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PMID: 18005708 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Gamma-herpesvirus kinase actively initiates a DNA damage response by inducing phosphorylation of H2AX to foster viral replication.

Cell host & microbe ·Vol. 1 ·No. 4 ·2007-06-14 ·Pages 275-86

Tarakanova VL, Leung-Pineda V, Hwang S, Yang CW, Matatall K, Basson M, Sun R, Piwnica-Worms H, Sleckman BP, Virgin HW

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.

MeSH Terms
Animals DNA Damage Gammaherpesvirinae/enzymology,genetics,pathogenicity,physiology Herpesviridae Infections/physiopathology Herpesvirus 4, Human/physiology Histones/metabolism Humans Open Reading Frames Phosphoproteins/metabolism Phosphorylation Plasmids Protein Kinases/metabolism Viral Proteins/metabolism Virus Replication
Chemicals
H2AX protein, human Histones Phosphoproteins Viral Proteins Protein Kinases
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Tarakanova Vera L
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Leung-Pineda Van
Hwang Seungmin
Yang Chiao-Wen
Matatall Katie
Basson Mickael
Sun Ren
Piwnica-Worms Helen
Sleckman Barry P
Virgin Herbert W
References (52)
52 references, click to expand
  1. Molecular linkage between the kinase ATM and NF-kappaB signaling in response to genotoxic stimuli.
    Science. 2006 Feb 24;311(5764):1141-6 PMID: 16497931
  2. Proteomics of herpes simplex virus replication compartments: association of cellular DNA replication, repair, recombination, and chromatin remodeling proteins with ICP8.
    J Virol. 2004 Jun;78(11):5856-66 PMID: 15140983
  3. Detection of Epstein-Barr virus BGLF4 protein kinase in virus replication compartments and virus particles.
    J Gen Virol. 2005 Dec;86(Pt 12):3215-3225 PMID: 16298966
  4. Epstein-Barr virus lytic replication elicits ATM checkpoint signal transduction while providing an S-phase-like cellular environment.
    J Biol Chem. 2005 Mar 4;280(9):8156-63 PMID: 15611093
  5. Oncogenic gamma-herpesviruses: comparison of viral proteins involved in tumorigenesis.
    Nat Rev Microbiol. 2004 Aug;2(8):656-68 PMID: 15263900
  6. Expression and localization of the Epstein-Barr virus-encoded protein kinase.
    J Virol. 2004 Nov;78(22):12140-6 PMID: 15507600
  7. Genomic instability in mice lacking histone H2AX.
    Science. 2002 May 3;296(5569):922-7 PMID: 11934988
  8. STAT-1 facilitates the ATM activated checkpoint pathway following DNA damage.
    J Cell Sci. 2005 Apr 15;118(Pt 8):1629-39 PMID: 15784679
  9. Epstein-Barr virus: 40 years on.
    Nat Rev Cancer. 2004 Oct;4(10):757-68 PMID: 15510157
  10. The murine gammaherpesvirus 68 v-cyclin is a critical regulator of reactivation from latency.
    J Virol. 2000 Aug;74(16):7451-61 PMID: 10906198
  11. Defective DNA-dependent protein kinase activity is linked to V(D)J recombination and DNA repair defects associated with the murine scid mutation.
    Cell. 1995 Mar 10;80(5):813-23 PMID: 7889575
  12. Cell apoptosis: requirement of H2AX in DNA ladder formation, but not for the activation of caspase-3.
    Mol Cell. 2006 Jul 7;23(1):121-32 PMID: 16818236
  13. Identification of viral genes essential for replication of murine gamma-herpesvirus 68 using signature-tagged mutagenesis.
    Proc Natl Acad Sci U S A. 2005 Mar 8;102(10):3805-10 PMID: 15738413
  14. Adenovirus oncoproteins inactivate the Mre11-Rad50-NBS1 DNA repair complex.
    Nature. 2002 Jul 18;418(6895):348-52 PMID: 12124628
  15. Ongoing viral replication is required for gammaherpesvirus 68-induced vascular damage.
    J Virol. 2000 Dec;74(23):11304-10 PMID: 11070030
  16. Conserved protein kinases encoded by herpesviruses and cellular protein kinase cdc2 target the same phosphorylation site in eukaryotic elongation factor 1delta.
