γ-Herpesvirus Kinase Actively Initiates a DNA Damage Response by Inducing Phosphorylation of H2AX to Foster Viral Replication

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Cell host & microbe (Impact Factor: 12.19). 07/2007; 1(4):275-86. DOI: 10.1016/j.chom.2007.05.008
Source: PubMed

ABSTRACT DNA virus infection can elicit the DNA damage response in host cells, including ATM kinase activation and H2AX phosphorylation. This is considered to be the host cell response to replicating viral DNA. In contrast, we show that during infection of macrophages murine gamma-herpesvirus 68 (gammaHV68) actively induces H2AX phosphorylation by expressing a viral kinase (orf36). GammaHV68-encoded orf36 kinase and its EBV homolog, BGLF4, induce H2AX phosphorylation independently of other viral genes. The process requires the kinase domain of Orf36 and is enhanced by ATM. Orf36 is important for gammaHV68 replication in infected animals, and orf36, H2AX, and ATM are all critical for efficient gammaHV68 replication in primary macrophages. Thus, activation of proximal components of the DNA damage signaling response is an active viral kinase-driven strategy required for efficient gamma-herpesvirus replication.

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Available from: Vera L Tarakanova, Aug 30, 2015
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    • "A common feature of herpesviruses is their capacity to activate DDRs in infected cells (Shirata et al., 2005; Gaspar and Shenk, 2006; Koopal et al., 2007; Tarakanova et al., 2007; Nikitin et al., 2010). Although in some cases this is associated with lytic or productive infection, when the virus has a requirement for rapid replication of its genome prior to virion assembly, at least two gamma-herpesviruses (Kaposi’s Sarcoma associated herpes virus (KSHV, aka HHV8) and EBV) trigger DDRs during the establishment of a latent infection. "
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    Frontiers in Genetics 10/2013; 4:212. DOI:10.3389/fgene.2013.00212
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    • "Senescence, however induced, leads to increased ROS production, leading to increased DSB foci within the cell [30]. Viruses, including EBV, induce c-H2AX in infected cells [31]. Herpes virus c-HV68 infection in a murine model led to c-H2AX induction, which in turn increased viral replication [31]. "
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    ABSTRACT: Background & Aims Age is the dominant prognostic factor influencing the natural history of hepatitis C virus (HCV) infection and treatment response. Accelerated lymphocyte telomere shortening in HCV infection correlates with adverse clinical outcomes. Critical telomere shortening generates double-stranded DNA breaks (DSB) inducing the DNA damage response, leading to replicative senescence. The phenotype and function of CD8+ T lymphocytes and the in vitro response to IFN-α in relation to the DNA damage response were investigated in patients with chronic HCV infection. Methods CD8+ T lymphocytes with DSB were identified by expression of γ-H2AX (Ser-139) in 134 HCV-exposed subjects and 27 controls. Telomere length was determined by flow-FISH; cytokine expression by intracellular cytokine staining; in vitro responses to IFN-α, IL-2 or IL-6 by phospho-STAT1 (Y701) or phospho-STAT5 (Y694) expression. Results The proportion of circulating CD8 + γ-H2AX+ T lymphocytes rose with increasing fibrosis stage (p = 0.0023). CD8 + γ-H2AX+ T lymphocytes were enriched in liver compared to blood (p = 0.03). CD8 + γ-H2AX+ T lymphocytes demonstrated increased IFN-γ (p = 0.02) and reduced IL-2 expression (p = 0.02). CD8 + γ-H2AX+ T lymphocytes failed to phosphorylate STAT1 in response to IFN-α compared to unfractionated CD8+ T lymphocytes (p <0.0001). More widespread failure of Jak/Stat signalling in CD8 + γ-H2AX+ T lymphocytes was suggested by impaired phosphorylation of STAT1 with IL-6 (p = 0.002) and STAT5 with IL-2 (p = 0.0039) compared to unfractionated CD8+ T-lymphocytes. Conclusions In chronic HCV infection, CD8 + γ-H2AX+ T lymphocytes are highly differentiated with shortened telomeres, are more frequent within the liver, are associated with severe fibrosis and fail to activate Jak/Stat pathways in response to IFN-α, IL-2 or IL-6, perhaps explaining treatment failure in those with severe fibrosis.
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    • "LANA represses p53 transcriptional activity, inhibiting its ability to induce apoptosis. Interestingly, infection with the related murine c-herpesvirus 68 (cHV68) also results in phosphorylation of H2AX and this has been attributed to the activity of the orf36 kinase together with ATM (Tarakanova et al., 2007). cHV68 orf36 and the EBV homologue BGL4 can phosphorylate H2AX in vitro and it has been shown that ATM and H2AX, as well as orf36, are required for optimal cHV68 replication in mouse macrophages. "
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