title: Gammaherpesvirus gene expression and DNA synthesis are facilitated by viral protein kinase and histone variant H2AX.
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.
authors.affiliation: Department of Microbiology and Molecular Genetics, Cancer Center, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA.
authors.forename: Bryan C
authors.initials: BC
authors.lastname: Mounce
authors.forename: Fei Chin
authors.initials: FC
authors.lastname: Tsan
authors.forename: Lindsay
authors.initials: L
authors.lastname: Droit
authors.forename: Sarah
authors.initials: S
authors.lastname: Kohler
authors.forename: Justin M
authors.initials: JM
authors.lastname: Reitsma
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Cirillo
authors.forename: Vera L
authors.initials: VL
authors.lastname: Tarakanova
mesh_terms: D000818:Animals; D047369:Chromatin Immunoprecipitation; D004260:DNA Repair; D004261:DNA Replication / Q000235:genetics*; D004279:DNA, Viral / Q000096:biosynthesis; D015967:Gene Expression Regulation, Viral; D006657:Histones / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism / Q000821:virology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011494:Protein Kinases / Q000378:metabolism*; D018144:Rhadinovirus / Q000235:genetics* / Q000472:pathogenicity; D014158:Transcription, Genetic; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D004279:DNA, Viral; D006657:Histones; D017874:Immediate-Early Proteins; D011494:Protein Kinases; D014764:Viral Proteins; C475961:gamma-H2AX protein, mouse