vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/vjgb-25-46vavilov-4609Research ArticleГЕНЕТИКА ЧЕЛОВЕКАHUMAN GENETICSЭкспрессия генов системы репарации и контроля клеточного цикла при ВПЧ-инфекцииExpression of DNA repair and cell cycle control genes in HPV infectionМашкинаЕ. В.MashkinaE. V.

Ростов-на-Дону

Rostov-on-Don

lenmash@mail.ruВольчикВ. В.VolchikV. V.

Ростов-на-Дону

Rostov-on-Don

МузлаеваЕ. С.MuzlaevaE. S.

Ростов-на-Дону

Rostov-on-Don

ДеревянчукЕ. Г.DerevyanchukE. G.

Ростов-на-Дону

Rostov-on-Don

Южный федеральный университетРоссияSouthern Federal UniversityRussian Federation202503062025293433439Copyright © Машкина Е.В., Вольчик В.В., Музлаева Е.С., Деревянчук Е.Г., 20252025Машкина Е.В., Вольчик В.В., Музлаева Е.С., Деревянчук Е.Г.Mashkina E.V., Volchik V.V., Muzlaeva E.S., Derevyanchuk E.G.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/4609

Одним из основных этиологических факторов развития рака шейки матки является инфицирование вирусом папилломы человека (ВПЧ). При этом риск развития злокачественного процесса увеличивается с  ростом вирусной нагрузки. Целью данного исследования было изучение уровня транскрипции генов репарации ДНК и контроля клеточного цикла в эпителиальных клетках цервикального канала женщин с клинически значимой вирусной нагрузкой при ВПЧ-инфекции. Материалом для исследования послужили образцы ДНК и РНК, выделенные из эпителиальных клеток. Всего было проанализировано 107 образцов: 55 женщин были ВПЧ-положительными (с клинически значимой вирусной нагрузкой – более 103 геномов ВПЧ на 100 тыс. клеток человека), контрольную группу составили 52 ВПЧ-отрицательные женщины. Все женщины были старше 30 лет. Уровень транскрипции генов APEX1, ERCC2, CHEK2, TP53, TP73, CDKN2A, SIRT1 определяли с помощью ОТ-ПЦР. Показано, что частота обнаружения транскриптов генов APEX1 и ERCC2 была повышена в группе женщин с клинически значимой вирусной нагрузкой. Уровень транскрипции всех исследованных генов не различался между контрольной группой и группой ВПЧ-инфицированных женщин. Однако установлено, что уровень транскрипции генов TP53 и TP73 снижается с ростом вирусной нагрузки. В контроле выявлена корреляция между уровнями транскрипции генов, участвующих в обеспечении функционирования белка p53. Увеличение вирусной нагрузки при инфицировании ВПЧ связано с изменением коэкспрессии генов репарации ДНК и контроля клеточного цикла. 

One of the main etiological factors in the development of cervical cancer is infection with human papillomavirus (HPV). At the same time, the risk of developing a malignant process increases with an increase in viral load. The aim of this study was to investigate the transcription level of DNA repair and cell cycle control genes in the cervical epithelial cells of women with a clinically significant HPV viral load. The material for the study was DNA and RNA samples isolated from cervical epithelial cells in women. A total of 107 samples were analyzed. 55 women were HPV-positive (with a clinically significant viral load – more than 103 HPV genomes per 100 thousand human cells); the control group consisted of 52 HPV-negative women. All women were over 30 years old. The transcription level of the APEX1, ERCC2, CHEK2, TP53, TP73, CDKN2A, SIRT1 genes was determined using RT-PCR. It was shown that the detection frequency of the APEX1 and ERCC2 gene transcripts was increased in the group of women with a clinically significant viral load. The transcription level of all the studied genes did not differ between the control group and the group with clinically significant HPV concentrations. However, the transcription level of the TP53 and TP73 genes decreased with increasing viral load. In the control, a correlation between the transcription levels of genes involved in the functioning of the p53 protein was revealed. An increase in viral load during HPV infection is associated with a change in the coexpression of DNA repair and cell cycle control genes.

