{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T14:56:58Z","timestamp":1791644218174,"version":"4.3.4"},"reference-count":40,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T00:00:00Z","timestamp":1775952000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of University and Research","award":["RP124190255A2CB7"],"award-info":[{"award-number":["RP124190255A2CB7"]}]},{"name":"Italian Ministry of University and Research","award":["RP125199A48F33A6"],"award-info":[{"award-number":["RP125199A48F33A6"]}]},{"name":"Italian Ministry of University and Research","award":["2022FRE3RH"],"award-info":[{"award-number":["2022FRE3RH"]}]},{"award":["RP124190255A2CB7"],"award-info":[{"award-number":["RP124190255A2CB7"]}],"id":[{"id":"https:\/\/ror.org\/01ehyh486","id-type":"ROR","asserted-by":"publisher"}]},{"award":["RP125199A48F33A6"],"award-info":[{"award-number":["RP125199A48F33A6"]}],"id":[{"id":"https:\/\/ror.org\/01ehyh486","id-type":"ROR","asserted-by":"publisher"}]},{"award":["2022FRE3RH"],"award-info":[{"award-number":["2022FRE3RH"]}],"id":[{"id":"https:\/\/ror.org\/01ehyh486","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"crossref","award":["CUPB83C23006400005"],"award-info":[{"award-number":["CUPB83C23006400005"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Merkel Cell Polyomavirus is an oncogenic virus associated with Merkel Cell Carcinoma (MCC). However, considering viral detection in respiratory specimens and similarities between MCC and neuroendocrine lung cancer, its plausible role in the respiratory tract is disputed. MCPyV-mediated oncogenesis involves viral antigens interfering with host signaling as a DNA Damage Response (DDR). In the current study, respiratory models, including lung cancer cell lines (A549 and H1299), and non-malignant bronchial systems (HBEC-KT and a 2D ALI model) were used to investigate DDR genes\u2019 expression following MCPyV infection. Once the capability to support viral replication and transcription was assessed using qPCR and RT-qPCR, respectively, the mRNA levels of DDR genes, including ATM, ATR, Chk1, Chk2, H2AX, Rad51, p53 and p21, were examined. Our findings showed MCPyV replication in all cellular systems, as proven by the detection of viral DNA and transcripts. Viral infection induced an overexpression of DDR genes, suggesting a role of the virus in manipulating DDR to favor its replication or contribute to tumor progression. These preliminary results provide in vitro models for studying the interplay between MCPyV and DDR within malignant and non-malignant contexts across the respiratory tract, laying the basis for future research exploring the clinical relevance of DDR activation in virus-driven malignancies.<\/jats:p>","DOI":"10.3390\/ijms27083449","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T08:49:02Z","timestamp":1776070142000},"page":"3449","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Respiratory Models Reveal DNA Damage Response Modulation by Merkel Cell Polyomavirus"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0678-5537","authenticated-orcid":false,"given":"Sara","family":"Passerini","sequence":"first","affiliation":[{"name":"Department of Public Health and Infectious Diseases, Sapienza University, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1916-6508","authenticated-orcid":false,"given":"Marta","family":"De Angelis","sequence":"additional","affiliation":[{"name":"Department of Public Health and Infectious Diseases, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University, 00185 Rome, Italy"},{"name":"Laboratory of Virology, Department of Molecular Medicine, Sapienza University, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6640-9683","authenticated-orcid":false,"given":"Sara","family":"Messina","sequence":"additional","affiliation":[{"name":"Department of Public Health and Infectious Diseases, Sapienza University, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2901-265X","authenticated-orcid":false,"given":"Daniela","family":"Scribano","sequence":"additional","affiliation":[{"name":"Department of Public Health and Infectious Diseases, Sapienza University, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2163-1613","authenticated-orcid":false,"given":"Cecilia","family":"Ambrosi","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology, IRCCS San Raffaele Roma, 00143 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ugo","family":"Moens","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Faculty of Health Sciences, UiT-The Arctic University of Norway, 9037 Troms\u00f8, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4427-4823","authenticated-orcid":false,"given":"Lucia","family":"Nencioni","sequence":"additional","affiliation":[{"name":"Department of Public Health and Infectious Diseases, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5723-8886","authenticated-orcid":false,"given":"Valeria","family":"Pietropaolo","sequence":"additional","affiliation":[{"name":"Department of Public Health and Infectious Diseases, Sapienza University, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1126\/science.1152586","article-title":"Clonal integration of a polyomavirus in human Merkel cell carcinoma","volume":"319","author":"Feng","year":"2008","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Pietropaolo, V., Prezioso, C., and