{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T02:57:43Z","timestamp":1792205863756,"version":"4.4.0"},"reference-count":67,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,28]],"date-time":"2022-07-28T00:00:00Z","timestamp":1658966400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>Cervical cancer is the fourth most common cancer in women worldwide. More than 90% of cases are caused by the human papillomavirus (HPV). Vaccines developed only guard against a few HPV types and do not protect people who have already been infected. HPV is a small DNA virus that infects the basal layer of the stratified epithelium of the skin and mucosa through small breaks and replicates as the cells differentiate. The mucosal types of HPV can be classified into low-risk and high-risk groups, based on their association with cancer. Among HPV types in high-risk group, HPV type 16 (HPV-16) is the most common, causing 50% of all cancer cases. HPV infection can occur as transient or persistent infections, based on the ability of immune system to clear the virus. Persistent infection is characterized by the integration of HPV genome. HPV-16 exhibits a different integration pattern, with only 50% reported to be integrated at the carcinoma stage. Replication of the HPV genome depends on protein E1, an ATP-dependent helicase. E1 is essential for the amplification of the viral episome in infected cells. Previous studies have shown that E1 does not only act as a helicase protein but is also involved in recruiting and interacting with other host proteins. E1 has also been deemed to drive host cell proliferation. Recent studies have emphasized the emerging role of HPV E1 in cervical carcinogenesis. In this review, a possible mechanism by which E1 drives cell proliferation and oncogenesis will be discussed.<\/jats:p>","DOI":"10.3389\/fcimb.2022.955847","type":"journal-article","created":{"date-parts":[[2022,7,28]],"date-time":"2022-07-28T13:20:17Z","timestamp":1659014417000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":27,"title":["Role of HPV16 E1 in cervical carcinogenesis"],"prefix":"10.3389","volume":"12","author":[{"given":"Fern","family":"Baedyananda","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thanayod","family":"Sasivimolrattana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arkom","family":"Chaiwongkot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shankar","family":"Varadarajan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parvapan","family":"Bhattarakosol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,28]]},"reference":[{"key":"B1","article-title":"Fundamentals of Molecular Virology. (Hoboken, New Jersey)","volume-title":"USA: John Wiley & Sons, INC","author":"Acheson","year":"2011"},{"key":"B2","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1159\/000487048","article-title":"Elevated HPV16 E1 expression is associated with cervical cancer progression","volume":"60","author":"Baedyananda","year":"2017","journal-title":"Intervirology"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0260841","article-title":"HPV16 E1 dysregulated cellular genes involved in cell proliferation and host DNA damage: A possible role in cervical carcinogenesis","volume":"16","author":"Baedyananda","year":"2021","journal-title":"PloS One"},{"key":"B4","doi-asserted-by":"publisher","first-page":"3853","DOI":"10.1128\/JVI.71.5.3853-3863.1997","article-title":"Functional interactions between papillomavirus E1 and E2 proteins","volume":"71","author":"Berg","year":"1997","journal-title":"J. Virol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.virol.2013.07.020","article-title":"The E1 proteins","volume":"445","author":"Bergvall","year":"2013","journal-title":"Virology"},{"key":"B6","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.lungcan.2009.03.013","article-title":"FOXO3a elicits a pro-apoptotic transcription program and cellular response to human lung carcinogen nicotine-derived nitrosaminoketone (NNK)","volume":"67","author":"Blake","year":"2010","journal-title":"Lung Cancer"},{"key":"B7","doi-asserted-by":"crossref","first-page":"6805","DOI":"10.1128\/jvi.71.9.6805-6815.1997","article-title":"Bovine papillomavirus type 1 DNA replication: the transcriptional activator E2 acts in vitro as a specificity factor","volume":"71","author":"Bonne-Andrea","year":"1997","journal-title":"J. Virol."},{"key":"B8","volume-title":"Medical Microbiology","author":"Brooks","year":"2013"},{"key":"B9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1128\/CMR.16.1.1-17.2003","article-title":"Human papillomavirus and cervical cancer","volume":"16","author":"Burd","year":"2003","journal-title":"Clin. Microbiol. Rev."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1156","DOI":"10.1101\/gad.189837.112","article-title":"Structures of inactive retinoblastoma protein reveal multiple mechanisms for cell cycle control","volume":"26","author":"Burke","year":"2012","journal-title":"Genes Dev."