вирус папилломы человекаконтроль клеточного циклатранскрипция геновкоэкспрессия геновhuman papillomaviruscell cycle controlgene transcriptioncoexpression genesThe study was carried out with the financial support of the Ministry of Science and Higher Education of the Russian Federation within the state assignment framework in the field of scientific activity No. FENW-2023-0018.ReferencesAlBosale A., Mashkina E. Association between ТР53, MDM2 and NQO1 gene polymorphisms and viral load among women with human papillomavirus. Vavilov J Genet Breed. 2022;26(1):59-64. doi 10.18699/VJGB-22-09AlBosale A., Mashkina E. Association between ТР53, MDM2 and NQO1 gene polymorphisms and viral load among women with human papillomavirus. Vavilov J Genet Breed. 2022;26(1):59-64. doi 10.18699/VJGB-22-09Allison S., Jiang M., Milner J. Oncogenic viral protein HPV E7 upregulates the SIRT1 longevity protein in human cervical cancer cells. Aging (Albany NY). 2009;1(3):316-227. doi 10.18632/aging.100028Allison S., Jiang M., Milner J. Oncogenic viral protein HPV E7 upregulates the SIRT1 longevity protein in human cervical cancer cells. Aging (Albany NY). 2009;1(3):316-227. doi 10.18632/aging.100028AmpliSens HPV HCR screen-titre-FRT PCR kit Instruction Manual. 2018. URL: https://www.pcrdiagnostics.eu/data/machines/hpv-hcrscreen-titre-frt-250321.pdfAmpliSens HPV HCR screen-titre-FRT PCR kit Instruction Manual. 2018. URL: https://www.pcrdiagnostics.eu/data/machines/hpv-hcrscreen-titre-frt-250321.pdfBajpai D., Banerjee A., Pathak S., Jain S.K., Singh N. Decreased expression of DNA repair genes (XRCC1, ERCC1, ERCC2, and ERCC4) in squamous intraepithelial lesion and invasive squamous cell carcinoma of the cervix. Mol Cell Biochem. 2013;377(1-2): 45-53. doi 10.1007/s11010-013-1569-yBajpai D., Banerjee A., Pathak S., Jain S.K., Singh N. Decreased expression of DNA repair genes (XRCC1, ERCC1, ERCC2, and ERCC4) in squamous intraepithelial lesion and invasive squamous cell carcinoma of the cervix. Mol Cell Biochem. 2013;377(1-2): 45-53. doi 10.1007/s11010-013-1569-yBartek J., Falck J., Lukas J. Chk2 kinase – a busy messenger. Nat Rev Mol Cell Biol. 2001;2(12):877-886. doi 10.1038/35103059Bartek J., Falck J., Lukas J. Chk2 kinase – a busy messenger. Nat Rev Mol Cell Biol. 2001;2(12):877-886. doi 10.1038/35103059Bava S., Thulasidasan A., Sreekanth C., Anto R. Cervical cancer: a comprehensive approach towards extermination. Ann Med. 2016; 48(3):149-161. doi 10.3109/07853890.2016.1145796Bava S., Thulasidasan A., Sreekanth C., Anto R. Cervical cancer: a comprehensive approach towards extermination. Ann Med. 2016; 48(3):149-161. doi 10.3109/07853890.2016.1145796Bieging K., Mello S., Attardi L. Unravelling mechanisms of p53-mediated tumour suppression. Nat Rev Cancer. 2014;14(5):359-370. doi 10.1038/nrc3711Bieging K., Mello S., Attardi L. Unravelling mechanisms of p53-mediated tumour suppression. Nat Rev Cancer. 2014;14(5):359-370. doi 10.1038/nrc3711Bruyere D., Roncarati P., Lebeau A., Lerho T., Poulain F., Hendrick E., Pilard C., … Hubert P., McBride A., Gillet N., Masson M., Herfs M. Human papillomavirus E6/E7 oncoproteins promote radiotherapy-mediated tumor suppression by globally hijacking host DNA damage repair. Theranostics. 2023;13(3):1130-1149. doi 10.7150/thno.78091Bruyere D., Roncarati P., Lebeau A., Lerho T., Poulain F., Hendrick E., Pilard C., … Hubert P., McBride A., Gillet N., Masson M., Herfs M. Human papillomavirus E6/E7 oncoproteins promote radiotherapy-mediated tumor suppression by globally hijacking host DNA damage repair. Theranostics. 