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Gammaherpesvirus gene expression and DNA synthesis are facilitated by viral protein kinase and histone variant H2AX. Virology 2011 Nov 25;420(2):73-81

Date

09/29/2011

Pubmed ID

21943826

Pubmed Central ID

PMC3204369

DOI

10.1016/j.virol.2011.08.019

Scopus ID

2-s2.0-80054053305   14 Citations

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.

Author List

Mounce BC, Tsan FC, Droit L, Kohler S, Reitsma JM, Cirillo LA, Tarakanova VL

Authors

Lisa A. Cirillo PhD Assistant Dean, Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Vera Tarakanova PhD Associate Professor in the Microbiology and Immunology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Chromatin Immunoprecipitation
DNA Repair
DNA Replication
DNA, Viral
Gene Expression Regulation, Viral
Histones
Immediate-Early Proteins
Macrophages
Mice
Mice, Inbred C57BL
Mice, Knockout
Protein Kinases
Rhadinovirus
Transcription, Genetic
Viral Proteins
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a