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Abstract

High-risk human papillomaviruses (HPVs) are associated with several human cancers. HPVs are small, DNA viruses that rely on host cell machinery for viral replication. The HPV life cycle takes place in the stratified epithelium, which is composed of different cell states, including terminally differentiating cells that are no longer active in the cell cycle. HPVs have evolved mechanisms to persist and replicate in the stratified epithelium by hijacking and modulating cellular pathways, including the DNA damage response (DDR). HPVs activate and exploit DDR pathways to promote viral replication, which in turn increases the susceptibility of the host cell to genomic instability and carcinogenesis. Here, we review recent advances in our understanding of the regulation of the host cell DDR by high-risk HPVs during the viral life cycle and discuss the potential cellular consequences of modulating DDR pathways.

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2023-09-29
2024-10-09
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Literature Cited

  1. 1.
    Van Doorslaer K, Li Z, Xirasagar S, Maes P, Kaminsky D et al. 2017. The Papillomavirus Episteme: a major update to the papillomavirus sequence database. Nucleic Acids Res. 45:D499–506
    [Crossref] [Google Scholar]
  2. 2.
    McBride AA. 2022. Human papillomaviruses: diversity, infection and host interactions. Nat. Rev. Microbiol. 20:95–108
    [Crossref] [Google Scholar]
  3. 3.
    Egawa N, Doorbar J. 2017. The low-risk papillomaviruses. Virus Res. 231:119–27
    [Crossref] [Google Scholar]
  4. 4.
    Franco EL, Villa LL, Sobrinho JP, Prado JM, Rousseau MC et al. 1999. Epidemiology of acquisition and clearance of cervical human papillomavirus infection in women from a high-risk area for cervical cancer. J. Infect. Dis. 180:1415–23
    [Crossref] [Google Scholar]
  5. 5.
    Ho GY, Bierman R, Beardsley L, Chang CJ, Burk RD. 1998. Natural history of cervicovaginal papillomavirus infection in young women. N. Engl. J. Med. 338:423–28
    [Crossref] [Google Scholar]
  6. 6.
    Gillison ML, Chaturvedi AK, Anderson WF, Fakhry C. 2015. Epidemiology of human papillomavirus–positive head and neck squamous cell carcinoma. J. Clin. Oncol. 33:3235–42
    [Crossref] [Google Scholar]
  7. 7.
    Stanley M. 2010. Pathology and epidemiology of HPV infection in females. Gynecol. Oncol. 117:S5–10
    [Crossref] [Google Scholar]
  8. 8.
    Mac M, Moody CA. 2020. Epigenetic regulation of the human papillomavirus life cycle. Pathogens 9:6483
    [Crossref] [Google Scholar]
  9. 9.
    McBride AA. 2017. Mechanisms and strategies of papillomavirus replication. Biol. Chem. 398:919–27
    [Crossref] [Google Scholar]
  10. 10.
    Day PM, Schelhaas M. 2014. Concepts of papillomavirus entry into host cells. Curr. Opin. Virol. 4:24–31
    [Crossref] [Google Scholar]
  11. 11.
    McBride AA. 2013. The papillomavirus E2 proteins. Virology 445:57–79
    [Crossref] [Google Scholar]
  12. 12.
    Bienkowska-Haba M, Zwolinska K, Keiffer T, Scott RS, Sapp M. 2023. Human papillomavirus genome copy number is maintained by S-phase amplification, genome loss to the cytosol during mitosis, and degradation in G1 phase. J. Virol. 7:e01879–22
    [Google Scholar]
  13. 13.
    Moody CA, Laimins LA. 2010. Human papillomavirus oncoproteins: pathways to transformation. Nat. Rev. Cancer 10:550–60
    [Crossref] [Google Scholar]
  14. 14.
    Anacker DC, Moody CA. 2017. Modulation of the DNA damage response during the life cycle of human papillomaviruses. Virus Res. 231:41–49
    [Crossref] [Google Scholar]
  15. 15.
    Gusho E, Laimins L. 2021. Human papillomaviruses target the DNA damage repair and innate immune response pathways to allow for persistent infection. Viruses 13:71390
    [Crossref] [Google Scholar]
  16. 16.
    Graham SV. 2017. Keratinocyte differentiation-dependent human papillomavirus gene regulation. Viruses 9:9245
    [Crossref] [Google Scholar]
  17. 17.
    Egawa N, Nakahara T, Ohno S, Narisawa-Saito M, Yugawa T et al. 2012. The E1 protein of human papillomavirus type 16 is dispensable for maintenance replication of the viral genome. J. Virol. 86:3276–83
    [Crossref] [Google Scholar]
  18. 18.
