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Polyomavirus interaction with the DNA damage response

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Virologica Sinica

Abstract

Viruses are obligate intracellular parasites that subvert cellular metabolism and pathways to mediate their own replication—normally at the expense of the host cell. Polyomaviruses are a group of small DNA viruses, which have long been studied as a model for eukaryotic DNA replication. Polyomaviruses manipulate host replication proteins, as well as proteins involved in DNA maintenance and repair, to serve as essential cofactors for productive infection. Moreover, evidence suggests that polyomavirus infection poses a unique genotoxic threat to the host cell. In response to any source of DNA damage, cells must initiate an effective DNA damage response (DDR) to maintain genomic integrity, wherein two protein kinases, ataxia telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR), are major regulators of DNA damage recognition and repair. Recent investigation suggests that these essential DDR proteins are required for productive polyomavirus infection. This review will focus on polyomaviruses and their interaction with ATM- and ATR-mediated DNA damage responses and the effect of this interaction on host genomic stability.

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References

  • Abend JR, Low JA, Imperiale MJ. 2010. Global effects of BKV infection on gene expression in human primary kidney epithelial cells. Virology, 397: 73–79.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • An P, Saenz Robles MT, Pipas JM. 2012. Large T antigens of polyomaviruses: Amazing molecular machines. Annu Rev Microbiol, 66: 213–236.

    Article  CAS  PubMed  Google Scholar 

  • Andrabi S, Hwang JH, Choe JK, Roberts TM, Schaffhausen BS. 2011. Comparisons between murine polyomavirus and Simian virus 40 show significant differences in small t antigen function. J Virol, 85: 10649–10658.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Banerjee P, DeJesus R, Gjoerup O, Schaffhausen BS. 2013. Viral interference with DNA repair by targeting of the single-stranded DNA binding protein rpa. PLoS Pathog, 9: e1003725.

    Article  PubMed Central  PubMed  Google Scholar 

  • Boichuk S, Hu L, Hein J, Gjoerup OV. 2010. Multiple DNA damage signaling and repair pathways deregulated by Simian virus 40 large T antigen. J Virol, 84: 8007–8020.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bracken AP, Ciro M, Cocito A, Helin K. 2004. E2F target genes: Unraveling the biology. Trends Biochem Sci, 29: 409–417.

    Article  CAS  PubMed  Google Scholar 

  • Cegielska A, Moarefi I, Fanning E, Virshup DM. 1994. T-antigen kinase inhibits simian virus 40 DNA replication by phospho-rylation of intact T antigen on serines 120 and 123. J Virol, 68: 269–275.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Chaurushiya MS, Weitzman MD. 2009. Viral manipulation of DNA repair and cell cycle checkpoints. DNA Repair (Amst), 8: 1166–1176.

    Article  CAS  Google Scholar 

  • Ciccia A, Elledge SJ. 2010. The DNA damage response: Making it safe to play with knives. Mol Cell, 40: 179–204.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Dahl J, You J, Benjamin TL. 2005. Induction and utilization of an ATM signaling pathway by polyomavirus. J Virol, 79: 13007–13017.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • DeCaprio JA, Garcea RL. 2013. A cornucopia of human polyoma-viruses. Nat Rev Microbiol, 11: 264–276.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Demetriou SK, Ona-Vu K, Sullivan EM, Dong TK, Hsu SW, Oh DH. 2012. Defective DNA repair and cell cycle arrest in cells expressing merkel cell polyomavirus T antigen. Int J Cancer, 131: 1818–1827.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Dey D, Dahl J, Cho S, Benjamin TL. 2002. Induction and bypass of p53 during productive infection by polyomavirus. Journal of Virology, 76: 9526–9532.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Dyson N, Bernards R, Friend SH, Gooding LR, Hassell JA, Major EO, Pipas JM, Vandyke T, Harlow E. 1990. Large T antigens of many polyomaviruses are able to form complexes with the retinoblastoma protein. J Virol, 64: 1353–1356.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Erickson KD, Bouchet-Marquis C, Heiser K, Szomolanyi-Tsuda E, Mishra R, Lamothe B, Hoenger A, Garcea RL. 2012. Virion assembly factories in the nucleus of polyomavirus-infected cells. PLoS Pathog, 8: e1002630.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Feng H, Shuda M, Chang Y, Moore PS. 2008. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science, 319: 1096–1100.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Garcea RL, Imperiale MJ. 2003. Simian virus 40 infection of humans. J Virol, 77: 5039–5045.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gjoerup O, Chang Y. 2010. Update on human polyomaviruses and cancer. Adv Cancer Res, 106: 1–51.