},{"key":"B11","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.jmb.2013.09.031","article-title":"Multiple mechanisms for E2F binding inhibition by phosphorylation of the retinoblastoma protein c-terminal domain","volume":"426","author":"Burke","year":"2014","journal-title":"J. Mol. Biol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1098\/rsob.130119","article-title":"A systems biology analysis of the changes in gene expression via silencing of HPV-18 E1 expression in HeLa cells","volume":"4","author":"Castillo","year":"2014","journal-title":"Open Biol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"13620","DOI":"10.1038\/s41598-019-49886-4","article-title":"The human papillomavirus (HPV) E1 protein regulates the expression of cellular genes involved in immune response","volume":"9","author":"Castro-Mu\u00f1oz","year":"2019","journal-title":"Sci. Rep."},{"key":"B14","doi-asserted-by":"publisher","first-page":"2087","DOI":"10.1002\/ijc.27906","article-title":"Differential methylation of E2 binding sites in episomal and integrated HPV 16 genomes in preinvasive and invasive cervical lesions","volume":"132","author":"Chaiwongkot","year":"2013","journal-title":"Int. J. Cancer"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/3257939","article-title":"Human papillomavirus infection and cervical cancer: Epidemiology, screening, and vaccination-review of current perspectives","volume":"2019","author":"Chan","year":"2019","journal-title":"J. Oncol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1093\/nar\/gkx1103","article-title":"The human papillomavirus DNA helicase E1 binds, stimulates, and confers processivity to cellular DNA polymerase epsilon","volume":"46","author":"Chojnacki","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"B17","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1016\/0092-8674(91)90529-8","article-title":"Degradation of p53 can be targeted by HPV E6 sequences distinct from those required for p53 binding and trans-activation","volume":"67","author":"Crook","year":"1991","journal-title":"Cell"},{"key":"B18","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1006\/viro.1996.0171","article-title":"Analysis of HPV1 E4 complexes and their association with keratins in vivo","volume":"218","author":"Doorbar","year":"1996","journal-title":"Virology"},{"key":"B19","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1038\/nature04943","article-title":"Mechanism of DNA translocation in a replicative hexameric helicase","volume":"442","author":"Enemark","year":"2006","journal-title":"Nature"},{"key":"B20","doi-asserted-by":"publisher","first-page":"21730","DOI":"10.1074\/jbc.M200113200","article-title":"The human papillomavirus 16 E6 protein binds to tumor necrosis factor (TNF) R1 and protects cells from TNF-induced apoptosis","volume":"277","author":"Filippova","year":"2002","journal-title":"J. Biol. Chem."},{"key":"B21","doi-asserted-by":"publisher","first-page":"8996","DOI":"10.1128\/JVI.00542-11","article-title":"Nuclear accumulation of the papillomavirus E1 helicase blocks s-phase progression and triggers an ATM-dependent DNA damage response","volume":"85","author":"Fradet-Turcotte","year":"2011","journal-title":"J. Virol."},{"key":"B22","doi-asserted-by":"crossref","first-page":"12398","DOI":"10.1073\/pnas.91.26.12398","article-title":"Binding of the human papillomavirus E1 origin-recognition protein is regulated through complex formation with the E2 enhancer-binding protein","volume":"91","author":"Frattini","year":"1994","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B23","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1007\/s13402-011-0069-x","article-title":"Human papillomavirus-16 E5 protein: oncogenic role and therapeutic value","volume":"35","author":"Ganguly","year":"2012","journal-title":"Cell Oncol. (Dordr)"},{"key":"B24","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/S0165-4608(96)00336-6","article-title":"Bloom's syndrome. XX. the first 100 cancers","volume":"93","author":"German","year":"1997","journal-title":"Cancer Genet. Cytogenet."},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3332\/ecancer.2015.526","article-title":"Role of human papillomaviruses in carcinogenesis","volume":"9","author":"Ghittoni","year":"2015","journal-title":"Ecancermedicalscience"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/v9090245","article-title":"Keratinocyte differentiation-dependent human papillomavirus gene regulation","volume":"9","author":"Graham","year":"2017","journal-title":"Viruses"},{"key":"B27","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/s0092-8674(00)81683-9","article-title":"The hallmarks of cancer","volume":"100","author":"Hanahan","year":"2000","journal-title":"Cell"},{"key":"B28","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: the next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2020.596334","article-title":"High levels of within-host variations of human papillomavirus 16 E1\/E2 genes in invasive cervical cancer","volume":"11","author":"Hirose","year":"2020","journal-title":"Front. Microbiol."},{"key":"B30","doi-asserted-by":"crossref","first-page":"5817","DOI":"10.1093\/nar\/21.25.5817","article-title":"E1 protein of human papillomavirus is a DNA helicase\/ATPase","volume":"21","author":"Hughes","year":"1993","journal-title":"Nucleic Acids Res."