Protein-priming of DNA replication.

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PROTEIN-PRIMING OF DNA REPLICATION Margarita Salas Centro de Biologfa Molecular (CSIC-UAM), Universidad Aut6noma, Canto Blanco, 28049 Madrid, Spai n .

KEY WORDS:

adenovirus, bacteriophage 4>29, DNA polymerase, initiation of replication, terminal protein.

CONTENTS PERSPECTIVES AND SUMMARY . . ...... . . . . . . .......................... . . . . . . ...... ... . . . . ...

40

ADENOVIRUS DNA REPLICATION . . . . . . . . . . . . .................. . . . . . . . . . . . . . . . . . . ... . . . . . . . .

41

�;;,t��:�� :�:o' :::::::::::::::::::::: : ::::::::::::::::::::::::::::::::::::::::::: : : : ::::::::: Viral Proteins Required for Replication . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . Cell�lar Protei�s Required for Replication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Repitcatwn OT/gm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Replication of the Nontemplate Strand . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

.

.

43 43 43

44

45 46

.

47 48 48 48 52 53 54

BACTERIOPHAGE PRDI DNA REPLICATION . ...... . . . . . ..... . . . . . . . . . .. . . . . . . . ... . . ... . . .

55

BACTERIOPHAGE Cp-l DNA REPLICATION . . . . . . . . . . . ...... ...... ......... . . . ...... . . ... .

56

BACTERIOPHAGE 4>29 DNA REPLICATION . . . . . . . . . . . . . . . . . . . . . . . ... . . . . . . . .... ...... . . . .

Replication in Vivo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Replication in Vitro . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . Viral Proteins Essential for the Initiation of Replication . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . Other Viral Proteins Involved in Replication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Repitcatwn OT/gm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Replication of the Nontemplate Strand . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . .

BACTERIOPHAGE HB-3 TP .. . . . . . . .................. . . . . . . . . . . . . . . ........ . . . . . . . . . . . . ...... . .. .

56

TERMINAL PROTEINS IN LINEAR PLASMIDS . . . . . . . . . . .... . .. . ...... . .. . . . . . . . . . .... . . . .

56

.

. . . . . . . . .

59

GENOME-LINKED PROTEINS OF RNA VIRUSES ................... ............ . . ....... .

60

CONCLUSION

63

HEPADNAVIRUS TP .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

.

. . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

39

0066-4154/91/0701-0039$02. 00

40

SALAS

PERSPECTIVES AND SUMMARY The fact that all known DNA polymerases require a free

3' -OH group for

chain elongation raised the problem of how replication is initiated. A general mechanism to initiate replication is the formation of an RNA primer syn thesized by specific enzymes, the primases (1); a primer can be used in the case of circular DNA molecules or linear DNAs that are converted either to


circular or concatemeric molecules. An alternative mechanism for the initia tion of replication is the specific nicking of one of the strands of a circular double-stranded DNA, producing a free

3' -OH group used for elongation (1).

In the case of linear DNAs that remain as such for replication, RNA priming cannot be used for the initiation of replication since, after removal of the RNA, it is not possible to fill the gap that would result at the

5' -ends of the

newly synthesized DNA chain. Some linear DNA molecules contain a palindromic nucleotide sequencc at the

3' -end which allows the formation of 3' -OH group for elongation (1, 2). The finding of specific proteins covalently linked to the 5' -ends of viral linear

a hairpin structure that provides the

double-stranded DNAs, the so-called terminal proteins (TP), led to the dis covery of a new mechanism for the initiation of replication in which the

primer, instead of being the 3' -OH group of a nucleotide provided by RNA or DNA molecules, is the

OH group of a serine, threonine, or tyrosine residue of

the TP. The protein-priming mechanism of DNA replication, as unravelled from the development of in vitro replication systems with purified proteins, mainly in the case of adenovirus and bacteriophage 4>29 DNAs, is summarized in Figure

1 . Specific initiation protein(s) (see Table 1 ) interact with the origin of

replication, giving rise to the unwinding of the double-helix to expose a region of single-stranded DNA. A free molecule of the TP forms a complex with a specific DNA polymerase, and this complex interacts with the origins of replication by recognition of the parental TP and specific sequences at either DNA end. In the presence of the dNTP corresponding to the

5' -termini,

the DNA polymerase catalyzes thc formation of a covalent bond between the dNMP and the

OH group of a specific serine, threonine, or tyrosine in the TP.