    Hoffmann R, Hirt B, Bechtold V, Beard P, Raj K 2006. Different modes of human papillomavirus DNA replication during maintenance. J. Virol. 80:4431–39
    [Crossref] [Google Scholar]
  19. 19.
    Vats A, Trejo-Cerro O, Thomas M, Banks L 2021. Human papillomavirus E6 and E7: What remains?. Tumour Virus Res. 11:200213
    [Crossref] [Google Scholar]
  20. 20.
    Sun TT, Green H. 1976. Differentiation of the epidermal keratinocyte in cell culture: formation of the cornified envelope. Cell 9:511–21
    [Crossref] [Google Scholar]
  21. 21.
    White EA. 2019. Manipulation of epithelial differentiation by HPV oncoproteins. Viruses 11:4369
    [Crossref] [Google Scholar]
  22. 22.
    Cheng S, Schmidt-Grimminger DC, Murant T, Broker TR, Chow LT. 1995. Differentiation-dependent up-regulation of the human papillomavirus E7 gene reactivates cellular DNA replication in suprabasal differentiated keratinocytes. Genes Dev. 9:2335–49
    [Crossref] [Google Scholar]
  23. 23.
    Flores ER, Allen-Hoffmann BL, Lee D, Lambert PF 2000. The human papillomavirus type 16 E7 oncogene is required for the productive stage of the viral life cycle. J. Virol. 74:6622–31
    [Crossref] [Google Scholar]
  24. 24.
    Garner-Hamrick PA, Fostel JM, Chien WM, Banerjee NS, Chow LT et al. 2004. Global effects of human papillomavirus type 18 E6/E7 in an organotypic keratinocyte culture system. J. Virol. 78:9041–50
    [Crossref] [Google Scholar]
  25. 25.
    Scheffner M, Huibregtse JM, Vierstra RD, Howley PM. 1993. The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 75:495–505
    [Crossref] [Google Scholar]
  26. 26.
    Banerjee NS, Wang H-K, Broker TR, Chow LT. 2011. Human papillomavirus (HPV) E7 induces prolonged G2 following S phase reentry in differentiated human keratinocytes. J. Biol. Chem. 286:15473–82
    [Crossref] [Google Scholar]
  27. 27.
    Chow LT, Duffy AA, Wang HK, Broker TR. 2009. A highly efficient system to produce infectious human papillomavirus: elucidation of natural virus-host interactions. Cell Cycle 8:1319–23
    [Crossref] [Google Scholar]
  28. 28.
    Blackford AN, Jackson SP. 2017. ATM, ATR, and DNA-PK: the trinity at the heart of the DNA damage response. Mol. Cell 66:801–17
    [Crossref] [Google Scholar]
  29. 29.
    Ciccia A, Elledge SJ. 2010. The DNA damage response: making it safe to play with knives. Mol. Cell 40:179–204
    [Crossref] [Google Scholar]
  30. 30.
    Hustedt N, Durocher D. 2016. The control of DNA repair by the cell cycle. Nat. Cell Biol. 19:1–9
    [Crossref] [Google Scholar]
  31. 31.
    Stucki M, Clapperton JA, Mohammad D, Yaffe MB, Smerdon SJ, Jackson SP. 2005. MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks. Cell 123:1213–26
    [Crossref] [Google Scholar]
  32. 32.
    Thorslund T, Ripplinger A, Hoffmann S, Wild T, Uckelmann M et al. 2015. Histone H1 couples initiation and amplification of ubiquitin signaling after DNA damage. Nature 527:389–93
    [Crossref] [Google Scholar]
  33. 33.
    Kelliher J, Ghosal G, Leung JWC. 2022. New answers to the old RIDDLE: RNF168 and the DNA damage response pathway. FEBS J. 289:2467–80
    [Crossref] [Google Scholar]
  34. 34.
    Bunting SF, Callen E, Wong N, Chen HT, Polato F et al. 2010. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell 141:243–54
    [Crossref] [Google Scholar]
  35. 35.
    Chapman JR, Sossick AJ, Boulton SJ, Jackson SP. 2012. BRCA1-associated exclusion of 53BP1 from DNA damage sites underlies temporal control of DNA repair. J. Cell Sci. 125:3529–34
    [Crossref] [Google Scholar]
  36. 36.
    Kakarougkas A, Ismail A, Katsuki Y, Freire R, Shibata A, Jeggo PA. 2013. Co-operation of BRCA1 and POH1 relieves the barriers posed by 53BP1 and RAP80 to resection. Nucleic Acids Res. 41:10298–311
    [Crossref] [Google Scholar]
  37. 37.
