is observed with a dominant-negative strategy targeting CAF-1. This process causes early developmental arrest at the midblastula transition (30). Additionally, the reprogramming of somatic cell nuclei by oocytes illustrates that HIRA-dependent H3.3 deposition is necessary during global changes in transcription that accompany changes in cell fate (199). Thus,

Table 2 Histone chaperone knockout studies in mouse and corresponding phenotype Histone chaperone

Phenotype

Reference

ASF1a

Embryonic lethal

ASF1b

Viable

195

p150 CAF-1

Embryonic lethal at 8–16-cell stage; abnormal PCH

191

HIRA

Embryonic lethal at E11; abnormal gastrulation

192

http://www.informatics. jax.org

DAXX

Embryonic lethal at E9.5

194

ATRX

Embryonic lethal at E9.5 pc; abnormal trophoblast development

193

Abbreviations: ASF1, antisilencing function 1; ATRX, α-thalassemia/mental retardation X-linked; CAF-1, chromatin assembly factor 1; DAXX, death domain–associated protein; E, embryonic day; HIRA, histone regulator A; PCH, pericentric heterochromatin; pc, postcoitus.

histone chaperones not only help maintain chromatin organization during normal lineage propagation, but also help facilitate changes in the chromatin landscape that enable different expression profiles to regulate developmental programs.

Histone Chaperone Misfunction and Disease Several studies recently identified a connection between histone chaperones and disease (for a review, see Reference 82). Evidence for this finding is that mutations in DAXX and ATRX appear in 44% of pediatric glioblastoma tumor samples (200). These mutations may cause errors in the timing and placement of particular histone variants. Also, the expression level of histone chaperones can affect cell fate, as illustrated by research showing that human ASF1b, but not ASF1a, has a major role in proliferation and is a marker for breast cancer (100), having prognostic value for metastasis (201). Thus, histone chaperones could represent new opportunities in drug discovery, both in prognosis and as therapeutic targets. www.annualreviews.org • Histone Chaperones

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Questions About Histone Chaperones for Future Perspectives


Based on the current knowledge as discussed in this review, new interesting questions have arisen. How are histone chaperones regulated in terms of their expression and availability during the cell cycle? In this respect, the role of histone chaperones in their own disposal remains to be explored, and how this may link with histones that are marked for disposal or those that are to be protected. How does HJURP specifically target centromeric chromatin, and what is the role of dimerization of various histone chaperones in depositing histones? In these areas,

structural analyses with additional (full-length) partners are needed to better understand the molecular basis for these interactions and to establish larger complexes, perhaps in combination with mass spectrometry approaches to identify interactions between large complexes at the single-residue level (202). The link between histone chaperones, development, and pathology is an area that will continue to receive much attention, will shed more light on the role of histone chaperones in the maintenance of genome integrity and function, and will find applications in drug discovery for disease treatment.

SUMMARY POINTS 1. Histone chaperones are involved in histone transfer but are not necessarily part of the final product. 2. Histone chaperones escort histones throughout their cellular life in all aspects of histone metabolism, including regulation of their provision, their placement within chromatin, eviction, and degradation. 3. Histone chaperone binding to histones and variant selectivity have been illuminated by structural studies. 4. Histone chaperones provide interfaces that allow their recruitment to particular genomic loci or that link to specific biological processes. 5. Histone chaperones operate in an escort network and are implicated in DNA metabolic processes such as replication, repair, and transcription. Future studies should investigate rescue through cross talk with other chaperones. 6. The role of histone chaperones in development and disease is an area of interest.

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 thank Dominique Ray-Gallet and Marcus Buschbeck for critical reading of the manuscript. The authors acknowledge their affiliation with PSL, Sorbonne University. G.A.’s laboratory is supported by La Ligue contre le Cancer (Equipe Labellisée and postdoctoral fellowship to Z.A.G-L.), the European Commission Network of Excellence EpiGeneSys (HEALTH-F4-2010-257082), ERC Advanced Grant 2009-AdG_20090506 “Eccentric,” the European Commission largescale integrating project FP7_HEALTH-2010-259743 “MODHEP,” ANR “ChromaTin” ANR10-BLAN-1326-03, ANR-11-LABX-0044_DEEP and ANR-10-IDEX-0001-02 PSL, ANR “CHAPINHIB,” ANR-12-BSV5-0022-02, and Aviesan–ITMO cancer project “Epigenomics of Breast Cancer.” 508