After this initiation step, the same DNA polymerase catalyzes chain elonga tion by a strand-displacement mechanism, with the concomitant removal of the initiation protein(s) and the binding of SSB protein to the parental single-strand that is being displaced. Replication is continuous without the need of Okazaki fragments. No other accessory proteins seem to be needed to produce full-length DNA synthesis, except a topoisomerase I activity in the case of adenovirus. Indeed, it has been shown that the 4>29 DNA polymerase has helicase-like activity and is able to produce strand displacement. For the replication of the nontemplate (displaced) strand, two models have

PROTEIN-PRIMED REPLICATION Table 1

Proteins involved in the replication of TP-containing DNA viruses

Virus


41

Priming protein

DNA polymerase

Initiation proteins

Adenovirus

pTP

Ad pol

NFl, NFIII

Phage �29

p3

p2

p6

Phage PRDI

p8

pi

SSB

Topoisomerase

DBP

NFII

p5 p12

been proposed, In one, first presented by Daniell (3) , complete displacement of the parental strand is assumed to occur with the formation of a "panhandle" structure by hybridization of the self-complementary terminal sequences that provide a replication origin identical to the one present at the ends of double-stranded DNA. In the other, indicated in Figure I, before displace ment synthesis initiated at one end of the DNA is completed, initiation of replicatiolll occurs at the other end, giving rise to the so-called type-I mole cules with two single-stranded tails. When the two replication forks meet, separation occurs, producing type-II molecules. Replication is completed from the latter molecules with the concomitant removal of the SSB protein; once full-length synthesis has been achieved, the DNA polymerase will be recycled by joining another TP and starting a new initiation event. In this review I deal not only with the systems that have been shown to replicate by protein-priming, such as adenovirus and bacteriophages cp29, PRD 1 , and Cp- 1 , but also with linear double-stranded DNA plasmids that contain a TP and are likely to replicate by protein-priming. I also discuss the hepadnaviruses that contain TP at the 5' end of one of the strands of the circular DNA, which, it has been suggested, may be involved in a special protein-priming mechanism for reverse transcription. In addition, I review the TP-containing RNA viruses and their possible role in the initiation of replica tion. Recent reviews are available for adenovirus DNA replication (4-7), bacteriophages cp29, PRD 1 , and Cp-1 DNA replication (8, 9), eukaryotic linear plasmids ( 1 0) , hepadnavirus replication ( 1 1 , 1 2) , and TP-containing RNA viruses ( 1 2- 14). ADENOVIRUS DNA REPLICATION The human adenovirus DNA genome consists of a linear double-stranded DNA of 35-36 kb with a 1 03-1 63-bp-Iong inverted terminal repetition (lTR) ( 1 5-17). The finding of circular molecules and concatemers in the DNA isolated from viral particles, and their conversion into linear, unit-length DNA after protease treatment, suggested the existence of protein at the ends of adenovirus DNA ( 1 8). In addition, the infectivity of the adenovirus 5 DNA-protein complex was greatly reduced after treatment with pronase ( 19).