2023;13(3):1130-1149. doi 10.7150/thno.78091Chan S., Chiang J., Ngeow J. CDKN2A germline alterations and the relevance of genotype-phenotype associations in cancer predisposition. Hered Cancer Clin Pract. 2021;19(1):21. doi 10.1186/s13053-021-00178-xChan S., Chiang J., Ngeow J. CDKN2A germline alterations and the relevance of genotype-phenotype associations in cancer predisposition. Hered Cancer Clin Pract. 2021;19(1):21. doi 10.1186/s13053-021-00178-xChansaenroj J., Theamboonlers A., Junyangdikul P., Swangvaree S., Karalak A., Chinchai T., Poovorawan Y. Polymorphisms in TP53 (rs1042522), p16 (rs11515 and rs3088440) and NQO1 (rs1800566) genes in Thai cervical cancer patients with HPV 16 infection. Asian Pac J Cancer Prev. 2013;14(1):341-346. doi 10.7314/apjcp.2013.14.1.341Chansaenroj J., Theamboonlers A., Junyangdikul P., Swangvaree S., Karalak A., Chinchai T., Poovorawan Y. Polymorphisms in TP53 (rs1042522), p16 (rs11515 and rs3088440) and NQO1 (rs1800566) genes in Thai cervical cancer patients with HPV 16 infection. Asian Pac J Cancer Prev. 2013;14(1):341-346. doi 10.7314/apjcp.2013.14.1.341Chellappan S., Kraus V., Kroger B., Munger K., Howley P., Phelps W., Nevins J. Adenovirus E1A, simian virus 40 tumor antigen, and human papillomavirus E7 protein share the capacity to disrupt the interaction between transcription factor E2F and the retinoblastoma gene product. Proc Natl Acad Sci USA. 1992;89(10):4549-4553. doi 10.1073/pnas.89.10.4549Chellappan S., Kraus V., Kroger B., Munger K., Howley P., Phelps W., Nevins J. Adenovirus E1A, simian virus 40 tumor antigen, and human papillomavirus E7 protein share the capacity to disrupt the interaction between transcription factor E2F and the retinoblastoma gene product. Proc Natl Acad Sci USA. 1992;89(10):4549-4553. doi 10.1073/pnas.89.10.4549Chen J., Chen H., Pan L. SIRT1 and gynecological malignancies ( Review). Oncol Rep. 2021;45(4):43. doi 10.3892/or.2021.7994Chen J., Chen H., Pan L. SIRT1 and gynecological malignancies ( Review). Oncol Rep. 2021;45(4):43. doi 10.3892/or.2021.7994Choi Y., Bae S., Kim Y., Lee H., Kim Y., Park T., Ro D., Shin J., Shin S., Seo J.-S., Ahn W. Gene expression profiles in squamous cell cervical carcinoma using array-based comparative genomic hybridization analysis. Int J Gynecol Cancer. 2007;17(3):687-696. doi 10.1111/j.1525-1438.2007.00834.xChoi Y., Bae S., Kim Y., Lee H., Kim Y., Park T., Ro D., Shin J., Shin S., Seo J.-S., Ahn W. Gene expression profiles in squamous cell cervical carcinoma using array-based comparative genomic hybridization analysis. Int J Gynecol Cancer. 2007;17(3):687-696. doi 10.1111/j.1525-1438.2007.00834.xDas D., Bristol M., Smith N., James C., Wang X., Pichierri P., Morgan I. Werner helicase control of Human papillomavirus 16 E1-E2 DNA replication is regulated by SIRT1 deacetylation. mBio. 2019; 10(2):e00263-19. doi 10.1128/mBio.00263-19Das D., Bristol M., Smith N., James C., Wang X., Pichierri P., Morgan I. Werner helicase control of Human papillomavirus 16 E1-E2 DNA replication is regulated by SIRT1 deacetylation. mBio. 2019; 10(2):e00263-19. doi 10.1128/mBio.00263-19Flores E., Tsai K., Crowley D., Sengupta S., Yang A., McKeon F., Jacks T. p63 and p73 are required for p53-dependent apoptosis in response to DNA damage. Nature. 2002;416(6880):560-564. doi 10.1038/416560aFlores E., Tsai K., Crowley D., Sengupta S., Yang A., McKeon F., Jacks T. p63 and p73 are required for p53-dependent apoptosis in response to DNA damage. Nature. 