Host cellular functions supporting Epstein-Barr virus genome replication.

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Induction of Epstein-Barr virus lytic replication from latent state blocks cell cycle progression and induces ATM DNA damage checkpoint signaling. Phosphorylated ATM and MRN complex are clustered to the sites of viral genome synthesis in nuclei. Here we report that the 32 kDa subunit of replication protein A (RPA) is extensively phosphorylated when lytic replication was induced. Although the total levels of the RPA proved constant throughout the lytic infection, the levels of DNA-bound form increased as lytic infection proceeded. The phosphorylated RPA was recruited and retained in viral replication compartments as well as phosphorylated ATM. The phosphorylation sites on RPA-32 were accorded with those by ATM and DNAPK that were activated during EBV lytic infection. Since hyper-phosphorylation of RPA32 in response to DNA damage causes a change in RPA conformation that down-regulates activity in DNA replication but participates in DNA repair process. Collectively, the EBV lytic program might actively inhibit chromosomal DNA replication through phosphorylation of RPA32 and allows hyperphosphorylated RPA to be involved in recombination and/or repair of viral DNA genome in the viral replication compartments.