42

SALAS

1

orl·lnlUaUon proteln(S complex

INITIATION


duplex opening f priming

[� -29 DNA molecules containing parental TP at only one DNA end were constructed ( 1 86). No replication in B. subtilis protoplasts was obtained, suggesting that the fully displaced nontemplate DNA strand is not an active template for replication in vivo. In agreement with the in vivo results, when replication of 4>29 DNA-TP was studied in the purified in vitro system , a significant amount of type-II replicative intermediates was found at an incuba tion time at which no synthesis of full-length 1J29 DNA was detected (c. Gutierrez, J. M. Sogo, M . Salas, unpublished results). These results indicate that the appearance of type-II replicative intermediates does not require synthesis of full-length DNA and displacement of the nontemplate strand;

PROTEIN-PRIMED REPLICATION

55

rather the results support the model in which initiation of replication can occur from both DNA ends, while type-II molecules are produced by separation of the two displacement forks when they meet.


BACTERIOPHAGE PRD 1 DNA REPLICATION B acteriophage PRDI is a member of a family of lipid-containing phages (reviewed in 200) that infect a variety of Gram-negative bacteria including Escherichia coli and Salmonella typhimurium. The PRDI genome is a linear, double-stranded DNA of about 14,700 bp with a TP linked to the 5' ends (20 1 ). Other lipid-containing phages closely related to PRDI are PR3 , PR4, PR5, PR722 , and L 1 7 (200). The DNA of all these phages have an ITR 1 10-1 1 1 bp long (202, 203). Two very early genes,V I I I and I, located at the left-hand terminus of PRD 1 DNA, are involved in the synthesis of the viral DNA (204) . Gene VIII codes for the TP p8 of 259 amino acids ( 1 65,20 1 , 205,206). Gene I encodes the DNA polymerase pI, of 553 amino acids ( 1 65, 166). Gene XII, the third known very early gene, located at the right-hand terminus,encodes protein p 1 2,of 1 60 amino acids, involved in the shut- �ff of early protein synthesis and in the synthesis of the viral DNA (204,207,208). Protein p l 2 has been purified and shown to have affinity for single-stranded DNA and, to a lesser extent, for double-stranded DNA. The purified protein p l 2 stimulates replica tion when cfJ29 DNA-TP is used as template (353) to an extent similar to the cfJ29 singll;-stranded DNA binding protein p5 ( 1 97 , 352). When extracts from PRDI-infected S. typhimurium were incubated with [a-32P]dGTP, a labeled protein with the electrophoretic mobility of the TP was found (20 1). This reaction required genes I and VIII as the only two viral genes (205) . Synthesis of full-length PRDI DNA was obtained,starting at or near the ends of the DNA molecules (209). The covalent linkage between p8 and dGMP was shown to be a phosphoester bond with tyrosine (205). The use of extracts from E. coli cells temperature-sensitive for replication genes suggested that the host replication complex may be needed for the initiation reaction (205; reviewed in 9) . Gene VIII has been recently cloned and protein p8 was overproduced and purified in a functional form (2 1 0). No substantial sequence homology was found between the PRD I TP and those of cfJ29 and Nf. However,when the hydropathic profiles of the three TPs were compared they were superimposable at the C-terminal portion, suggesting a functional homology at the carboxyl end of the three proteins. Taking these results into account as well as the fact that the linking site in the cfJ29 TP is at the serine residue at position 232 ( 1 2 1 ),it has been proposed that the linking site in the PRD I -TP is the tyrosine residue 226 (206).