    Article  CAS  PubMed  Google Scholar 

  • Hein J, Boichuk S, Wu J, Cheng Y, Freire R, Jat PS, Roberts TM, Gjoerup OV. 2009. Simian virus 40 large T antigen disrupts genome integrity and activates a DNA damage response via Bub1 binding. J Virol, 83: 117–127.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hoeijmakers JH. 2009. DNA damage, aging, and cancer. N Engl J Med, 361: 1475–1485.

    Article  CAS  PubMed  Google Scholar 

  • Hu L, Filippakis H, Huang H, Yen TJ, Gjoerup OV. 2013. Replication stress and mitotic dysfunction in cells expressing simian virus 40 large T antigen. J Virol, 87: 13179–13192.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jiang M, Zhao L, Gamez M, Imperiale MJ. 2012. Roles of ATM and ATR-mediated DNA damage responses during lytic BK polyomavirus infection. PLoS Pathog, 8: e1002898.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kassem A, Schopflin A, Diaz C, Weyers W, Stickeler E, Werner M, Zur Hausen A. 2008. Frequent detection of merkel cell polyomavirus in human merkel cell carcinomas and identification of a unique deletion in the VP1 gene. Cancer Res, 68: 5009–5013.

    Article  CAS  PubMed  Google Scholar 

  • Li J, Diaz J, Wang X, Tsang SH, You J. 2014. Phosphorylation of merkel cell polyomavirus large T antigen at serine 816 by atm kinase induces apoptosis in host cells. J Biol Chem, 290: 1874–1884.

    Article  PubMed  Google Scholar 

  • Li J, Wang X, Diaz J, Tsang SH, Buck CB, You J. 2013. Merkel cell polyomavirus large T antigen disrupts host genomic integrity and inhibits cellular proliferation. J Virol, 87: 9173–9188.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lilley CE, Chaurushiya MS, Boutell C, Everett RD, Weitzman MD. 2011. The intrinsic antiviral defense to incoming HSV-1 genomes includes specific DNA repair proteins and is counteracted by the viral protein ICP0. PLoS Pathog, 7: e1002084.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Liu Q, Guntuku S, Cui XS, Matsuoka S, Cortez D, Tamai K, Luo G, Carattini-Rivera S, DeMayo F, Bradley A, Donehower LA, Elledge SJ. 2000. Chk1 is an essential kinase that is regulated by atr and required for the G(2)/M DNA damage checkpoint. Genes Dev, 14: 1448–1459.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Luftig MA. 2014. Viruses and the DNA damage response: Activation and antagonism. Annu Rev Virol, 1: 605–625.

    Article  CAS  Google Scholar 

  • Luo Y, Qiu J. 2013. Parvovirus infection-induced DNA damage response. Future Virol, 8: 245–257.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Moens U, Van Ghelue M, Ehlers B. 2014. Are human polyomaviruses co-factors for cancers induced by other oncoviruses?. Rev Med Virol, 24: 343–360.

    Article  CAS  PubMed  Google Scholar 

  • Mullane KP, Ratnofsky M, Cullere X, Schaffhausen B. 1998. Signaling from polyomavirus middle T and small T defines different roles for protein phosphatase 2A. Mol Cell Biol, 18: 7556–7564.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Novoa RR, Calderita G, Arranz R, Fontana J, Granzow H, Risco C. 2005. Virus factories: Associations of cell organelles for viral replication and morphogenesis. Biol Cell, 97: 147–172.

    Article  CAS  PubMed  Google Scholar 

  • Okubo E, Lehman JM, Friedrich TD. 2003. Negative regulation of mitotic promoting factor by the checkpoint kinase Chk1 in simian virus 40 lytic infection. J Virol, 77: 1257–1267.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Orba Y, Suzuki T, Makino Y, Kubota K, Tanaka S, Kimura T, Sawa H. 2010. Large T antigen promotes JC virus replication in G2- arrested cells by inducing ATM- and ATR-mediated G2 checkpoint signaling. J Biol Chem, 285: 1544–1554.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Pietruska JR, Kane AB. 2007. SV40 oncoproteins enhance asbestos-induced DNA double-strand breaks and abrogate senescence in murine mesothelial cells. Cancer Res, 67: 3637–3645.

    Article  CAS  PubMed  Google Scholar 

  • Pinto M, Dobson S. 2014. Bk and jc virus: A review. J Infect, 68Suppl 1: S2–8.

    Article  PubMed  Google Scholar 

  • Pipas JM, Levine AJ. 2001. Role of t antigen interactions with p53 in tumorigenesis. Semin Cancer Biol, 11: 23–30.