},{"key":"B31","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1038\/nrc.2016.58","article-title":"A fate worse than death: apoptosis as an oncogenic process","volume":"16","author":"Ichim","year":"2016","journal-title":"Nat. Rev. Cancer"},{"key":"B32","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1002\/1873-3468.13646","article-title":"The homeobox transcription factor HOXC13 upregulates human papillomavirus E1 gene expression and contributes to viral genome maintenance","volume":"594","author":"Ishii","year":"2020","journal-title":"FEBS Lett."},{"key":"B33","doi-asserted-by":"publisher","first-page":"2989","DOI":"10.1128\/JVI.69.5.2989-2997.1995","article-title":"Integration of human papillomavirus type 16 into the human genome correlates with a selective growth advantage of cells","volume":"69","author":"Jeon","year":"1995","journal-title":"J. Virol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1419","DOI":"10.1038\/onc.2011.328","article-title":"GILZ inhibits the mTORC2\/AKT pathway in BCR-ABL(+) cells","volume":"31","author":"Joha","year":"2012","journal-title":"Oncogene"},{"key":"B35","doi-asserted-by":"publisher","first-page":"3737","DOI":"10.1128\/JVI.79.6.3737-3747.2005","article-title":"The global transcriptional effects of the human papillomavirus E6 protein in cervical carcinoma cell lines are mediated by the E6AP ubiquitin ligase","volume":"79","author":"Kelley","year":"2005","journal-title":"J. Virol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.virol.2010.06.033","article-title":"Human papillomavirus E1 and E2 mediated DNA replication is not arrested by DNA damage signalling","volume":"406","author":"King","year":"2010","journal-title":"Virology"},{"key":"B37","doi-asserted-by":"publisher","first-page":"S61","DOI":"10.1093\/carcin\/bgv031","article-title":"Causes of genome instability: the effect of low dose chemical exposures in modern society","author":"Langie","year":"2015","journal-title":"Carcinogenesis"},{"key":"B38","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1128\/MMBR.68.2.362-372.2004","article-title":"Pathogenesis of human papillomaviruses in differentiating epithelia","volume":"68","author":"Longworth","year":"2004","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"B39","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1128\/JVI.78.4.1605-1615.2004","article-title":"Recruitment of replication protein a by the papillomavirus E1 protein and modulation by single-stranded DNA","volume":"78","author":"Loo","year":"2004","journal-title":"J. Virol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"7874","DOI":"10.1038\/sj.onc.1204869","article-title":"The human papillomavirus E6 protein and its contribution to malignant progression","volume":"20","author":"Mantovani","year":"2001","journal-title":"Oncogene"},{"key":"B41","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/978-1-4684-7853-2_5","article-title":"Genetics and aging; the Werner syndrome as a segmental progeroid syndrome","volume":"190","author":"Martin","year":"1985","journal-title":"Adv. Exp. Med. Biol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1016\/j.apsb.2015.05.007","article-title":"HIF-1\u03b1 pathway: role, regulation and intervention for cancer therapy","volume":"5","author":"Masoud","year":"2015","journal-title":"Acta Pharm. Sin. B"},{"key":"B43","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1098\/rstb.2016.0273","article-title":"Oncogenic human papillomaviruses","volume":"372","author":"McBride","year":"2017","journal-title":"Philos. Trans. R Soc. Lond. B Biol. Sci."},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000605","article-title":"Human papillomaviruses activate the ATM DNA damage pathway for viral genome amplification upon differentiation","volume":"5","author":"Moody","year":"2009","journal-title":"PloS Pathog."},{"key":"B45","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1038\/nrc2886","article-title":"Human papillomavirus oncoproteins: pathways to transformation","volume":"10","author":"Moody","year":"2010","journal-title":"Nat. Rev. Cancer"},{"key":"B46","first-page":"197","article-title":"Interactions of HPV E6 and E7 oncoproteins with tumour suppressor gene products","volume":"12","author":"Munger","year":"1992","journal-title":"Cancer Surv."},{"key":"B47","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1038\/nrm2858","article-title":"Genomic instability\u2013an evolving hallmark of cancer","volume":"11","author":"Negrini","year":"2010","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"13039","DOI":"10.1128\/jvi.76.24.13039-13048.2002","article-title":"A mutant of human papillomavirus type 16 E6 deficient in binding alpha-helix partners displays reduced oncogenic potential in vivo","volume":"76","author":"Nguyen","year":"2002","journal-title":"J. Virol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"59","DOI":"10.3109\/00365513.2014.936683","article-title":"HPV and cervical cancer","volume":"244","author":"Petry","year":"2014","journal-title":"Scand. J. Clin. Lab. Invest. Suppl."},{"key":"B50","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1136\/jcp.50.7.600","article-title":"Analysis of HPV16, 18, 31, and 35 DNA in pre-invasive and invasive lesions of the uterine cervix","volume":"50","author":"Pirami","year":"1997","journal-title":"J. Clin. Pathol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"1582","DOI":"10.1086\/516784","article-title":"A 2-year prospective study of human papillomavirus persistence among women with a cytological diagnosis of atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion","volume":"195","author":"Plummer","year":"2007","journal-title":"J. Infect. Dis."