56

SALAS


BACTERIOPHAGE Cp- l DNA REPLICATION The Streptococcus pneumoniae phage Cp- l contains a linear, double-stranded DNA of about 1 2 X 1 06 daltons with a TP of 28 ,000 daltons covalently linked to the two 5 ' -ends (21 1 ). The Cp- l -related phages Cp-5 and Cp-7 also have a TP (2 1 2) . Phage Cp- l , Cp-5, and Cp-7 DNAs have a long ITR of 236, 343 , and 347 bp, respectively (2 1 3 , 2 1 4) . Incubation of extracts o f Cp- l -infected S . pneumoniae with [a_32p] dATP produced a labeled protein with the electrophoretic mobility of the TP. Treatment of the 32P-Iabeled protein with piperidine released 5 I dAMP, in dicating the formation of a covalent complex between the TP and dAMP. Moreover, the TP-dAMP complex could be elongated in vitro by addition of the four dNTPs (2 1 5). The linkage between the TP and dAMP is a phosphoes ter bond with threonine (2 1 5 ) . BACTERIOPHAGE HB-3 TP B acteriophage HB-3 is a member of a family of temperate phages from S. pneumoniae (2 1 6) . The HB-3 genome consists in a linear, double-stranded DNA of about 40 kb (21 7). Other members of the same family are phages HB-623 and HB-746. A protein of 23 ,000 daltons was shown to be covalently linked at the 5 I -ends of the DNA of these phages ( 2 1 7). The function of the TP, it has been speculated, may be to protect the DNA molecules during their transport from the membrane to the insertion region of the host bacteria, or it may serve a function during integration. In this relation , the free linear double-stranded T-DNA molecules from Agrobacterium tumefaciens become covalently linked through the 5' -ends to the VirD2 protein before these T-DNA molecules are transferred to the genome of the host plant (2 1 8 , 2 1 9) . The possible role o f these 5 I -linked proteins i n DNA replication remains to be determined; a model, the invertron, has been recently proposed, suggesting a role in replication and integration (220). TERMINAL PROTEINS IN LINEAR PLASMIDS A variety of linear plasmids have been isolated in the past 1 0 years from bacteria, fungi, and higher plants. In most of the cases long ITRs have been characterized, and in many of them evidence for the existence of a TP linked at the 5 ' -ends of the DNA has been reported. Table 2 shows a summary of the different linear plasmids isolated and their sources , as well as of the characterization of TP and ITR. Only relevant features not indicated in the table are described below. The yeast Kluyveromyces lactis contains two linear killer plasmids,pGKLI

PROTEIN-PRIMED REPLICATION Table 2

57

Linear plasmids with TP and ITR

Linear plasmid

Source

Size

ITR

TP

Refs.

Bacteria pSLA I

Sireptomyees rochei

1 7 kb

nd

yes

(22 1 , 222)

pSLA2

Sireptomyees rochei

1 7 kb

6 1 4 bp

yes

( 22 1 , 222)

pSCL

Streptomyces clavuligerus

yes

yes

(223)

pSCPI

Streptomyces coelicolor

70 kb

yes

(224 -226)

1 2 kb 350 kb


Yeast pGKL l

Kluyveromyees lactis

8 . 9 kb

202 bp

28 kDa

(227-23 1 )

pGKL2

Kluyveromyces lactis

1 3.4 kb

1 82- 1 84 bp

36 kDa

( 1 69 , 227-23 1 )

pSKL

Saccharomyces klu)'veri

1 4 . 2 kb

483 bp

yes

(236)

Fungi pAI2

Ascobolus immersus

5 . 6 kb

=700 bp

yes

(237, 238)

pMC32

Morchella coniea

6 kb

=750 bp

nd

(239)

pCF637

Ceraloeystis jimbriata

8 . 2 kb

nd

yes

(240)

CeralOcystis fimbriata

6 kb

nd

( 24 1 )

pRS64

Rhizoctonia solani

2.6 kb

750 bp nd

nd

( 2 42 )

pEM

Agaricus bitorquis

7.3 kb

= 1 kb

nd

(243)

pMP)

Agaricus bitorquis

3 . 6 kb

nd

nd

(243)

kal DNA

Neurospora illlermedia

9 kb

1 36 1 bp

yes

(244, 245)

pFOXC2

Fusarium oxysporum

50 bp

yes

( 1 0 , 246)

pCI K I

Claviceps

purpurea

1 . 9 kb

pFQ50 1

Fusarium

6. 7 kb

327 bp

yes

(247)

pFSCI

solani Lsp.