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Contents

Annual Review of Biochemistry Volume 83, 2014


Journeys in Science: Glycobiology and Other Paths Raymond A. Dwek p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1 Lipids and Extracellular Materials William Dowhan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p45 Topological Regulation of Lipid Balance in Cells Guillaume Drin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p51 Lipidomics: Analysis of the Lipid Composition of Cells and Subcellular Organelles by Electrospray Ionization Mass Spectrometry Britta Brugger ¨ p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p79 Biosynthesis and Export of Bacterial Lipopolysaccharides Chris Whitfield and M. Stephen Trent p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p99 Demystifying Heparan Sulfate–Protein Interactions Ding Xu and Jeffrey D. Esko p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 129 Dynamics and Timekeeping in Biological Systems Christopher M. Dobson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 159 Metabolic and Nontranscriptional Circadian Clocks: Eukaryotes Akhilesh B. Reddy and Guillaume Rey p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 165 Interactive Features of Proteins Composing Eukaryotic Circadian Clocks Brian R. Crane and Michael W. Young p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 191 Metabolic Compensation and Circadian Resilience in Prokaryotic Cyanobacteria Carl Hirschie Johnson and Martin Egli p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 221 Activity-Based Profiling of Proteases Laura E. Sanman and Matthew Bogyo p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 249 Asymmetry of Single Cells and Where That Leads Mark S. Bretscher p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 275 Bringing Dynamic Molecular Machines into Focus by Methyl-TROSY NMR Rina Rosenzweig and Lewis E. Kay p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 291

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Chlorophyll Modifications and Their Spectral Extension in Oxygenic Photosynthesis Min Chen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 317 Enzyme Inhibitor Discovery by Activity-Based Protein Profiling Micah J. Niphakis and Benjamin F. Cravatt p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 341 Expanding and Reprogramming the Genetic Code of Cells and Animals Jason W. Chin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 379 Genome Engineering with Targetable Nucleases Dana Carroll p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 409 Annu. Rev. Biochem. 2014.83:487-517. Downloaded from www.annualreviews.org by Seattle University on 06/08/14. For personal use only.

Hierarchy of RNA Functional Dynamics Anthony M. Mustoe, Charles L. Brooks, and Hashim M. Al-Hashimi p p p p p p p p p p p p p p p p p p 441 High-Resolution Structure of the Eukaryotic 80S Ribosome Gulnara Yusupova and Marat Yusupov p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 467 Histone Chaperones: Assisting Histone Traffic and Nucleosome Dynamics Zachary A. Gurard-Levin, Jean-Pierre Quivy, and Geneviève Almouzni p p p p p p p p p p p p p p 487 Human RecQ Helicases in DNA Repair, Recombination, and Replication Deborah L. Croteau, Venkateswarlu Popuri, Patricia L. Opresko, and Vilhelm A. Bohr p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 519 Intrinsically Disordered Proteins and Intrinsically Disordered Protein Regions Christopher J. Oldfield and A. Keith Dunker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 553 Mechanism and Function of Oxidative Reversal of DNA and RNA Methylation Li Shen, Chun-Xiao Song, Chuan He, and Yi Zhang p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 585 Progress Toward Synthetic Cells J. Craig Blain and Jack W. Szostak p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 615 PTEN Carolyn A. Worby and Jack E. Dixon p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 641 Regulating the Chromatin Landscape: Structural and Mechanistic Perspectives Blaine Bartholomew p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 671 RNA Helicase Proteins as Chaperones and Remodelers Inga Jarmoskaite and Rick Russell p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 697

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Contents

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ARI

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Selection-Based Discovery of Druglike Macrocyclic Peptides Toby Passioura, Takayuki Katoh, Yuki Goto, and Hiroaki Suga p p p p p p p p p p p p p p p p p p p p p p p p p 727 Small Proteins Can No Longer Be Ignored Gisela Storz, Yuri I. Wolf, and Kumaran S. Ramamurthi p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 753 The Scanning Mechanism of Eukaryotic Translation Initiation Alan G. Hinnebusch p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 779 Understanding Nucleic Acid–Ion Interactions Jan Lipfert, Sebastian Doniach, Rhiju Das, and Daniel Herschlag p p p p p p p p p p p p p p p p p p p p p p 813


Indexes Cumulative Index of Contributing Authors, Volumes 79–83 p p p p p p p p p p p p p p p p p p p p p p p p p p p 843 Cumulative Index of Article Titles, Volumes 79–83 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 847 Errata An online log of corrections to Annual Review of Biochemistry articles may be found at http://www.annualreviews.org/errata/biochem

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Annual Reviews It’s about time. Your time. It’s time well spent.

New From Annual Reviews:

Annual Review of Statistics and Its Application Volume 1 • Online January 2014 • http://statistics.annualreviews.org

Editor: Stephen E. Fienberg, Carnegie Mellon University


Associate Editors: Nancy Reid, University of Toronto Stephen M. Stigler, University of Chicago The Annual Review of Statistics and Its Application aims to inform statisticians and quantitative methodologists, as well as all scientists and users of statistics about major methodological advances and the computational tools that allow for their implementation. It will include developments in the field of statistics, including theoretical statistical underpinnings of new methodology, as well as developments in specific application domains such as biostatistics and bioinformatics, economics, machine learning, psychology, sociology, and aspects of the physical sciences.