2002;416(6880):560-564. doi 10.1038/416560aGiacinti C., Giordano A. RB and cell cycle progression. Oncogene. 2006;25(38):5220-5227. doi 10.1038/sj.onc.1209615Giacinti C., Giordano A. RB and cell cycle progression. Oncogene. 2006;25(38):5220-5227. doi 10.1038/sj.onc.1209615Gillespie K., Mehta K., Laimins L., Moody C. Human papillomaviruses recruit cellular DNA repair and homologous recombination factors to viral replication centers. J Virol. 2012;86(17):9520-9526. doi 10.1128/JVI.00247-12Gillespie K., Mehta K., Laimins L., Moody C. Human papillomaviruses recruit cellular DNA repair and homologous recombination factors to viral replication centers. J Virol. 2012;86(17):9520-9526. doi 10.1128/JVI.00247-12Guo C., Qu X., Tang X., Song Y., Wang J., Hua K., Qiu J. Spatiotemporally deciphering the mysterious mechanism of persistent HPVinduced malignant transition and immune remodelling from HPVinfected normal cervix, precancer to cervical cancer: integrating single-cell RNA-sequencing and spatial transcriptome. Clin Transl Med. 2023;13(3):e1219. doi 10.1002/ctm2.1219Guo C., Qu X., Tang X., Song Y., Wang J., Hua K., Qiu J. Spatiotemporally deciphering the mysterious mechanism of persistent HPVinduced malignant transition and immune remodelling from HPVinfected normal cervix, precancer to cervical cancer: integrating single-cell RNA-sequencing and spatial transcriptome. Clin Transl Med. 2023;13(3):e1219. doi 10.1002/ctm2.1219Hafkamp H., Mooren J., Claessen S., Klingenberg B., Voogd A., Bot F., Klussmsnn J., Hopman A., Manni J., Kremer B., Ramaekers F., Speel E. P21Cip1/WAF1 expression is strongly associated with HPVpositive tonsillar carcinoma and a favorable prognosis. Mod Pathol. 2009;22(5):686-698. doi 10.1038/modpathol.2009.23 Kim J., Song S., Jin C., Lee J., Lee N., Lee K. Factors affecting the clearance of high-risk human papillomavirus infection and the progression of cervical intraepithelial neoplasia. J Int Med Res. 2012; 40(2):486-496. doi 10.1177/147323001204000210Hafkamp H., Mooren J., Claessen S., Klingenberg B., Voogd A., Bot F., Klussmsnn J., Hopman A., Manni J., Kremer B., Ramaekers F., Speel E. P21Cip1/WAF1 expression is strongly associated with HPVpositive tonsillar carcinoma and a favorable prognosis. Mod Pathol. 2009;22(5):686-698. doi 10.1038/modpathol.2009.23 Kim J., Song S., Jin C., Lee J., Lee N., Lee K. Factors affecting the clearance of high-risk human papillomavirus infection and the progression of cervical intraepithelial neoplasia. J Int Med Res. 2012; 40(2):486-496. doi 10.1177/147323001204000210Klaes R., Friedrich T., Spitkovsky D., Ridder R., Rudy W., Petry U., Dallenbach-Hellweg G., Schmidt D., Doeberitz M. Overexpression of p16INK4A as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri. Int J Cancer. 2001;92(2):276-284. doi 10.1002/ijc.1174Klaes R., Friedrich T., Spitkovsky D., Ridder R., Rudy W., Petry U., Dallenbach-Hellweg G., Schmidt D., Doeberitz M. Overexpression of p16INK4A as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri. Int J Cancer. 2001;92(2):276-284. doi 10.1002/ijc.1174Kulaeva E., Muzlaeva E., Mashkina E. mRNA-lncRNA gene expression signature in HPV-associated neoplasia and cervical cancer. Vavilov J Genet Breed. 2024;28(3):342-350. doi 10.18699/vjgb-24-39Kulaeva E., Muzlaeva E., Mashkina E. mRNA-lncRNA gene expression signature in HPV-associated neoplasia and cervical cancer. Vavilov J Genet Breed. 