9 . 2 kb

1 2 1 1 bp

�O kDa

(248 , 249)

pFSC2

Fusarium solani f.sp .

8.3 kb

1 027 bp

80 kDa

(248, 249)

nd

yes

(250)

nd

yes

(250)

I I kb

nd

ycs

(25 1 )

cucurbitae cucurbitae pLPO I

Pleurotus ostrealus

pLP02

Pleurotus ostreatus

pLLEI

Lentillus edodes

1 0 kb 9.4 kb

Higher plants

Brassica campestris

1 1 . 5 kb

325 bp

yes

(252)

1 0.4 kb plasmid

Beta marilima

1 0.4 kb

nd

nd

(253)

N- J

Sorghum bieolor

5.7 kb

nd

nd

(254, 255)

N-2

Sorghum bieolor

5 . 3 kb

nd

nd

(254, 255)

S- I

Zea mil)'S L .

6.4 kb

208 bp

yes

(256, 257 , 260)

S-2

Zea nlilYS L .

5.4 k b

2 0 8 bp

yes

(256, 257, 260)

2.35 kb

1 70 bp

yes

(25 8 , 259, 260)

1 1 . 5 kb plasmid

n

Zea mays

L.

and pGKL 2 . Plasmid pGKL2,

required for the maintenance of pGKL l in the

cell, can replicate in the absence of pGKL l . Both plasmids replicate by a

type-I and type-II molecules were found (232). ORFI in plasmid pGKLl (1 61 , 233) and ORF2 in pGKL2 ( 1 69) contain three regions of amino acid homol ogy that are found at the carboxyl part of a-Iikc DNA polymerases . By analogy with the viral systems it is likely that the TPs of pGKL l and pGKL2 are plasmid-encoded products. Since strand-displacement mechanism and both


58

SALAS

functions have been assigned to the four ORFs of pGKL l , it is possible that the TPs for both plasmids are encoded in pGKL2. A DNA-binding protein has been detected in extracts of yeast cells carrying pGKL I and pGKL2. B y deletion mapping and DNase I footprinting the binding occurs within the 202 bp ITR of pGKL l (D . McNeel , F. Tamanoi , personal communication) . This binding protein could be similar in function to protein p6 and factors NF-I and NF-III that bind to the replication origins of phage cf>29 and adenovirus, respectively, and stimulate the initiation of replication. When the pGKL plasmids were transferred into Saccharomyces cerevisiae, nonkiller transformants harboring pGKL2 and two new plasmids, F l and F2, of 7 . 8 kb and 3 .9 kb, respectively , were obtained. F2 was a linear DNA formed by a 5-kb deletion of the right part of pGKL l and has two different terminal structures. One end has a protein attached at the 5 ' terminus, whereas the two strands are linked together at the other end forming a hairpin structure. F l was an inverted dimer of F2, and it was thought to be generated from F2 by protein-priming and elongation by strand-displacement and to contain a TP at each 5 ' -end of the DNA (234) . By UV-irradiation of K. lactis containing pGKL l and pGKL2 . two deleted plasmids of pGKL l were found, pKI 92L and pK I 92S. They are linear and arose by a 6 . 5-kb deletion of the right part of pGKL l . The pK 1 92L is a palindromic plasmid of 4903 bp, consisting in a unique sequence of 2 1 5 bp and ITRs of 2344 bp. The pK l 92S was suggested to be a fold-back form of p K 1 92L, consisting of 2344 bases of double-stranded DNA and 2 1 5 unpaired nuc1eotides forming a hairpin structure. These findings suggested that pK 1 92L has the terminal structure of pGKL l , which is 202-bp ITRs and TP in both termini , and that p K 1 92S has this structure only at one end (235) . The 2 .4-kb left terminal fragment of pGKL l carried in the p K I 92 plasmids contained only part of the ORFI gene, encoding the putative DNA polymer ase required for the protein-primed replication . Segregation analysis showed that the two plasmids were maintained only in cells carrying pGKL l with the intact ORF l , as well as pGKL2, whereas plasmids F l and F2, which contain the complete ORF I from pGKL l , are stably maintained in cells harboring only pGKL2. These results suggest that, for the replication of thc pGKL l derived plasmids, the presence of the putative DNA polymerase encoded in ORFI is necessary and, therefore , that the putative DNA polymerase coded by pGKL2 does not function in the replication of pGKL l (235). If the TPs of pGKL l and pGKL2 form a specific complex with the corresponding DNA polymerase , this complex is likely to recognize specifically the different terminal nucleotide sequences present in pGKL I and pGKL2. Replication of plasmid pAI2 from Ascobolus immersus starts at the DNA ends ( 1 73 ) . A large ORF spanning 1 202 amino acids shares homology with the three conserved regions present in a-like DNA polymerases and in