    Densham RM, Garvin AJ, Stone HR, Strachan J, Baldock RA et al. 2016. Human BRCA1-BARD1 ubiquitin ligase activity counteracts chromatin barriers to DNA resection. Nat. Struct. Mol. Biol. 23:647–55
    [Crossref] [Google Scholar]
  38. 38.
    Zhao F, Kim W, Kloeber JA, Lou Z. 2020. DNA end resection and its role in DNA replication and DSB repair choice in mammalian cells. Exp. Mol. Med. 52:1705–14
    [Crossref] [Google Scholar]
  39. 39.
    Lieber MR. 2010. The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu. Rev. Biochem. 79:181–211
    [Crossref] [Google Scholar]
  40. 40.
    Betermier M, Bertrand P, Lopez BS. 2014. Is non-homologous end-joining really an inherently error-prone process?. PLOS Genet. 10:e1004086
    [Crossref] [Google Scholar]
  41. 41.
    Zeman MK, Cimprich KA. 2014. Causes and consequences of replication stress. Nat. Cell Biol. 16:2–9
    [Crossref] [Google Scholar]
  42. 42.
    Saldivar JC, Cortez D, Cimprich KA. 2017. The essential kinase ATR: ensuring faithful duplication of a challenging genome. Nat. Rev. Mol. Cell Biol. 18:10622–36
    [Crossref] [Google Scholar]
  43. 43.
    Fanning E, Klimovich V, Nager AR. 2006. A dynamic model for replication protein A (RPA) function in DNA processing pathways. Nucleic Acids Res. 34:4126–37
    [Crossref] [Google Scholar]
  44. 44.
    Murphy AK, Fitzgerald M, Ro T, Kim JH, Rabinowitsch AI et al. 2014. Phosphorylated RPA recruits PALB2 to stalled DNA replication forks to facilitate fork recovery. J. Cell Biol. 206:493–507
    [Crossref] [Google Scholar]
  45. 45.
    Liu S, Opiyo SO, Manthey K, Glanzer JG, Ashley AK et al. 2012. Distinct roles for DNA-PK, ATM and ATR in RPA phosphorylation and checkpoint activation in response to replication stress. Nucleic Acids Res. 40:10780–94
    [Crossref] [Google Scholar]
  46. 46.
    da Costa A, Chowdhury D, Shapiro GI, D'Andrea AD, Konstantinopoulos PA. 2023. Targeting replication stress in cancer therapy. Nat. Rev. Drug Discov. 22:38–58
    [Crossref] [Google Scholar]
  47. 47.
    Banerjee NS, Wang HK, Broker TR, Chow LT. 2011. Human papillomavirus (HPV) E7 induces prolonged G2 following S phase reentry in differentiated human keratinocytes. J. Biol. Chem. 286:15473–82
    [Crossref] [Google Scholar]
  48. 48.
    Moody CA, Laimins LA. 2009. Human papillomaviruses activate the ATM DNA damage pathway for viral genome amplification upon differentiation. PLOS Pathog. 5:e1000605
    [Crossref] [Google Scholar]
  49. 49.
    Hong S, Cheng S, Iovane A, Laimins LA. 2015. STAT-5 regulates transcription of the topoisomerase IIβ-binding protein 1 (TopBP1) gene to activate the ATR pathway and promote human papillomavirus replication. mBio 6:e02006–15
    [Crossref] [Google Scholar]
  50. 50.
    Anacker DC, Aloor HL, Shepard CN, Lenzi GM, Johnson BA et al. 2016. HPV31 utilizes the ATR-Chk1 pathway to maintain elevated RRM2 levels and a replication-competent environment in differentiating Keratinocytes. Virology 499:383–96
    [Crossref] [Google Scholar]
  51. 51.
    King LE, Fisk JC, Dornan ES, Donaldson MM, Melendy T, Morgan IM. 2010. Human papillomavirus E1 and E2 mediated DNA replication is not arrested by DNA damage signaling. Virology 406:95–102
    [Crossref] [Google Scholar]
  52. 52.
    Mehta K, Gunasekharan V, Satsuka A, Laimins LA. 2015. Human papillomaviruses activate and recruit SMC1 cohesin proteins for the differentiation-dependent life cycle through association with CTCF insulators. PLOS Pathog. 11:e1004763
    [Crossref] [Google Scholar]
  53. 53.
    Fradet-Turcotte A, Bergeron-Labrecque F, Moody CA, Lehoux M, Laimins LA, Archambault J. 2011. Nuclear accumulation of the papillomavirus E1 helicase blocks S-phase progression and triggers an ATM-dependent DNA damage response. J. Virol. 85:8996–9012
    [Crossref] [Google Scholar]
  54. 54.
