Postreplicative Mismatch Repair Factors Are Recruited to Epstein-Barr Virus Replication Compartments

Abstract

The mismatch repair (MMR) system, highly conserved throughout evolution, corrects nucleotide mispairing that arise during cellular DNA replication. We report here that proliferating cell nuclear antigen (PCNA), the clamp loader complex (RF-C), and a series of MMR proteins like MSH-2, MSH-6, MLH1, and hPSM2 can be assembled to Epstein-Barr virus replication compartments, the sites of viral DNA synthesis. Levels of the DNA-bound form of PCNA increased with progression of viral productive replication. Bromodeoxyuridine-labeled chromatin immunodepletion analyses confirmed that PCNA is loaded onto newly synthesized viral DNA as well as BALF2 and BMRF1 viral proteins during lytic replication. Furthermore, the anti-PCNA, -MSH2, -MSH3, or -MSH6 antibodies could immunoprecipitate BMRF1 replication protein probably via the viral DNA genome. PCNA loading might trigger transfer of a series of host MMR proteins to the sites of viral DNA synthesis. The MMR factors might function for the repair of mismatches that arise during viral replication or act to inhibit recombination between moderately divergent (homologous) sequences. The mismatch repair (MMR) system, highly conserved throughout evolution, corrects nucleotide mispairing that arise during cellular DNA replication. We report here that proliferating cell nuclear antigen (PCNA), the clamp loader complex (RF-C), and a series of MMR proteins like MSH-2, MSH-6, MLH1, and hPSM2 can be assembled to Epstein-Barr virus replication compartments, the sites of viral DNA synthesis. Levels of the DNA-bound form of PCNA increased with progression of viral productive replication. Bromodeoxyuridine-labeled chromatin immunodepletion analyses confirmed that PCNA is loaded onto newly synthesized viral DNA as well as BALF2 and BMRF1 viral proteins during lytic replication. Furthermore, the anti-PCNA, -MSH2, -MSH3, or -MSH6 antibodies could immunoprecipitate BMRF1 replication protein probably via the viral DNA genome. PCNA loading might trigger transfer of a series of host MMR proteins to the sites of viral DNA synthesis. The MMR factors might function for the repair of mismatches that arise during viral replication or act to inhibit recombination between moderately divergent (homologous) sequences. Mismatch repair (MMR) 2The abbreviations used are: MMR, mismatch repair; MSH, MutS homolog; MLH, MutL homolog; PCNA, proliferating cell nuclear antigen; BrdUrd, 5-bromo-2′-deoxyuridine; RF-C, replication factor C; EBV, Epstein-Barr virus; Pipes, 1,4-piperazinediethanesulfonic acid; PBS, phosphate-buffered saline; PAA, phosphonoacetic acid. systems play a primary role in mutation avoidance by removing base-base and small insertion-deletion mismatches that arise during DNA replication (1Modrich P. Lahue R. Annu. Rev. Biochem. 1996; 65: 101-133Crossref PubMed Scopus (1337) Google Scholar). Prokaryotes and eukaryotes have evolved similar systems for repair (2Kunkel T.A. Erie D.A. Annu. Rev. Biochem. 2005; 74: 681-710Crossref PubMed Scopus (1023) Google Scholar) and in Escherichia coli MMR is initiated when MutS binds to mismatched DNA, possibly through its interaction with the β-clamp accessory protein that is required for processive DNA replication (3Lopez de Saro F.J. O'Donnell M. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 8376-8380Crossref PubMed Scopus (182) Google Scholar, 4Su S.S. Lahue R.S. Au K.G. Modrich P. J. Biol. Chem. 1988; 263: 6829-6835Abstract Full Text PDF PubMed Google Scholar, 5Jiricny J. Su S.S. Wood S.G. Modrich P. Nucleic Acids Res. 1988; 16: 7843-7853Crossref PubMed Scopus (75) Google Scholar, 6Parker B.O. Marinus M.G. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 1730-1734Crossref PubMed Scopus (184) Google Scholar). MutL binds to MutS to form MutS-MutL-DNA complexes that stimulate MutH binding and cleavage of unmethylated DNA strands at GATC sequences, either 5′ or 3′ of recognized mismatches. Exonucleases then chew away at the DNA beyond the mismatch site so that highly accurate DNA polymerase III can correctly re-synthesize the strand. In eukaryotes, mismatch recognition is accomplished by MSH2 (MutS homolog 2) forming a heterodimer with either MSH3 or MSH6 to bind to distinct but overlapping spectra of mismatches (7Kolodner R.D. Marsischky G.T. Curr. Opin. Genet. Dev. 1999; 9: 89-96Crossref PubMed Scopus (730) Google Scholar). In both the yeast Saccharomyces cerevisiae and humans, the repair of base-base mismatches appears to be solely dependent on MSH2-MSH6, whereas both MSH2-MSH6 and MSH2-MSH3 can participate in the repair of small (1 to 12-nucleotide) loop insertions. Currently, it is thought that MSH heterodimer binding to a mismatch triggers ATP-dependent steps that allow interactions with MLH (MutL homolog) heterodimers composed of MLH1-Pms1 or MLH1-MLH3 (7Kolodner R.D. Marsischky G.T. Curr. Opin. Genet. Dev. 1999; 9: 89-96Crossref PubMed Scopus (730) Google Scholar, 8Jiricny J. Nat. Genet. 