2024;28(3):342-350. doi 10.18699/vjgb-24-39Kushwah A., Srivastava K., Banerjee M. Differential expression of DNA repair genes and treatment outcome of chemoradiotherapy (CRT) in cervical cancer. Gene. 2023;868:147389. doi 10.1016/j.gene.2023.147389Kushwah A., Srivastava K., Banerjee M. Differential expression of DNA repair genes and treatment outcome of chemoradiotherapy (CRT) in cervical cancer. Gene. 2023;868:147389. doi 10.1016/j.gene.2023.147389Langsfeld E., Bodily J., Laimins L. 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. 2015;11(9):e1005181. doi 10.1371/ journal.ppat.1005181Langsfeld E., Bodily J., Laimins L. 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. 2015;11(9):e1005181. doi 10.1371/ journal.ppat.1005181Li Q., Zhou Z., Duan W., Qian C., Wang S., Deng M., Zi D., Wang J.- M., Mao C.-Y., Song G., Wang D., Westover K., Xu C.-X. Inhibiting the redox function of APE1 suppresses cervical cancer metastasis via disengagement of ZEB1 from E-cadherin, in EMT. J Exp Clin Cancer Res. 2021;40(1):220. doi 10.1186/s13046-021-02006-5Li Q., Zhou Z., Duan W., Qian C., Wang S., Deng M., Zi D., Wang J.- M., Mao C.-Y., Song G., Wang D., Westover K., Xu C.-X. Inhibiting the redox function of APE1 suppresses cervical cancer metastasis via disengagement of ZEB1 from E-cadherin, in EMT. J Exp Clin Cancer Res. 2021;40(1):220. doi 10.1186/s13046-021-02006-5Liu S., Leung R., Chan K., Chiu P., Cheung A., Tam K., Ng T.-Y., Wong L.-C., Ngan H. p73 expression is associated with the cellular radiosensitivity in cervical cancer after radiotherapy. Clin CancerLiu S., Leung R., Chan K., Chiu P., Cheung A., Tam K., Ng T.-Y., Wong L.-C., Ngan H. p73 expression is associated with the cellular radiosensitivity in cervical cancer after radiotherapy. Clin CancerRes. 2004;10(10):3309-3316. doi 10.1158/1078-0432.CCR-03-0119Res. 2004;10(10):3309-3316. doi 10.1158/1078-0432.CCR-03-0119Livak K., Schmittgen T. Analysis of relative gene expression data using real-time quantitative PCR and the 2–ΔΔCT Method. Methods. 2001; 25(4):402-408. doi 10.1006/meth.2001.1262Livak K., Schmittgen T. Analysis of relative gene expression data using real-time quantitative PCR and the 2–ΔΔCT Method. Methods. 2001; 25(4):402-408. doi 10.1006/meth.2001.1262Longworth M., Laimins L. Pathogenesis of human papillomaviruses in differentiating epithelia. Microbiol Mol Biol Rev. 2004;68(2):362372. doi 10.1128/MMBR.68.2.362-372.2004Longworth M., Laimins L. Pathogenesis of human papillomaviruses in differentiating epithelia. Microbiol Mol Biol Rev. 2004;68(2):362372. doi 10.1128/MMBR.68.2.362-372.2004Luan Y., Zhang W., Xie J., Mao J. CDKN2A inhibits cell proliferation and invasion in cervical cancer through LDHA-mediated AKT/ mTOR pathway. Clin Transl Oncol. 2021;23(2):222-228. doi 10.1007/s12094-020-02409-4Luan Y., Zhang W., Xie J., Mao J. CDKN2A inhibits cell proliferation and invasion in cervical cancer through LDHA-mediated AKT/ mTOR pathway. Clin Transl Oncol. 2021;23(2):222-228. doi 10.1007/s12094-020-02409-4Magni M., Ruscica V., Buscemi G., Kim J., Nachimuthu B., Fontanella E., Delia D., Zannini L. Chk2 and REGγ-dependent DBC1 regulation in DNA damage induced apoptosis. Nucleic Acids Res. 2014;42(21):13150-13160. doi 10.1093/nar/gku1065Magni M., Ruscica V., Buscemi G., Kim J., Nachimuthu B., Fontanella E., Delia D., Zannini L. Chk2 and REGγ-dependent DBC1 regulation in DNA damage induced apoptosis. Nucleic Acids Res. 2014;42(21):13150-13160. doi 10.1093/nar/gku1065Mashkina E., Muzlaeva E., Volchik V., Shulga A., Derevyanchuk E. Association of SIRT1, CDKN2A, TP73 genes polymorphisms with the risk of viral load increase in women infected with human papillomavirus. Russ J Genet. 