    J Virol. 2003 Feb;77(4):2359-68 PMID: 12551973
  17. Murine herpesvirus 68 is genetically related to the gammaherpesviruses Epstein-Barr virus and herpesvirus saimiri.
    J Gen Virol. 1990 Jun;71 ( Pt 6):1365-72 PMID: 2161903
  18. Induction and utilization of an ATM signaling pathway by polyomavirus.
    J Virol. 2005 Oct;79(20):13007-17 PMID: 16189003
  19. Identification of interferon-stimulated gene 15 as an antiviral molecule during Sindbis virus infection in vivo.
    J Virol. 2005 Nov;79(22):13974-83 PMID: 16254333
  20. Murine gammaherpesvirus 68 establishes a latent infection in mouse B lymphocytes in vivo.
    J Gen Virol. 1992 Dec;73 ( Pt 12):3275-9 PMID: 1469366
  21. A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage.
    Curr Biol. 2000 Jul 27-Aug 10;10(15):886-95 PMID: 10959836
  22. Recruitment of cellular recombination and repair proteins to sites of herpes simplex virus type 1 DNA replication is dependent on the composition of viral proteins within prereplicative sites and correlates with the induction of the DNA damage response.
    J Virol. 2004 May;78(9):4783-96 PMID: 15078960
  23. Complete sequence and genomic analysis of murine gammaherpesvirus 68.
    J Virol. 1997 Aug;71(8):5894-904 PMID: 9223479
  24. Mycobacteriophage exploit NHEJ to facilitate genome circularization.
    Mol Cell. 2006 Sep 1;23(5):743-8 PMID: 16949369
  25. A noninverting genome of a viable herpes simplex virus 1: presence of head-to-tail linkages in packaged genomes and requirements for circularization after infection.
    J Virol. 1985 Feb;53(2):587-95 PMID: 2982037
  26. Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks.
    Nat Cell Biol. 2003 Jul;5(7):675-9 PMID: 12792649
  27. In vitro and in vivo inhibition of murine gamma herpesvirus 68 replication by selected antiviral agents.
    Antimicrob Agents Chemother. 1998 Jan;42(1):170-2 PMID: 9449280
  28. Increased ionizing radiation sensitivity and genomic instability in the absence of histone H2AX.
    Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8173-8 PMID: 12034884
  29. Latent murine gamma-herpesvirus infection is established in activated B cells, dendritic cells, and macrophages.
    J Immunol. 2000 Jul 15;165(2):1074-81 PMID: 10878386
  30. Interfaces between the detection, signaling, and repair of DNA damage.
    Science. 2002 Jul 26;297(5581):547-51 PMID: 12142523
  31. Atm-deficient mice: a paradigm of ataxia telangiectasia.
    Cell. 1996 Jul 12;86(1):159-71 PMID: 8689683
  32. Transcription program of murine gammaherpesvirus 68.
    J Virol. 2003 Oct;77(19):10488-503 PMID: 12970434
  33. Herpesvirus saimiri as a model for gammaherpesvirus oncogenesis.
    Semin Cancer Biol. 1999 Jun;9(3):231-9 PMID: 10343074
  34. DNA-PK is activated by nucleosomes and phosphorylates H2AX within the nucleosomes in an acetylation-dependent manner.
    Nucleic Acids Res. 2003 Dec 1;31(23):6819-27 PMID: 14627815
  35. Herpes virus replication.
    IUBMB Life. 2003 Jan;55(1):13-22 PMID: 12716057
  36. Murine gammaherpesvirus 68 infection is associated with lymphoproliferative disease and lymphoma in BALB beta2 microglobulin-deficient mice.
