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OGG1 removes 8-oxoG opposite C, and MUTYH removes A misinserted opposite 8-oxoG to prevent mutations. While OGG1 has an established role in telomere protection, the contribution of MUTYH to telomere stability in cancer cells after oxidative DNA damage remains poorly understood. Using a chemoptogenetic system to induce targeted 8-oxoG lesions specifically at telomeres in HeLa cancer cells, we demonstrate that MUTYH is required to prevent telomere shortening, telomere loss, and genomic instability after chronic damage. Yet, telomere damage in MUTYH-deficient cells does not cause sustained DNA damage signaling or reduced cellular proliferation. Whole-genome sequencing further reveals enrichment of G to T transversions within telomeric repeats in MUTYH-deficient cells, consistent with increased mutagenesis due to unrepaired 8-oxoG:A mispairs. Combined loss of MUTYH and OGG1 rescues damage-induced telomere aberrations and genomic instability, implicating BER-generated single-strand break (SSB) intermediates as major contributors to telomere instability. In agreement, exo-FISH and S1-END-seq analyses reveal that repair-proficient cells rapidly accumulate SSB intermediates after damage, which are later resolved, whereas glycosylase-deficient cells exhibit SSBs at later time points. Together, these findings identify MUTYH as a critical guardian of telomere integrity during chronic oxidative stress and provide insight into how defective BER at telomeres contributes to genomic instability in cancer cells, with implications for cancers associated with MUTYH deficiency and mutations.<\/jats:p>","DOI":"10.3390\/biom16091234","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T09:05:46Z","timestamp":1787735146000},"page":"1234","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["MUTYH Activity Maintains Telomere Stability in Response to Chronic Telomeric 8-Oxoguanine Damage in Cancer Cells"],"prefix":"10.3390","volume":"16","author":[{"given":"Mariarosaria","family":"De Rosa","sequence":"first","affiliation":[{"name":"UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213-1863, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3449-6071","authenticated-orcid":false,"given":"Theresa M.","family":"Heidenreich","sequence":"additional","affiliation":[{"name":"UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213-1863, USA"},{"name":"Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Libby","family":"Childs","sequence":"additional","affiliation":[{"name":"UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213-1863, USA"},{"name":"Department of Human Genetics, University of Pittsburgh School of Public Health, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7243-384X","authenticated-orcid":false,"given":"Benura","family":"Azeroglu","sequence":"additional","affiliation":[{"name":"Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2388-5425","authenticated-orcid":false,"given":"Sneh M.","family":"Toprani","sequence":"additional","affiliation":[{"name":"Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4666-9175","authenticated-orcid":false,"given":"Nader","family":"Aryamanesh","sequence":"additional","affiliation":[{"name":"Bioinformatics Unit, Children\u2019s Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW 2145, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7170-3166","authenticated-orcid":false,"given":"Pablo","family":"Galaviz","sequence":"additional","affiliation":[{"name":"Bioinformatics Unit, Children\u2019s Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW 2145, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilda A.","family":"Pickett","sequence":"additional","affiliation":[{"name":"Telomere Length Regulation Unit, Children\u2019s Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead,  NSW 2145, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eros","family":"Lazzerini Denchi","sequence":"additional","affiliation":[{"name":"Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary D.","family":"Nagel","sequence":"additional","affiliation":[{"name":"Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6470-2189","authenticated-orcid":false,"given":"Patricia L.","family":"Opresko","sequence":"additional","affiliation":[{"name":"UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213-1863, USA"},{"name":"Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1038\/nrm2848","article-title":"Telomeres: Protecting chromosomes against genome instability","volume":"11","author":"Karlseder","year":"2010","journal-title":"Nat. Rev. Mol. 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