2023;59(Suppl.2):S184-S190. doi 10.1134/S1022795423140089Mashkina E., Muzlaeva E., Volchik V., Shulga A., Derevyanchuk E. Association of SIRT1, CDKN2A, TP73 genes polymorphisms with the risk of viral load increase in women infected with human papillomavirus. Russ J Genet. 2023;59(Suppl.2):S184-S190. doi 10.1134/S1022795423140089Münger K., Baldwin A., Edwards K., Hayakawa H., Nguyen C., Owens M., Grace M., Huh K. Mechanisms of human papillomavirus-induced oncogenesis. J Virol. 2004;78(21):11451-11460. doi 10.1128/JVI.78.21.11451-11460.2004Münger K., Baldwin A., Edwards K., Hayakawa H., Nguyen C., Owens M., Grace M., Huh K. Mechanisms of human papillomavirus-induced oncogenesis. J Virol. 2004;78(21):11451-11460. doi 10.1128/JVI.78.21.11451-11460.2004Ngan H., Cheung A., Liu S., Cheng D., Ng T., Wong L. Abnormal expression of pan-ras, c-myc and tp53 in squamous cell carcinoma of cervix: correlation with HPV and prognosis. Oncol Rep. 2001;8(3): 557-561. doi 10.3892/or.8.3.557Ngan H., Cheung A., Liu S., Cheng D., Ng T., Wong L. Abnormal expression of pan-ras, c-myc and tp53 in squamous cell carcinoma of cervix: correlation with HPV and prognosis. Oncol Rep. 2001;8(3): 557-561. doi 10.3892/or.8.3.557Park J., Kim E., Lee J., Sin H., Namkoong S., Um S. Functional inactivation of p73, a homolog of p53 tumor suppressor protein, by human papillomavirus E6 proteins. Int J Cancer. 2001;91(6):822-827. doi 10.1002/1097-0215(200002)9999:9999<::aid-ijc1130>3.0.co;2-0Park J., Kim E., Lee J., Sin H., Namkoong S., Um S. Functional inactivation of p73, a homolog of p53 tumor suppressor protein, by human papillomavirus E6 proteins. Int J Cancer. 2001;91(6):822-827. doi 10.1002/1097-0215(200002)9999:9999<::aid-ijc1130>3.0.co;2-0Templeton C., Laimins L. HPV induced R-loop formation represses innate immune gene expression while activating DNA damage repair pathways. PLoS Pathog. 2024;20(8):e1012454. doi 10.1371/journal.ppat.1012454Templeton C., Laimins L. HPV induced R-loop formation represses innate immune gene expression while activating DNA damage repair pathways. PLoS Pathog. 2024;20(8):e1012454. doi 10.1371/journal.ppat.1012454Thomas M., Kalita A., Labrecque S., Pim D., Banks L., Matlashewski G. Two polymorphic variants of wild-type p53 differ biochemically and biologically. Mol Cell Biol. 1999;19(2):1092-1100. doi 10.1128/MCB.19.2.1092Thomas M., Kalita A., Labrecque S., Pim D., Banks L., Matlashewski G. Two polymorphic variants of wild-type p53 differ biochemically and biologically. Mol Cell Biol. 1999;19(2):1092-1100. doi 10.1128/MCB.19.2.1092van der Weele P., van Logchem E., Wolffs P., van den Broek I., Feltkamp M., de Melker H., Meijer C., Boot H., King A. Correlation between viral load, multiplicity of infection, and persistence of HPV16 and HPV18 infection in a Dutch cohort of young women. J Clin Virol. 2016;83:6-11. doi 10.1016/j.jcv.2016.07.020van der Weele P., van Logchem E., Wolffs P., van den Broek I., Feltkamp M., de Melker H., Meijer C., Boot H., King A. Correlation between viral load, multiplicity of infection, and persistence of HPV16 and HPV18 infection in a Dutch cohort of young women. J Clin Virol. 2016;83:6-11. doi 10.1016/j.jcv.2016.07.020Vaziri H., Dessain S., Eaton N., Imai S., Frye R., Pandita T., Guarente L., Weinberg R. hSIR2SIRT1 functions as an NAD-dependent p53 deacetylase. Cell. 2001;107(2):149-159. doi 10.1016/s0092-8674(01)00527-xVaziri H., Dessain S., Eaton N., Imai S., Frye R., Pandita T., Guarente L., Weinberg R. hSIR2SIRT1 functions as an NAD-dependent p53 deacetylase. Cell. 2001;107(2):149-159. doi 10.1016/s0092-8674(01)00527-xYang H., Bi Y., Xue L., Wang J., Lu Y., Zhang Z., Chen X., Chu Y., Yang R., Wang R., Liu G. Multifaceted modulation of SIRT1 in cancer and inflammation. Crit Rev Oncog. 