    J Virol. 2005 Dec;79(23):14668-79 PMID: 16282467
  37. Mature B cells are required for acute splenic infection, but not for establishment of latency, by murine gammaherpesvirus 68.
    J Virol. 1996 Oct;70(10):6775-80 PMID: 8794315
  38. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor.
    Nature. 2005 Aug 25;436(7054):1186-90 PMID: 15995699
  39. Crystal structure of a complex between the catalytic and regulatory (RIalpha) subunits of PKA.
    Science. 2005 Feb 4;307(5710):690-6 PMID: 15692043
  40. Long-term latent murine Gammaherpesvirus 68 infection is preferentially found within the surface immunoglobulin D-negative subset of splenic B cells in vivo.
    J Virol. 2003 Aug;77(15):8310-21 PMID: 12857900
  41. A protein kinase activity associated with Epstein-Barr virus BGLF4 phosphorylates the viral early antigen EA-D in vitro.
    J Virol. 2000 Apr;74(7):3093-104 PMID: 10708424
  42. Hyperphosphorylation of EBNA2 by Epstein-Barr virus protein kinase suppresses transactivation of the LMP1 promoter.
    J Virol. 2005 May;79(9):5880-5 PMID: 15827205
  43. Macrophages are the major reservoir of latent murine gammaherpesvirus 68 in peritoneal cells.
    J Virol. 1999 Apr;73(4):3273-83 PMID: 10074181
  44. DNA repair proteins affect the lifecycle of herpes simplex virus 1.
    Proc Natl Acad Sci U S A. 2005 Apr 19;102(16):5844-9 PMID: 15824307
  45. Epstein-Barr virus protein kinase BGLF4 is a virion tegument protein that dissociates from virions in a phosphorylation-dependent process and phosphorylates the viral immediate-early protein BZLF1.
    J Virol. 2006 Jun;80(11):5125-34 PMID: 16698993
  46. Postreplicative mismatch repair factors are recruited to Epstein-Barr virus replication compartments.
    J Biol Chem. 2006 Apr 21;281(16):11422-30 PMID: 16510450
  47. Activation of ataxia telangiectasia-mutated DNA damage checkpoint signal transduction elicited by herpes simplex virus infection.
    J Biol Chem. 2005 Aug 26;280(34):30336-41 PMID: 15964848
  48. Human cytomegalovirus inhibits a DNA damage response by mislocalizing checkpoint proteins.
    Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2821-6 PMID: 16477038
  49. The DNA damage response: sensing and signaling.
    Curr Opin Cell Biol. 2004 Dec;16(6):629-33 PMID: 15530773
  50. Structural modes of stabilization of permissive phosphorylation sites in protein kinases: distinct strategies in Ser/Thr and Tyr kinases.
    J Mol Biol. 2004 Jun 18;339(5):1025-39 PMID: 15178245
  51. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints.
    Annu Rev Biochem. 2004;73:39-85 PMID: 15189136
  52. ATM phosphorylates histone H2AX in response to DNA double-strand breaks.
    J Biol Chem. 2001 Nov 9;276(45):42462-7 PMID: 11571274
Article Info
Journal
Cell host & microbe
Abbr.
Cell Host Microbe
ISSN
1934-6069
DOI
10.1016/j.chom.2007.05.008
Published
2007-06-14
Pages
275-86
Language
English
Region
United States
NLM ID
101302316
PMCID
PMC2034359
Subset
IM
Grants
NCI NIH HHS · R01 CA074730-07 · United States
NIGMS NIH HHS · R01 GM047017 · United States
NCI NIH HHS · CA 74730 · United States
NIGMS NIH HHS · GM47017 · United States
NCI NIH HHS · R01 CA074730-09 · United States
NIDDK NIH HHS · P30 DK52514 · United States
NCI NIH HHS · R01 CA074730-08 · United States
NCI NIH HHS · R01 CA074730 · United States
External Links
PubMed source DOI: 10.1016/j.chom.2007.05.008 PMC Full Text View journal details
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