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Virology. 2011 Nov 25;420(2):73-81. doi: 10.1016/j.virol.2011.08.019. Epub 2011 Sep 22.

Gammaherpesvirus gene expression and DNA synthesis are facilitated by viral protein kinase and histone variant H2AX.

Author information

  • 1Department of Microbiology and Molecular Genetics, Cancer Center, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA.

Abstract

Gammaherpesvirus protein kinases are an attractive therapeutic target as they support lytic replication and latency. Via an unknown mechanism these kinases enhance expression of select viral genes and DNA synthesis. Importantly, the kinase phenotypes have not been examined in primary cell types. Mouse gammaherpesvirus-68 (MHV68) protein kinase orf36 activates the DNA damage response (DDR) and facilitates lytic replication in primary macrophages. Significantly, H2AX, a DDR component and putative orf36 substrate, enhances MHV68 replication. Here we report that orf36 facilitated expression of RTA, an immediate early MHV68 gene, and DNA synthesis during de novo infection of primary macrophages. H2AX expression supported efficient RTA transcription and phosphorylated H2AX associated with RTA promoter. Furthermore, viral DNA synthesis was attenuated in H2AX-deficient macrophages, suggesting that the DDR system was exploited throughout the replication cycle. The interactions between a cancer-associated gammaherpesvirus and host tumor suppressor system have important implications for the pathogenesis of gammaherpesvirus infection.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID:
21943826
[PubMed - indexed for MEDLINE]
PMCID:
PMC3204369
Free PMC Article

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