    Gillespie KA, Mehta KP, Laimins LA, Moody CA. 2012. Human papillomaviruses recruit cellular DNA repair and homologous recombination factors to viral replication centers. J. Virol. 86:9520–26
    [Crossref] [Google Scholar]
  55. 55.
    Anacker DC, Gautam D, Gillespie KA, Chappell WH, Moody CA. 2014. Productive replication of human papillomavirus 31 requires DNA repair factor Nbs1. J. Virol. 88:8528–44
    [Crossref] [Google Scholar]
  56. 56.
    Chappell WH, Gautam D, Ok ST, Johnson BA, Anacker DC, Moody CA. 2015. Homologous recombination repair factors Rad51 and BRCA1 are necessary for productive replication of human papillomavirus 31. J. Virol. 90:2639–52
    [Crossref] [Google Scholar]
  57. 57.
    Flores ER, Lambert PF. 1997. Evidence for a switch in the mode of human papillomavirus type 16 DNA replication during the viral life cycle. J. Virol. 71:7167–79
    [Crossref] [Google Scholar]
  58. 58.
    Mehta K, Laimins L. 2018. Human papillomaviruses preferentially recruit DNA repair factors to viral genomes for rapid repair and amplification. mBio 9:e00064–18
    [Crossref] [Google Scholar]
  59. 59.
    Gudjonsson T, Altmeyer M, Savic V, Toledo L, Dinant C et al. 2012. TRIP12 and UBR5 suppress spreading of chromatin ubiquitylation at damaged chromosomes. Cell 150:697–709
    [Crossref] [Google Scholar]
  60. 60.
    Sitz J, Blanchet SA, Gameiro SF, Biquand E, Morgan TM et al. 2019. Human papillomavirus E7 oncoprotein targets RNF168 to hijack the host DNA damage response. PNAS 116:19552–62
    [Crossref] [Google Scholar]
  61. 61.
    Becker JR, Clifford G, Bonnet C, Groth A, Wilson MD, Chapman JR. 2021. BARD1 reads H2A lysine 15 ubiquitination to direct homologous recombination. Nature 596:433–37
    [Crossref] [Google Scholar]
  62. 62.
    Luijsterburg MS, Typas D, Caron MC, Wiegant WW, van den Heuvel D et al. 2017. A PALB2-interacting domain in RNF168 couples homologous recombination to DNA break-induced chromatin ubiquitylation. eLife 6:e20922
    [Crossref] [Google Scholar]
  63. 63.
    Alves-Fernandes DK, Jasiulionis MG 2019. The role of SIRT1 on DNA damage response and epigenetic alterations in cancer. Int. J. Mol. Sci. 20:3153
    [Crossref] [Google Scholar]
  64. 64.
    Oberdoerffer P, Michan S, McVay M, Mostoslavsky R, Vann J et al. 2008. SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell 135:907–18
    [Crossref] [Google Scholar]
  65. 65.
    Uhl M, Csernok A, Aydin S, Kreienberg R, Wiesmuller L, Gatz SA. 2010. Role of SIRT1 in homologous recombination. DNA Repair 9:383–93
    [Crossref] [Google Scholar]
  66. 66.
    Langsfeld ES, Bodily JM, Laimins LA. 2015. The deacetylase sirtuin 1 regulates human papillomavirus replication by modulating histone acetylation and recruitment of DNA damage factors NBS1 and Rad51 to viral genomes. PLOS Pathog. 11:e1005181
    [Crossref] [Google Scholar]
  67. 67.
    Das D, Bristol ML, Smith NW, James CD, Wang X et al. 2019. Werner helicase control of human papillomavirus 16 E1-E2 DNA replication is regulated by SIRT1 deacetylation. mBio 10:2e00263–19
    [Crossref] [Google Scholar]
  68. 68.
    James CD, Das D, Morgan EL, Otoa R, Macdonald A, Morgan IM. 2020. Werner Syndrome protein (WRN) regulates cell proliferation and the human papillomavirus 16 life cycle during epithelial differentiation. mSphere 5:5e00858–20
    [Crossref] [Google Scholar]
  69. 69.
    Mukherjee S, Sinha D, Bhattacharya S, Srinivasan K, Abdisalaam S, Asaithamby A. 2018. Werner syndrome protein and DNA replication. Int. J. Mol. Sci. 19:113442
    [Crossref] [Google Scholar]
  70. 70.
    Aymard F, Bugler B, Schmidt CK, Guillou E, Caron P et al. 2014. Transcriptionally active chromatin recruits homologous recombination at DNA double-strand breaks. Nat. Struct. Mol. Biol. 21:366–74
    [Crossref] [Google Scholar]
  71. 71.