2000; 24: 6-8Crossref PubMed Scopus (62) Google Scholar). No MutH homolog, however, has been identified in eukaryotes, and the exact details of strand discrimination and error removal are not known, although in both yeast and humans a number of other proteins have been implicated in MMR, including proliferating cell nuclear antigen (PCNA), replication factor C (RF-C), and DNA polymerases δ and ϵ (9Tran H.T. Gordenin D.A. Resnick M.A. Mol. Cell. Biol. 1999; 19: 2000-2007Crossref PubMed Scopus (182) Google Scholar, 10Longley M.J. Pierce A.J. Modrich P. J. Biol. 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A. 1997; 94: 7487-7492Crossref PubMed Scopus (334) Google Scholar). PCNA was originally characterized as a DNA sliding clamp for replicative DNA polymerases, but subsequent studies have revealed its striking ability to interact with multiple partners involved in several meta-bolic pathways (17Maga G. Hubscher U. J. Cell Sci. 2003; 116: 3051-3060Crossref PubMed Scopus (877) Google Scholar). One role of PCNA in MMR is mediated by interactions with MSH2-MSH6 or MSH2-MSH3 complexes through PCNA interaction motifs present in MSH6 and MSH3 (18Clark A.B. Valle F. Drotschmann K. Gary R.K. Kunkel T.A. J. Biol. Chem. 2000; 275: 36498-36501Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar, 19Flores-Rozas H. Clark D. Kolodner R.D. Nat. Genet. 2000; 26: 375-378Crossref PubMed Scopus (196) Google Scholar, 20Kleczkowska H.E. Marra G. Lettieri T. Jiricny J. Genes Dev. 2001; 15: 724-736Crossref PubMed Scopus (198) Google Scholar). PCNA increases the in vitro mispair binding specificity of the MSH2-MSH6 complex, and this is eliminated by amino acid substitutions in PCNA that cause MMR defects (19Flores-Rozas H. Clark D. Kolodner R.D. Nat. Genet. 2000; 26: 375-378Crossref PubMed Scopus (196) Google Scholar). It has been suggested that MMR may be coupled to DNA replication through the physical interaction between MutS family proteins and PCNA and through co-localization of PCNA with MSH6 and MSH3 in replication foci (18Clark A.B. Valle F. Drotschmann K. Gary R.K. Kunkel T.A. J. Biol. Chem. 2000; 275: 36498-36501Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar, 19Flores-Rozas H. Clark D. Kolodner R.D. Nat. Genet. 2000; 26: 375-378Crossref PubMed Scopus (196) Google Scholar, 20Kleczkowska H.E. Marra G. Lettieri T. Jiricny J. Genes Dev. 2001; 15: 724-736Crossref PubMed Scopus (198) Google Scholar). The PCNA-MSH6-MSH2 complex can form a stable ternary complex with fully base-paired DNA, but when a mispair is present, PCNA is excluded from the complex in an ATP-dependent fashion (21Lau P.J. Kolodner R.D. J. Biol. Chem. 2003; 278: 14-17Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar), suggesting that MSH2-MSH6 binds to PCNA to search of mispairs on newly replicated DNA and is then transferred from PCNA to the mispaired bases. PCNA with RF-C, between and and an that is by present, its function is to PCNA onto DNA J. F. H. J. N. O'Donnell M. J. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar, N. J. F. D. J. O'Donnell M. Genes 1996; PubMed Scopus (180) Google Scholar, G. O'Donnell M. J. Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google Scholar). its with DNA at a PCNA and it onto DNA in the of this required for MMR Y. C. 1999; PubMed Google Scholar). PCNA loading is conserved and the DNA replication is with host cellular DNA and The Epstein-Barr virus is a with a DNA, in R. P.J. G. C. PubMed Scopus Google Scholar). In cell of viral are and is of virus this from can or be is characterized by the of lytic to the of and to host cell The is by viral DNA replication composed of viral replication an a DNA a polymerase a and and to be and J. 1995; PubMed Google Scholar). lytic replication in sites in replication compartments, of viral replication viral DNA T. A. M. Y. H. N. T. J. 2005; PubMed Scopus Google Scholar, S. K. T. PubMed Scopus Google Scholar). progression of lytic replication the replication and to to form that the in T. A. M. Y. H. N. T. J. 2005; PubMed Scopus Google Scholar). We have in protein is the of a to highly of lytic replication A. M. T. K. Y. S. Y. T. J. 2003; PubMed Scopus Google Scholar). this system, could that of the lytic in of replication of cellular DNA replication of viral DNA A. M. T. K. Y. S. Y. T. J. 2003; PubMed Scopus Google Scholar). We here for the that PCNA, RF-C, and a series of MMR proteins like MSH-2, MSH-6, MLH1, and hPSM2 are assembled to sites of viral DNA of lytic replication. Levels of the DNA-bound form of PCNA with progression of lytic replication and chromatin immunodepletion analyses with revealed that PCNA is loaded onto newly synthesized viral DNA as well as the BALF2 and BMRF1 viral PCNA and are viral replication might PCNA onto newly synthesized viral and interact with PCNA (19Flores-Rozas H. Clark D. Kolodner R.D. Nat. Genet. 