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Proc Natl Acad Sci U S A. 2014 Aug 12;111(32):11816-21. doi: 10.1073/pnas.1404219111. Epub 2014 Jul 28.

Kaposi's sarcoma-associated herpesvirus LANA recruits the DNA polymerase clamp loader to mediate efficient replication and virus persistence.

Author information

1
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
2
Department of Biology, Kyushu University, Fukuoka 812-8581, Japan; and.
3
Proteomics Center, National Institute of Biological Sciences, Beijing 102206, People's Republic of China.
4
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; kkaye@rics.bwh.harvard.edu.

Erratum in

  • Proc Natl Acad Sci U S A. 2014 Sep 30;111(39):14308.

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) latently infects tumor cells and persists as a multiple-copy, extrachromosomal, circular episome. To persist, the viral genome must replicate with each cell cycle. The KSHV latency-associated nuclear antigen (LANA) mediates viral DNA replication and persistence, but little is known regarding the underlying mechanisms. We find that LANA recruits replication factor C (RFC), the DNA polymerase clamp [proliferating cell nuclear antigen (PCNA)] loader, to drive DNA replication efficiently. Mutated LANA lacking RFC interaction was deficient for LANA-mediated DNA replication and episome persistence. RFC depletion had a negative impact on LANA's ability to replicate and maintain viral DNA in cells containing artificial KSHV episomes or in infected cells, leading to loss of virus. LANA substantially increased PCNA loading onto DNA in vitro and recruited RFC and PCNA to KSHV DNA in cells. These findings suggest that PCNA loading is a rate-limiting step in DNA replication that is incompatible with viral survival. LANA enhancement of PCNA loading permits efficient virus replication and persistence, revealing a previously unidentified mechanism for KSHV latency.

PMID:
25071216
PMCID:
PMC4136584
DOI:
10.1073/pnas.1404219111
[Indexed for MEDLINE]
Free PMC Article

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