Moens, U. (2020). Merkel Cell Polyomavirus and Merkel Cell Carcinoma. Cancers, 12.","DOI":"10.3390\/cancers12071774"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Ahmed, M.M., Cushman, C.H., and DeCaprio, J.A. (2021). Merkel Cell Polyomavirus: Oncogenesis in a Stable Genome. Viruses, 14.","DOI":"10.3390\/v14010058"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Krump, N.A., and You, J. (2021). From Merkel Cell Polyomavirus Infection to Merkel Cell Carcinoma Oncogenesis. Front. Microbiol., 12.","DOI":"10.3389\/fmicb.2021.739695"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.jcv.2011.08.012","article-title":"Identification and validation of a novel mature microRNA encoded by the Merkel cell polyomavirus in human Merkel cell carcinomas","volume":"52","author":"Lee","year":"2011","journal-title":"J. Clin. Virol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1146\/annurev-virology-011720-121757","article-title":"Molecular Mechanisms of Merkel Cell Polyomavirus Transformation and Replication","volume":"7","author":"Liu","year":"2020","journal-title":"Annu. Rev. Virol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"200272","DOI":"10.1016\/j.tvr.2023.200272","article-title":"Interplay between the DNA damage response and the life cycle of DNA tumor viruses","volume":"16","author":"Studstill","year":"2023","journal-title":"Tumour Virus Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.molcel.2010.09.019","article-title":"The DNA damage response: Making it safe to play with knives","volume":"40","author":"Ciccia","year":"2010","journal-title":"Mol. Cell."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1038\/nature08467","article-title":"The DNA-damage response in human biology and disease","volume":"461","author":"Jackson","year":"2009","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"188556","DOI":"10.1016\/j.bbcan.2021.188556","article-title":"Tumor suppressor p53: Biology, signaling pathways, and therapeutic targeting","volume":"1876","year":"2021","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"9173","DOI":"10.1128\/JVI.01216-13","article-title":"Merkel cell polyomavirus large T antigen disrupts host genomic integrity and inhibits cellular proliferation","volume":"87","author":"Li","year":"2013","journal-title":"J. Virol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3285","DOI":"10.1128\/JVI.03656-13","article-title":"Host DNA damage response factors localize to merkel cell polyomavirus DNA replication sites to support efficient viral DNA replication","volume":"88","author":"Tsang","year":"2014","journal-title":"J. Virol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1007\/s12672-025-02651-8","article-title":"Investigation of mRNA expression levels of DNA damage response genes in Merkel Cell Polyomavirus-positive Merkel Cell Carcinoma: A pilot study","volume":"16","author":"Passerini","year":"2025","journal-title":"Discov. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Mazziotta, C., and Rotondo, J.C. (2025). Emerging in vitro models to study Merkel cell carcinoma pathobiology. Front. Cell. Dev. Biol., 13.","DOI":"10.3389\/fcell.2025.1691110"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"489","DOI":"10.3201\/eid1503.081206","article-title":"Merkel cell polyomavirus in respiratory tract secretions","volume":"15","author":"Goh","year":"2009","journal-title":"Emerg. Infect. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Prezioso, C., Di Lella, F.M., Rodio, D.M., Bitossi, C., Trancassini, M., Mele, A., de Vito, C., Antonelli, G., and Pietropaolo, V. (2019). Merkel Cell Polyomavirus DNA Detection in Respiratory Samples: Study of a Cohort of Patients Affected by Cystic Fibrosis. Viruses, 11.","DOI":"10.3390\/v11060571"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Neumann, F., Borchert, S., Schmidt, C., Reimer, R., Hohenberg, H., Fischer, N., and Grundhoff, A. (2011). Replication, gene expression and particle production by a consensus Merkel Cell Polyomavirus (MCPyV) genome. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0029112"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e02004-18","DOI":"10.1128\/JVI.02004-18","article-title":"Infectious Entry of Merkel Cell Polyomavirus","volume":"93","author":"Becker","year":"2019","journal-title":"J. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Prezioso, C., Bianchi, M., Obregon, F., Ciotti, M., Sarmati, L., Andreoni, M., Palamara, A.T., Pascarella, S., Moens, U., and Pietropaolo, V. (2020). Structural Analysis of Merkel Cell Polyomavirus (MCPyV) Viral Capsid Protein 1 (VP1) in HIV-1 Infected Individuals. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21217998"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1136\/thx.2009.117911","article-title":"Merkel cell polyomavirus is prevalent in a subset of small cell lung cancer: A study of 31 patients","volume":"64","author":"Andres","year":"2009","journal-title":"Thorax"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Zhou, C., Lu, L., Hu, M., Suzuki, T., and Zhou, X. (2025). Merkel cell polyomavirus in lung carcinogenesis: Evidence and controversy. Front. Oncol., 15.","DOI":"10.3389\/fonc.2025.1612605"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1038\/bjc.2012.567","article-title":"Detection of Merkel cell polyomavirus with a tumour-specific signature in non-small cell lung cancer","volume":"108","author":"Hashida","year":"2013","journal-title":"Br. J. Cancer."