2000; 26: 375-378Crossref PubMed Scopus (196) Google Scholar, 20Kleczkowska H.E. Marra G. Lettieri T. Jiricny J. Genes Dev. 2001; 15: 724-736Crossref PubMed Scopus (198) Google Scholar), loading might trigger transfer of a series of host MMR proteins to sites of viral DNA synthesis. Cell A. M. T. K. Y. S. Y. T. 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Biol. 1998; PubMed Scopus Google Scholar) and polymerase δ by The or antibodies with or from with or at a of and at the The with phosphate-buffered at and for on with of Pipes, multiple for cell and The then to to nuclear that with in and at for The then to the chromatin and the nuclear was to the by and to for at for and with primary with and with on for and to the with for on with PBS, with in for for in in PBS, and then with the primary antibodies in The antibodies and used at the at and the and antibodies at The then for with or antibodies with or of the antibodies in either or newly synthesized DNA was by with to the for to the the with for at and then for with and with on for and to the then with for on and for with to the The with and with for in an was with and used for the of was as and then in to in on with in and with a in DNA DNA and yeast (1 and at for and at at with in for and then in and in was a with a and assembled in an at the with with PBS, and with for on and to the at for at and cell for protein a of proteins loaded for The proteins then as A. M. T. K. Y. S. Y. T. J. 2003; PubMed Scopus Google Scholar). of proteins was with an immunodepletion as in in the of for synthesized DNA was by with to the for to in PBS, in for on and to The in with of in for at and then at for Cell in at and to the DNA to on not the for with of or of or as complexes of proteins to DNA with protein and with and for at by at for and then DNA was a from and onto DNA was with of and in the of at and with The with The with of -MSH2, -MSH3, and -MSH6 for at the of of the for at The then with and the in The to and to of PCNA to of with to lytic replication A. M. T. K. Y. S. Y. T. J. 2003; PubMed Scopus Google Scholar), and with a at not but nuclear proteins not to nuclear is to nuclear but the nuclear nuclear P. A.B. D.A. Cell. Full Text PDF PubMed Scopus Google Scholar), and proteins in have been to bind to chromatin or viral M. C. H. N. K. M. T. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, M. Y. H. T. T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). We have that the BMRF1 polymerase factor a not in viral replication and the BALF2 protein is as distinct the replication T. A. M. Y. H. N. T. J. 2005; PubMed Scopus Google Scholar). in a and the sites with antibodies with the foci of newly synthesized viral DNA as by and in analyses on Furthermore, that viral DNA of the as a of virus but cellular DNA in the and so the of by newly synthesized with for at and then for of DNA in was during the a and the that a of the DNA of the with that at are viral and not cellular BMRF1 sites of viral DNA BMRF1 protein was used as a for viral replication the MMR is involved in lytic DNA of PCNA, a protein involved in the of MMR, in lytic PCNA is an protein that is throughout the in it appears to be in foci of that have been to with newly replicated DNA with in H. P. A. T. D. J. Cell Biol. 2000; PubMed Scopus Google Scholar). both and are to with PCNA to foci H.E. Marra G. Lettieri T. Jiricny J. 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Furthermore, as was in the and in of DNA is viral newly synthesized with for to and then with in with and to the DNA with or or as complexes of proteins to DNA from the protein DNA was from the to and with and can the with in and with primary and protein in could the protein from the or in the and of DNA from the that viral replication proteins to the bind to newly synthesized viral DNA, whereas The form of protein was of the viral replication in T. and T. suggesting DNA binding of the The could not DNA as the that PCNA is loaded onto viral DNA synthesized of lytic MLH1, and with PCNA to with multiple partners including MMR proteins (17Maga G. Hubscher U. J. Cell Sci. 2003; 116: 3051-3060Crossref PubMed Scopus (877) Google Scholar). MMR is involved in viral of MMR proteins in the lytic antibodies to MLH1, and with a and then for studies that in viral productive DNA MLH1, and with PCNA in the viral replication that the of PCNA and the MutS and is with the interaction between PCNA and to form a complex, for mismatched sites during DNA replication (19Flores-Rozas H. Clark D. Kolodner R.D. Nat. Genet. 2000; 26: 375-378Crossref PubMed Scopus (196) Google Scholar, P.J. Kolodner R.D. J. Biol. Chem. 2003; 278: 14-17Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar). the other although MutL and PCNA PCNA in the and might of the complexes with either MSH2-MSH6 or MSH2-MSH3 at mispaired in the DNA Y. Sung P. Prakash L. Prakash S. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar, Y. Sung P. Prakash L. Prakash S. Curr. Biol. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, S. Modrich P. J. Biol. 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