Complimentary online access to the first volume will be available until January 2015. table of contents:

• What Is Statistics? Stephen E. Fienberg • A Systematic Statistical Approach to Evaluating Evidence from Observational Studies, David Madigan, Paul E. Stang, Jesse A. Berlin, Martijn Schuemie, J. Marc Overhage, Marc A. Suchard, Bill Dumouchel, Abraham G. Hartzema, Patrick B. Ryan

• High-Dimensional Statistics with a View Toward Applications in Biology, Peter Bühlmann, Markus Kalisch, Lukas Meier • Next-Generation Statistical Genetics: Modeling, Penalization, and Optimization in High-Dimensional Data, Kenneth Lange, Jeanette C. Papp, Janet S. Sinsheimer, Eric M. Sobel

• The Role of Statistics in the Discovery of a Higgs Boson, David A. van Dyk

• Breaking Bad: Two Decades of Life-Course Data Analysis in Criminology, Developmental Psychology, and Beyond, Elena A. Erosheva, Ross L. Matsueda, Donatello Telesca

• Brain Imaging Analysis, F. DuBois Bowman

• Event History Analysis, Niels Keiding

• Statistics and Climate, Peter Guttorp

• Statistical Evaluation of Forensic DNA Profile Evidence, Christopher D. Steele, David J. Balding

• Climate Simulators and Climate Projections, Jonathan Rougier, Michael Goldstein • Probabilistic Forecasting, Tilmann Gneiting, Matthias Katzfuss • Bayesian Computational Tools, Christian P. Robert • Bayesian Computation Via Markov Chain Monte Carlo, Radu V. Craiu, Jeffrey S. Rosenthal • Build, Compute, Critique, Repeat: Data Analysis with Latent Variable Models, David M. Blei • Structured Regularizers for High-Dimensional Problems: Statistical and Computational Issues, Martin J. Wainwright

• Using League Table Rankings in Public Policy Formation: Statistical Issues, Harvey Goldstein • Statistical Ecology, Ruth King • Estimating the Number of Species in Microbial Diversity Studies, John Bunge, Amy Willis, Fiona Walsh • Dynamic Treatment Regimes, Bibhas Chakraborty, Susan A. Murphy • Statistics and Related Topics in Single-Molecule Biophysics, Hong Qian, S.C. Kou • Statistics and Quantitative Risk Management for Banking and Insurance, Paul Embrechts, Marius Hofert

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Annual Reviews | Connect With Our Experts Tel: 800.523.8635 (us/can) | Tel: 650.493.4400 | Fax: 650.424.0910 | Email: [email protected]

Histone core modifications regulating nucleosome structure and dynamics.

Enzymic acetylation of nucleosome histone.

Histone H3 disulfide dimers and nucleosome structure.

Histone chaperone-mediated nucleosome assembly process.

Effects of DNA sequence and histone-histone interactions on nucleosome placement.

Dissecting the Molecular Roles of Histone Chaperones in Histone Acetylation by Type B Histone Acetyltransferases (HAT-B).

Partial Unwrapping and Histone Tail Dynamics in Nucleosome Revealed by Coarse-Grained Molecular Simulations.

Acetylation of histone H3 at lysine 64 regulates nucleosome dynamics and facilitates transcription.

Structure and function of human histone H3.Y nucleosome.

SNF.

Structural insights into the histone H1-nucleosome complex.

Histone hyperacetylation can induce unfolding of the nucleosome core particle.

Nucleosome Dancing at the Tempo of Histone Tail Acetylation.

Histone packing in the nucleosome core particle of chromatin.

RNase P protein subunit Rpp29 represses histone H3.3 nucleosome deposition.

Crosslinked histone octamer as a model of the nucleosome core.

Histone contributions to the structure of DNA in the nucleosome.

DNA damage by histone radicals in nucleosome core particles.

Nucleosome Histone Tail Conformation and Dynamics: Impacts of Lysine Acetylation and a Nearby Minor Groove Benzo[a]pyrene-Derived Lesion.

The histone chaperone complex HIR maintains nucleosome occupancy and counterbalances impaired histone deposition in CAF-1 complex mutants.

Regulation of chaperone binding and nucleosome dynamics by key residues within the globular domain of histone H3.

Histone methylation has dynamics distinct from those of histone acetylation in cell cycle reentry from quiescence.

Histone H3 variants and their chaperones during development and disease: contributing to epigenetic control.

Histone chaperones in Arabidopsis and rice: genome-wide identification, phylogeny, architecture and transcriptional regulation.