    Marnef A, Cohen S, Legube G. 2017. Transcription-coupled DNA double-strand break repair: Active genes need special care. J. Mol. Biol. 429:1277–88
    [Crossref] [Google Scholar]
  72. 72.
    Khurana S, Markowitz TE, Kabat J, McBride AA. 2021. Spatial and functional organization of human papillomavirus replication foci in the productive stage of infection. mBio 12:e0268421
    [Crossref] [Google Scholar]
  73. 73.
    Gautam D, Johnson BA, Mac M, Moody CA. 2018. SETD2-dependent H3K36me3 plays a critical role in epigenetic regulation of the HPV31 life cycle. PLOS Pathog. 14:e1007367
    [Crossref] [Google Scholar]
  74. 74.
    Cao LL, Wei F, Du Y, Song B, Wang D et al. 2016. ATM-mediated KDM2A phosphorylation is required for the DNA damage repair. Oncogene 35:402
    [Crossref] [Google Scholar]
  75. 75.
    Mallette FA, Mattiroli F, Cui G, Young LC, Hendzel MJ et al. 2012. RNF8- and RNF168-dependent degradation of KDM4A/JMJD2A triggers 53BP1 recruitment to DNA damage sites. EMBO J. 31:1865–78
    [Crossref] [Google Scholar]
  76. 76.
    Sakakibara N, Mitra R, McBride AA 2011. The papillomavirus E1 helicase activates a cellular DNA damage response in viral replication foci. J. Virol. 85:8981–95
    [Crossref] [Google Scholar]
  77. 77.
    Fradet-Turcotte A, Moody C, Laimins LA, Archambault J. 2010. Nuclear export of human papillomavirus type 31 E1 is regulated by Cdk2 phosphorylation and required for viral genome maintenance. J. Virol. 84:11747–60
    [Crossref] [Google Scholar]
  78. 78.
    Duensing S, Munger K. 2002. The human papillomavirus type 16 E6 and E7 oncoproteins independently induce numerical and structural chromosome instability. Cancer Res. 62:7075–82
    [Google Scholar]
  79. 79.
    Shah GA, O'Shea CC 2015. Viral and cellular genomes activate distinct DNA damage responses. Cell 162:987–1002
    [Crossref] [Google Scholar]
  80. 80.
    Hong S, Laimins LA. 2013. The JAK-STAT transcriptional regulator, STAT-5, activates the ATM DNA damage pathway to induce HPV 31 genome amplification upon epithelial differentiation. PLOS Pathog. 9:e1003295
    [Crossref] [Google Scholar]
  81. 81.
    Hong S, Dutta A, Laimins LA. 2015. The acetyltransferase Tip60 is a critical regulator of the differentiation-dependent amplification of human papillomaviruses. J. Virol. 89:4668–75
    [Crossref] [Google Scholar]
  82. 82.
    Johnson BJ, Aloor HL, Moody CA. 2017. The Rb binding domain of HPV31 E7 is required to maintain high levels of DNA repair factors in infected cells. Virology 500:22–34
    [Crossref] [Google Scholar]
  83. 83.
    Pickering MT, Kowalik TF. 2006. Rb inactivation leads to E2F1-mediated DNA double-strand break accumulation. Oncogene 25:746–55
    [Crossref] [Google Scholar]
  84. 84.
    Kaminski P, Hong S, Kono T, Hoover P, Laimins L. 2021. Topoisomerase 2β induces DNA breaks to regulate human papillomavirus replication. mBio 12:1e00005–21
    [Crossref] [Google Scholar]
  85. 85.
    Pommier Y, Nussenzweig A, Takeda S, Austin C. 2022. Human topoisomerases and their roles in genome stability and organization. Nat. Rev. Mol. Cell Biol. 23:407–27
    [Crossref] [Google Scholar]
  86. 86.
    Lang F, Li X, Zheng W, Li Z, Lu D et al. 2017. CTCF prevents genomic instability by promoting homologous recombination-directed DNA double-strand break repair. PNAS 114:10912–17
    [Crossref] [Google Scholar]
  87. 87.
    Bester AC, Roniger M, Oren YS, Im MM, Sarni D et al. 2011. Nucleotide deficiency promotes genomic instability in early stages of cancer development. Cell 145:435–46
    [Crossref] [Google Scholar]
  88. 88.
    Spardy N, Duensing A, Hoskins EE, Wells SI, Duensing S. 2008. HPV-16 E7 reveals a link between DNA replication stress, fanconi anemia D2 protein, and alternative lengthening of telomere-associated promyelocytic leukemia bodies. Cancer Res. 68:9954–63
    [Crossref] [Google Scholar]
  89. 89.