2015;20(1-2):49-64. doi 10.1615/critrevoncog.2014012374Yang H., Bi Y., Xue L., Wang J., Lu Y., Zhang Z., Chen X., Chu Y., Yang R., Wang R., Liu G. Multifaceted modulation of SIRT1 in cancer and inflammation. Crit Rev Oncog. 2015;20(1-2):49-64. doi 10.1615/critrevoncog.2014012374Ye F., Jiao J., Zhou C., Cheng Q., Chen H. Nucleotide excision repair gene subunit XPD is highly expressed in cervical squamous cell carcinoma. Pathol Oncol Res. 2012;18(4):969-975. doi 10.1007/s12253-012-9527-7Ye F., Jiao J., Zhou C., Cheng Q., Chen H. Nucleotide excision repair gene subunit XPD is highly expressed in cervical squamous cell carcinoma. Pathol Oncol Res. 2012;18(4):969-975. doi 10.1007/s12253-012-9527-7Ylitalo N., Sørensen P., Josefsson A., Magnusson P., Andersen P., Pontén J., Adami H., Gyllensten U., Melbye M. Consistent high viral load of human papillomavirus 16 and risk of cervical carcinoma in situ: a nested case-control study. Lancet. 2000;355(9222):2194- 2198. doi 10.1016/S0140-6736(00)02402-8Ylitalo N., Sørensen P., Josefsson A., Magnusson P., Andersen P., Pontén J., Adami H., Gyllensten U., Melbye M. Consistent high viral load of human papillomavirus 16 and risk of cervical carcinoma in situ: a nested case-control study. Lancet. 2000;355(9222):2194- 2198. doi 10.1016/S0140-6736(00)02402-8Zannini L., Delia D., Buscemi G. CHK2 kinase in the DNA damage response and beyond. J Mol Cell Biol. 2014;6(6):442-457. doi 10.1093/jmcb/mju045Zannini L., Delia D., Buscemi G. CHK2 kinase in the DNA damage response and beyond. J Mol Cell Biol. 2014;6(6):442-457. doi 10.1093/jmcb/mju045Zhang Q., Yang L., Gao H., Kuang X., Xiao H., Yang C., Cheng Y., Zhang L., Guo X., Zhong Y., Li M. APE1 promotes non-homologous end joining by initiating DNA double-strand break formation and decreasing ubiquitination of artemis following oxidative genotoxic stress. J Transl Med. 2023;21(1):183. doi 10.1186/s12967-02304022-9Zhang Q., Yang L., Gao H., Kuang X., Xiao H., Yang C., Cheng Y., Zhang L., Guo X., Zhong Y., Li M. APE1 promotes non-homologous end joining by initiating DNA double-strand break formation and decreasing ubiquitination of artemis following oxidative genotoxic stress. J Transl Med. 2023;21(1):183. doi 10.1186/s12967-02304022-9Zhao L., Zhang Z., Lou H., Liang J., Yan X., Li W., Xu Y., Ou R. Exploration of the molecular mechanisms of cervical cancer based on mRNA expression profiles and predicted microRNA interactions. Oncol Lett. 2018;15(6):8965-8972. doi 10.3892/ol.2018.8494Zhao L., Zhang Z., Lou H., Liang J., Yan X., Li W., Xu Y., Ou R. Exploration of the molecular mechanisms of cervical cancer based on mRNA expression profiles and predicted microRNA interactions. Oncol Lett. 2018;15(6):8965-8972. doi 10.3892/ol.2018.8494Zhou R., Wei C., Liu J., Luo Y., Tang W. The prognostic value of p53 expression for patients with cervical cancer: a meta analysis. Eur J Obstet Gynecol Reprod Biol. 2015;195:210-213. doi 10.1016/j.ejogrb.2015.10.006Zhou R., Wei C., Liu J., Luo Y., Tang W. The prognostic value of p53 expression for patients with cervical cancer: a meta analysis. Eur J Obstet Gynecol Reprod Biol. 2015;195:210-213. doi 10.1016/j.ejogrb.2015.10.006

The authors declare that there are no conflicts of interest present.