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.
Highlights
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 [7]
Of proliferating cell nuclear antigen (PCNA) to Viral Replication Compartments after Induction of Lytic Replication—Tet-BZLF1/B95-8 cells were treated with doxycycline to induce lytic replication [30], harvested, and treated with a buffer containing non-ionic detergent Triton X-100 at relatively physiological salt condition, which extracts cytoplasmic and nuclear proteins not tightly bound to nuclear structures
We have previously demonstrated that the BMRF1 polymerase processivity factor shows a homologous, not dot-like, distribution in viral replication compartments and the BALF2 single-stranded DNA-binding protein is distributed as distinct dots within the replication compartments [28]
Summary
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 [7]. We show here for the first time that PCNA, RF-C, and a series of MMR proteins like MSH-2, MSH-6, MLH1, and hPSM2 are assembled precisely to sites of viral DNA synthesis after induction of EBV lytic replication.
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