    Edwards TG, Helmus MJ, Koeller K, Bashkin JK, Fisher C. 2013. Human papillomavirus episome stability is reduced by aphidicolin and controlled by DNA damage response pathways. J. Virol. 87:3979–89
    [Crossref] [Google Scholar]
  90. 90.
    Reinson T, Toots M, Kadaja M, Pipitch R, Allik M et al. 2013. Engagement of the ATR-dependent DNA damage response at the human papillomavirus 18 replication centers during the initial amplification. J. Virol. 87:951–64
    [Crossref] [Google Scholar]
  91. 91.
    Orav M, Geimanen J, Sepp EM, Henno L, Ustav E, Ustav M. 2015. Initial amplification of the HPV18 genome proceeds via two distinct replication mechanisms. Sci. Rep. 5:15952
    [Crossref] [Google Scholar]
  92. 92.
    Liblekas L, Piirsoo A, Laanemets A, Tombak EM, Laanevali A et al. 2021. Analysis of the replication mechanisms of the human papillomavirus genomes. Front. Microbiol. 12:738125
    [Crossref] [Google Scholar]
  93. 93.
    Berti M, Vindigni A. 2016. Replication stress: getting back on track. Nat. Struct. Mol. Biol. 23:103–9
    [Crossref] [Google Scholar]
  94. 94.
    Matos DA, Zhang JM, Ouyang J, Nguyen HD, Genois MM, Zou L. 2020. ATR protects the genome against R loops through a MUS81-triggered feedback loop. Mol. Cell 77:514–27
    [Crossref] [Google Scholar]
  95. 95.
    Hamperl S, Cimprich KA. 2016. Conflict resolution in the genome: how transcription and replication make it work. Cell 167:1455–67
    [Crossref] [Google Scholar]
  96. 96.
    Barroso S, Herrera-Moyano E, Munoz S, Garcia-Rubio M, Gomez-Gonzalez B, Aguilera A. 2019. The DNA damage response acts as a safeguard against harmful DNA-RNA hybrids of different origins. EMBO Rep. 20:e47250
    [Crossref] [Google Scholar]
  97. 97.
    Santos-Pereira JM, Aguilera A. 2015. R loops: new modulators of genome dynamics and function. Nat. Rev. Genet. 16:583–97
    [Crossref] [Google Scholar]
  98. 98.
    Sollier J, Cimprich KA. 2015. Breaking bad: R-loops and genome integrity. Trends Cell Biol. 25:514–22
    [Crossref] [Google Scholar]
  99. 99.
    Petermann E, Lan L, Zou L. 2022. Sources, resolution and physiological relevance of R-loops and RNA-DNA hybrids. Nat. Rev. Mol. Cell Biol. 23:521–40
    [Crossref] [Google Scholar]
  100. 100.
    Bertoli C, Herlihy AE, Pennycook BR, Kriston-Vizi J, de Bruin RAM. 2016. Sustained E2F-dependent transcription is a key mechanism to prevent replication-stress-induced DNA damage. Cell Rep. 15:1412–22
    [Crossref] [Google Scholar]
  101. 101.
    Buisson R, Boisvert JL, Benes CH, Zou L. 2015. Distinct but concerted roles of ATR, DNA-PK, and Chk1 in countering replication stress during S phase. Mol. Cell 59:1011–24
    [Crossref] [Google Scholar]
  102. 102.
    Kim D, Liu Y, Oberly S, Freire R, Smolka MB. 2018. ATR-mediated proteome remodeling is a major determinant of homologous recombination capacity in cancer cells. Nucleic Acids Res. 46:8311–25
    [Crossref] [Google Scholar]
  103. 103.
    Hong S, Li Y, Kaminski PJ, Andrade J, Laimins LA. 2020. Pathogenesis of human papillomaviruses requires the ATR/p62 autophagy-related pathway. mBio 11:4e01628–20
    [Crossref] [Google Scholar]
  104. 104.
    LaFleur DW, Nardelli B, Tsareva T, Mather D, Feng P et al. 2001. Interferon-κ, a novel type I interferon expressed in human keratinocytes. J. Biol. Chem. 276:39765–71
    [Crossref] [Google Scholar]
  105. 105.
    Spardy N, Covella K, Cha E, Hoskins EE, Wells SI et al. 2009. Human papillomavirus 16 E7 oncoprotein attenuates DNA damage checkpoint control by increasing the proteolytic turnover of claspin. Cancer Res. 69:7022–29
    [Crossref] [Google Scholar]
  106. 106.
    Debatisse M, Le Tallec B, Letessier A, Dutrillaux B, Brison O 2012. Common fragile sites: mechanisms of instability revisited. Trends Genet. 28:22–32
    [Crossref] [Google Scholar]
  107. 107.