59

putative DNA polymerases from linear plasmids ( 1 73). ORFI from the Claviceps purpurea plasmid pCIK I codifies for a protein of 1 097 amino acids, which is likely to be a DNA polymerase from the amino acid homology at the three regions conserved in a-like DNA polymerases and in the putative DNA polymerases from linear plasmids ( 1 74). The gene coding for the TP is unknown. Taking into account that in the case of the 29, has greatly contributed to the elucidation of the protein-priming mechanism of DNA replication. In all cases a specific DNA polymerase covalently links the 5 ' terminal dNMP to the OH group of a specific amino acid residue in the TP. In vitro systems have been developed also for the replication of bacteriophages PRD 1 and Cp- l , showing that they use a similar protein-priming mechanism fOf the initiation of replication. A


64

SALAS

TP has been characterized in most of the linear plasmids , and in the cases in which the DNA sequence is available, a putative DNA polymerase has been identified. Although in vitro systems are still lacking, it is very likely that linear plasmids also use the protein-priming mechanism for the initiation of replication. The TP of hepadnaviruses may function as a primer for the synthesis of minus-strand DNA , although direct evidence is still lacking. At the present time there is controversy as to the role of protein primers of the TP (VPg) linked at the 5 ' -end of RNA viruses , and further work is needed to answer this question . ACKNOWLEDGMENTS I thank all the authors who sent preprints and unpublished results of their work and my colleagues in the laboratory for many helpful discussions. I also thank Ms. Carmen Hermoso for efficiently typing the manuscript. Work in the author' s laboratory was supported by grants from the National Institutes of Health (5 RO l GM27242- 1 1) , Direccion General de Investigacion Cientifica y Tecnica (PB 87-0323) , and Fundaci6n Ramon Areces.

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PROTEIN-PRIMED REPLICAnON 30. Challberg , M. D . , Kelly, T. J. Jr. 1 98 1 . J. Viml. 38:272-77 3 1 . Stillman, B . W . , Lewis, J. B . , Chow,

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,

DNA replication.

Prokaryotic DNA replication.

Editorial. DNA replication.

Animal Mitochondrial DNA Replication.

Mutations and DNA replication.

DNA virus replication compartments.

Self-replication of DNA rings.

Defects of mitochondrial DNA replication.

Eukaryotic DNA replication complex.

Papillomavirus DNA replication.

DNA replication and beyond.

Eukaryotic DNA replication.

SnapShot: Origins of DNA replication.

Arrest of bacterial DNA replication.

Replication of polyoma DNA in isolated nuclei. V. Complementation of in vitro DNA replication.

DNA replication in Physarum polycephalum: bidirectional replication of DNA within replicons.

Chromatin dynamics during DNA replication.

Adeno-associated virus DNA replication.

Just-in-time DNA replication.

G1 cyclin driven DNA replication.

DNA Replication. Terminating the replisome.

Molecular biology: DNA replication reconstructed.

Adenovirus DNA replication in vitro.

Fidelity mechanisms in DNA replication.