    Article  CAS  PubMed  Google Scholar 

  • Pores Fernando AT, Andrabi S, Cizmecioglu O, Zhu C, Livingston DM, Higgins JM, Schaffhausen BS, Roberts TM. 2014. Polyoma small T antigen triggers cell death via mitotic catastrophe. Oncogene. doi: 10.1038/onc.2014.192.

    Google Scholar 

  • Raghava S, Giorda KM, Romano FB, Heuck AP, Hebert DN. 2011. The SV40 late protein VP4 is a viroporin that forms pores to disrupt membranes for viral release. PLoS Pathog, 7: e1002116.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Rohaly G, Korf K, Dehde S, Dornreiter I. 2010. Simian virus 40 activates ATR-Delta p53 signaling to override cell cycle and DNA replication control. J Virol, 84: 10727–10747.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Shi Y, Dodson GE, Shaikh S, Rundell K, Tibbetts RS. 2005. Ataxia-telangiectasia-mutated (ATM) is a T-antigen kinase that controls SV40 viral replication in vivo. J Biol Chem, 280: 40195–40200.

    Article  CAS  PubMed  Google Scholar 

  • Sowd GA, Li NY, Fanning E. 2013. Atm and atr activities maintain replication fork integrity during SV40 chromatin replication. PLoS Pathog, 9: e1003283.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sowd GA, Mody D, Eggold J, Cortez D, Friedman KL, Fanning E. 2014. SV40 utilizes ATM kinase activity to prevent non-homologous end joining of broken viral DNA replication products. PLoS Pathog, 10: e1004536.

    Article  PubMed Central  PubMed  Google Scholar 

  • Stracker TH, Carson CT, Weitzman MD. 2002. Adenovirus oncoproteins inactivate the Mre11-Rad50-Nbs1 DNA repair complex. Nature, 418: 348–352.

    Article  CAS  PubMed  Google Scholar 

  • Sweet BH, Hilleman MR. 1960. The vacuolating virus, S.V. 40. Proc Soc Exp Biol Med, 105: 420–427.

    Article  CAS  PubMed  Google Scholar 

  • Trojanek J, Croul S, Ho T, Wang JY, Darbinyan A, Nowicki M, Del Valle L, Skorski T, Khalili K, Reiss K. 2006. T-antigen of the human polyomavirus jc attenuates faithful DNA repair by forcing nuclear interaction between IRS-1 and Rad51. J Cell Physiol, 206: 35–46.

    Article  CAS  PubMed  Google Scholar 

  • Tsang SH, Wang X, Li J, Buck CB, You J. 2014. Host DNA damage response factors localize to merkel cell polyomavirus DNA replication sites to support efficient viral DNA replication. J Virol, 88: 3285–3297.

    Article  PubMed Central  PubMed  Google Scholar 

  • Verhalen B, Justice JL, Imperiale MJ, Jiang M. 2015. Viral DNA replication-dependent DNA damage response activation during bk polyomavirus infection. J Virol, 89: 5032–5039.

    Article  CAS  PubMed  Google Scholar 

  • Wileman T. 2007. Aggresomes and pericentriolar sites of virus assembly: Cellular defense or viral design? Annu Rev Microbiol, 61: 149–167.

    Article  CAS  PubMed  Google Scholar 

  • Wu X, Avni D, Chiba T, Yan F, Zhao Q, Lin Y, Heng H, Livingston D. 2004. SV40 T antigen interacts with nbs1 to disrupt DNA replication control. Genes Dev, 18: 1305–1316.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yu G, Greninger AL, Isa P, Phan TG, Martinez MA, de la Luz Sanchez M, Contreras JF, Santos-Preciado JI, Parsonnet J, Miller S, DeRisi JL, Delwart E, Arias CF, Chiu CY. 2012. Discovery of a novel polyomavirus in acute diarrheal samples from children. PLoS One, 7: e49449.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zhao X, Madden-Fuentes RJ, Lou BX, Pipas JM, Gerhardt J, Rigell CJ, Fanning E. 2008. Ataxia telangiectasia-mutated damage-signaling kinase- and proteasome-dependent destruction of Mre11-Rad50-Nbs1 subunits in Simian virus 40-infected primate cells. J Virol, 82: 5316–5328.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Correspondence to Mengxi Jiang.

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ORCID: 0000-0002-2222-3606

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Justice, J.L., Verhalen, B. & Jiang, M. Polyomavirus interaction with the DNA damage response. Virol. Sin. 30, 122–129 (2015). https://doi.org/10.1007/s12250-015-3583-6

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