    Korzeniewski N, Spardy N, Duensing A, Duensing S. 2011. Genomic instability and cancer: lessons learned from human papillomaviruses. Cancer Lett. 305:113–22
    [Crossref] [Google Scholar]
  108. 108.
    Lecona E, Fernandez-Capetillo O. 2014. Replication stress and cancer: It takes two to tango. Exp. Cell Res. 329:26–34
    [Crossref] [Google Scholar]
  109. 109.
    Munger K, Jones DL. 2015. Human papillomavirus carcinogenesis: an identity crisis in the retinoblastoma tumor suppressor pathway. J. Virol. 89:4708–11
    [Crossref] [Google Scholar]
  110. 110.
    Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D et al. 2006. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444:633–37
    [Crossref] [Google Scholar]
  111. 111.
    Wang N, Zhan T, Ke T, Huang X, Ke D et al. 2014. Increased expression of RRM2 by human papillomavirus E7 oncoprotein promotes angiogenesis in cervical cancer. Br. J. Cancer 110:1034–44
    [Crossref] [Google Scholar]
  112. 112.
    Soto DR, Barton C, Munger K, McLaughlin-Drubin ME. 2017. KDM6A addiction of cervical carcinoma cell lines is triggered by E7 and mediated by p21CIP1 suppression of replication stress. PLOS Pathog. 13:e1006661
    [Crossref] [Google Scholar]
  113. 113.
    Funk JO, Waga S, Harry JB, Espling E, Stillman B, Galloway DA. 1997. Inhibition of CDK activity and PCNA-dependent DNA replication by p21 is blocked by interaction with the HPV-16 E7 oncoprotein. Genes Dev. 11:2090–100
    [Crossref] [Google Scholar]
  114. 114.
    Jones DL, Alani RM, Munger K. 1997. The human papillomavirus E7 oncoprotein can uncouple cellular differentiation and proliferation in human keratinocytes by abrogating p21Cip1-mediated inhibition of cdk2. Genes Dev. 11:2101–11
    [Crossref] [Google Scholar]
  115. 115.
    He W, Staples D, Smith C, Fisher C. 2003. Direct activation of cyclin-dependent kinase 2 by human papillomavirus E7. J. Virol. 77:10566–74
    [Crossref] [Google Scholar]
  116. 116.
    Sakakibara N, Chen D, McBride AA 2013. Papillomaviruses use recombination-dependent replication to vegetatively amplify their genomes in differentiated cells. PLOS Pathog. 9:e1003321
    [Crossref] [Google Scholar]
  117. 117.
    Wilkinson DE, Weller SK. 2003. The role of DNA recombination in herpes simplex virus DNA replication. IUBMB Life 55:451–58
    [Crossref] [Google Scholar]
  118. 118.
    Lo Piano A, Martinez-Jimenez MI, Zecchi L, Ayora S. 2011. Recombination-dependent concatemeric viral DNA replication. Virus Res. 160:1–14
    [Crossref] [Google Scholar]
  119. 119.
    Liao H, Ji F, Helleday T, Ying S 2018. Mechanisms for stalled replication fork stabilization: new targets for synthetic lethality strategies in cancer treatments. EMBO Rep. 19:9e46263
    [Crossref] [Google Scholar]
  120. 120.
    Saleh-Gohari N, Bryant HE, Schultz N, Parker KM, Cassel TN, Helleday T. 2005. Spontaneous homologous recombination is induced by collapsed replication forks that are caused by endogenous DNA single-strand breaks. Mol. Cell. Biol. 25:7158–69
    [Crossref] [Google Scholar]
  121. 121.
    Li X, Stith CM, Burgers PM, Heyer WD. 2009. PCNA is required for initiation of recombination-associated DNA synthesis by DNA polymerase δ. Mol. Cell 36:704–13
    [Crossref] [Google Scholar]
  122. 122.
    Duensing S, Munger K. 2004. Mechanisms of genomic instability in human cancer: insights from studies with human papillomavirus oncoproteins. Int. J. Cancer 109:157–62
    [Crossref] [Google Scholar]
  123. 123.
    Moody CA. 2022. Regulation of the innate immune response during the human papillomavirus life cycle. Viruses 14:81797
    [Crossref] [Google Scholar]
  124. 124.
    Thorland EC, Myers SL, Gostout BS, Smith DI. 2003. Common fragile sites are preferential targets for HPV16 integrations in cervical tumors. Oncogene 22:1225–37
    [Crossref] [Google Scholar]
  125. 125.
    Bodelon C, Untereiner ME, Machiela MJ, Vinokurova S, Wentzensen N. 2016. Genomic characterization of viral integration sites in HPV-related cancers. Int. J. Cancer 139:2001–11
    [Crossref] [Google Scholar]
  126. 126.
