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Xeroderma pigmentosum variant (XP\u2010V) cells, deficient in DNA polymerase eta (pol eta), exhibit a heightened risk of skin cancer due to impaired TLS. While XP\u2010V patients are considered NER\u2010proficient, our findings challenge this assumption by demonstrating that UVA\u2010induced oxidative stress impaired NER activity, leading to increased C\u2009&gt;\u2009T transitions at CPD sites. Whole\u2010exome sequencing of UVA\u2010irradiated XP\u2010V cells revealed a substantial rise in mutations, with a distinct C\u2009&gt;\u2009T signature characteristic of defective CPD repair. Notably, pretreatment with the antioxidant <jats:italic>N<\/jats:italic>\u2010acetylcysteine (NAC) mitigated this effect, reducing C\u2009&gt;\u2009T transitions through enhanced NER function and decreasing C\u2009&gt;\u2009A transversions via its antioxidant properties. These results redefine the mutagenic landscape of XP\u2010V cells, revealing that oxidatively generated damage to NER proteins\u2014rather than TLS deficiency alone\u2014contributes to their elevated mutation burden. Our findings suggest that antioxidant strategies may partially protect XP\u2010V patients from UVA\u2010driven mutagenesis enhancing the cells' DNA repair capacity, ultimately reducing skin cancer and contributing to better overall health outcomes.<\/jats:p>","DOI":"10.1002\/mc.70028","type":"journal-article","created":{"date-parts":[[2025,8,12]],"date-time":"2025-08-12T15:11:10Z","timestamp":1755011470000},"page":"1823-1837","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Uncovering the Role of DNA Repair Impairment in UVA\u2010Induced Mutagenesis in Human Xeroderma Pigmentosum Variant Cells"],"prefix":"10.1002","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2587-7576","authenticated-orcid":false,"given":"Camila","family":"Corradi","sequence":"first","affiliation":[{"name":"Laboratory of DNA Repair, Institute of Biomedical Sciences University of S\u00e3o Paulo S\u00e3o Paulo SP 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