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.7150\/thno.78091","article-title":"Human papillomavirus E6\/E7 oncoproteins promote radiotherapy-mediated tumor suppression by globally hijacking host DNA damage repair","volume":"13","author":"Bruyere","year":"2023","journal-title":"Theranostics"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Schowalter, R.M., Reinhold, W.C., and Buck, C.B. (2012). Entry tropism of BK and Merkel cell polyomaviruses in cell culture. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0042181"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Notkins, A.L., and Oldstone, M.B.A. (1984). Viruses and Differentiation: The Molecular Basis of Viral Tissue Tropisms. Concepts in Viral Pathogenesis, Springer.","DOI":"10.1007\/978-1-4612-5250-4"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.canlet.2008.08.009","article-title":"Expression of DNA damage response genes indicate progressive breast tumors","volume":"273","author":"Gochhait","year":"2009","journal-title":"Cancer Lett."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"a012716","DOI":"10.1101\/cshperspect.a012716","article-title":"DNA damage sensing by the ATM and ATR kinases","volume":"5","author":"Zou","year":"2013","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1159\/000501419","article-title":"Merkel Cell Polyomavirus Small T Antigen Induces DNA Damage Response","volume":"62","author":"Wu","year":"2019","journal-title":"Intervirology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"9526","DOI":"10.1128\/JVI.76.18.9526-9532.2002","article-title":"Induction and bypass of p53 during productive infection by polyomavirus","volume":"76","author":"Dey","year":"2002","journal-title":"J. Virol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"13007","DOI":"10.1128\/JVI.79.20.13007-13017.2005","article-title":"Induction and utilization of an ATM signaling pathway by polyomavirus","volume":"79","author":"Dahl","year":"2005","journal-title":"J. Virol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/978-1-4939-0888-2_10","article-title":"Cell cycle regulation during viral infection","volume":"1170","author":"Bagga","year":"2014","journal-title":"Methods Mol. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1146\/annurev-virology-031413-085548","article-title":"Viruses and the DNA Damage Response: Activation and Antagonism","volume":"1","author":"Luftig","year":"2014","journal-title":"Annu. Rev. Virol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1038\/bjc.2011.612","article-title":"The DNA damage response in viral-induced cellular transformation","volume":"106","author":"Nikitin","year":"2012","journal-title":"Br. J. Cancer."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.clbc.2022.10.012","article-title":"Investigation of mRNA Expression Levels of Tip60 and Related DNA Repair Genes in Molecular Subtypes of Breast Cancer","volume":"23","author":"Demokan","year":"2023","journal-title":"Clin. Breast Cancer"},{"key":"ref_35","first-page":"793","article-title":"H2AX mRNA expression reflects DNA repair, cell proliferation, metastasis, and worse survival in breast cancer","volume":"12","author":"Katsuta","year":"2022","journal-title":"Am. J. Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.jid.2024.04.034","article-title":"DNA Damage Stress Control Is a Truncated Large T Antigen and Euchromatic Histone Lysine Methyltransferase 2-Dependent Central Feature of Merkel Cell Carcinoma","volume":"145","author":"Bachiri","year":"2025","journal-title":"J. Invest. Dermatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1186\/s12929-025-01159-1","article-title":"Goblet cell breakdown: Transcriptomics reveals Acinetobacter baumannii early and robust inflammatory response in differentiated human bronchial epithelial cells","volume":"32","author":"Scribano","year":"2025","journal-title":"J. Biomed. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4645","DOI":"10.1172\/JCI64116","article-title":"Improved detection suggests all Merkel cell carcinomas harbor Merkel polyomavirus","volume":"122","author":"Rodig","year":"2012","journal-title":"J. Clin. Invest."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"217530","DOI":"10.1016\/j.canlet.2025.217530","article-title":"Splicing factor SF3B4 acts as a switch in cancer cell senescence by regulating p21 mRNA stability","volume":"615","author":"Kang","year":"2025","journal-title":"Cancer Lett."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2639","DOI":"10.1128\/JVI.02495-15","article-title":"Homologous Recombination Repair Factors Rad51 and BRCA1 Are Necessary for Productive Replication of Human Papillomavirus 31","volume":"90","author":"Chappell","year":"2015","journal-title":"J. Virol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/8\/3449\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T04:16:04Z","timestamp":1776140164000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/8\/3449"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,12]]},"references-count":40,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["ijms27083449"],"URL":"https:\/\/doi.org\/10.3390\/ijms27083449","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,12]]}}}