},{"key":"B52","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.virusres.2016.11.014","article-title":"Host cell restriction factors that limit transcription and replication of human papillomavirus","volume":"231","author":"Porter","year":"2017","journal-title":"Virus Res."},{"key":"B53","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1128\/JVI.01943-12","article-title":"Engagement of the ATR-dependent DNA damage response at the human papillomavirus 18 replication centers during the initial amplification","volume":"87","author":"Reinson","year":"2013","journal-title":"J. Virol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"2134","DOI":"10.1002\/jmv.21304","article-title":"Identification of a novel human papillomavirus type 16 E1 gene variant with potentially reduced oncogenicity","volume":"80","author":"Sabol","year":"2008","journal-title":"J. Med. Virol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"8981","DOI":"10.1128\/JVI.00541-11","article-title":"The papillomavirus E1 helicase activates a cellular DNA damage response in viral replication foci","volume":"85","author":"Sakakibara","year":"2011","journal-title":"J. Virol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"890","DOI":"10.1016\/S0140-6736(07)61416-0","article-title":"Human papillomavirus and cervical cancer","volume":"370","author":"Schiffman","year":"2007","journal-title":"Lancet"},{"key":"B57","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1016\/j.mcp.2011.05.003","article-title":"The HPV16 transcriptome in cervical lesions of different grades","volume":"25","author":"Schmitt","year":"2011","journal-title":"Mol. Cell Probes"},{"key":"B58","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1038\/sj.cr.7310019","article-title":"Antiviral innate immunity pathways","volume":"16","author":"Seth","year":"2006","journal-title":"Cell Res."},{"key":"B59","doi-asserted-by":"publisher","first-page":"5654","DOI":"10.1158\/1078-0432.CCR-10-0376","article-title":"Foxo3a suppression of urothelial cancer invasiveness through Twist1, y-box-binding protein 1, and e-cadherin regulation","volume":"16","author":"Shiota","year":"2010","journal-title":"Clin. Cancer Res."},{"key":"B60","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1007\/s00432-011-1125-7","article-title":"Expression and prognosis of FOXO3a and HIF-1alpha in nasopharyngeal carcinoma","volume":"138","author":"Shou","year":"2012","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"B61","doi-asserted-by":"publisher","first-page":"2199","DOI":"10.1002\/cncr.10439","article-title":"Quantitation of human papillomavirus 16 E6 and E7 DNA and RNA in residual material from ThinPrep papanicolaou tests using real-time polymerase chain reaction analysis","volume":"94","author":"Wang-Johanning","year":"2002","journal-title":"Cancer"},{"key":"B62","doi-asserted-by":"publisher","first-page":"1425","DOI":"10.1038\/nsmb.2702","article-title":"JMJD1C demethylates MDC1 to regulate the RNF8 and BRCA1-mediated chromatin response to DNA breaks","volume":"20","author":"Watanabe","year":"2013","journal-title":"Nat. Struct. Mol. Biol."},{"key":"B63","doi-asserted-by":"publisher","first-page":"1465","DOI":"10.1097\/AOG.0b013e31827001d5","article-title":"Revised terminology for cervical histopathology and its implications for management of high-grade squamous intraepithelial lesions of the cervix","volume":"120","author":"Waxman","year":"2012","journal-title":"Obstet. Gynecol."},{"key":"B64","doi-asserted-by":"publisher","first-page":"45","DOI":"10.2217\/fvl.10.73","article-title":"HPV-DNA integration and carcinogenesis: putative roles for inflammation and oxidative stress","volume":"6","author":"Williams","year":"2011","journal-title":"Future Virol."},{"key":"B65","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1158\/2326-6066.Cir-14-0112","article-title":"NF-\u03baB, an active player in human cancers","volume":"2","author":"Xia","year":"2014","journal-title":"Cancer Immunol. Res."},{"key":"B66","doi-asserted-by":"publisher","first-page":"1042","DOI":"10.7150\/ijms.34279","article-title":"Human papillomavirus type 16 E1 mutations associated with cervical cancer in a han Chinese population","volume":"16","author":"Yao","year":"2019","journal-title":"Int. J. Med. Sci."},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.805695","article-title":"An update on human papilloma virus vaccines: History, types, protection, and efficacy","volume":"12","author":"Yousefi","year":"2021","journal-title":"Front. Immunol."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.955847\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,28]],"date-time":"2022-07-28T13:20:31Z","timestamp":1659014431000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.955847\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,28]]},"references-count":67,"alternative-id":["10.3389\/fcimb.2022.955847"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2022.955847","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,28]]},"article-number":"955847"}}