    McBride AA, Warburton A. 2017. The role of integration in oncogenic progression of HPV-associated cancers. PLOS Pathog. 13:e1006211
    [Crossref] [Google Scholar]
  127. 127.
    Kadaja M, Isok-Paas H, Laos T, Ustav E, Ustav M. 2009. Mechanism of genomic instability in cells infected with the high-risk human papillomaviruses. PLOS Pathog 5:e1000397
    [Crossref] [Google Scholar]
  128. 128.
    Christiansen IK, Sandve GK, Schmitz M, Dürst M, Hovig E. 2015. Transcriptionally active regions are the preferred targets for chromosomal HPV integration in cervical carcinogenesis. PLOS ONE 10:e0119566
    [Crossref] [Google Scholar]
  129. 129.
    DeFilippis RA, Goodwin EC, Wu L, DiMaio D. 2003. Endogenous human papillomavirus E6 and E7 proteins differentially regulate proliferation, senescence, and apoptosis in HeLa cervical carcinoma cells. J. Virol. 77:1551–63
    [Crossref] [Google Scholar]
  130. 130.
    Leeman JE, Li Y, Bell A, Hussain SS, Majumdar R et al. 2019. Human papillomavirus 16 promotes microhomology-mediated end-joining. PNAS 116:21573–79
    [Crossref] [Google Scholar]
  131. 131.
    Hu Z, Zhu D, Wang W, Li W, Jia W et al. 2015. Genome-wide profiling of HPV integration in cervical cancer identifies clustered genomic hot spots and a potential microhomology-mediated integration mechanism. Nat. Genet. 47:158–63
    [Crossref] [Google Scholar]
  132. 132.
    Czech-Sioli M, Günther T, Therre M, Spohn M, Indenbirken D et al. 2020. High-resolution analysis of Merkel cell polyomavirus in Merkel cell carcinoma reveals distinct integration patterns and suggests NHEJ and MMBIR as underlying mechanisms. PLOS Pathog. 16:e1008562
    [Crossref] [Google Scholar]
  133. 133.
    van de Kooij B, Kruswick A, van Attikum H, Yaffe MB. 2022. Multi-pathway DNA-repair reporters reveal competition between end-joining, single-strand annealing and homologous recombination at Cas9-induced DNA double-strand breaks. Nat. Commun. 13:5295
    [Crossref] [Google Scholar]
  134. 134.
    Wyatt DW, Feng W, Conlin MP, Yousefzadeh MJ, Roberts SA et al. 2016. Essential roles for polymerase θ-mediated end joining in the repair of chromosome breaks. Mol. Cell 63:662–73
    [Crossref] [Google Scholar]
  135. 135.
    Ma Z, Ni G, Damania B. 2018. Innate sensing of DNA virus genomes. Annu. Rev. Virol. 5:341–62
    [Crossref] [Google Scholar]
  136. 136.
    Ye Z, Shi Y, Lees-Miller SP, Tainer JA 2021. Function and molecular mechanism of the DNA damage response in immunity and cancer immunotherapy. Front. Immunol. 12:797880
    [Crossref] [Google Scholar]
  137. 137.
    Wischnewski M, Ablasser A. 2021. Interplay of cGAS with chromatin. Trends Biochem. Sci. 46:822–31
    [Crossref] [Google Scholar]
  138. 138.
    Motwani M, Pesiridis S, Fitzgerald KA. 2019. DNA sensing by the cGAS-STING pathway in health and disease. Nat. Rev. Genet. 20:657–74
    [Crossref] [Google Scholar]
  139. 139.
    James CD, Das D, Bristol ML, Morgan IM. 2020. Activating the DNA damage response and suppressing innate immunity: Human papillomaviruses walk the line. Pathogens 9:6467
    [Crossref] [Google Scholar]
  140. 140.
    Gusho E, Laimins LA. 2022. Human papillomaviruses sensitize cells to DNA damage induced apoptosis by targeting the innate immune sensor cGAS. PLOS Pathog. 18:e1010725
    [Crossref] [Google Scholar]
  141. 141.
    Wolf C, Rapp A, Berndt N, Staroske W, Schuster M et al. 2016. RPA and Rad51 constitute a cell intrinsic mechanism to protect the cytosol from self DNA. Nat. Commun. 7:11752
    [Crossref] [Google Scholar]
  142. 142.
    Prati B, da Silva Abjaude W, Termini L, Morale M, Herbster S et al. 2019. Three Prime Repair Exonuclease 1 (TREX1) expression correlates with cervical cancer cells growth in vitro and disease progression in vivo. Sci. Rep. 9:351
    [Crossref] [Google Scholar]
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