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MUTYH is a DNA repair enzyme that recognizes and repairs oxidatively damaged guanines [8-oxoguanine (8-oxoG)] mispaired with adenines (8-oxoG\u00b7A). While some mutations in the MUTYH gene are associated with colorectal cancer, most MUTYH variants identified in sequencing databases are classified as variants of uncertain significance. Convoluting clinical classification is the absence of data directly\u00a0comparing homozygous versus heterozygous MUTYH mutations. In this study, we present the first effort to functionally characterize MUTYH variants using precision genome editing to generate heterozygous and homozygous isogenic cell lines. Using a MUTYH-specific lesion reporter in which we site-specifically incorporate an 8-oxoG\u00b7A lesion in a fluorescent protein gene, we measure endogenous MUTYH enzymatic activity and classify them as pathogenic or benign. Further, we modify this reporter to incorporate the MUTYH repair intermediate (8-oxoG across from an abasic site) and validate it with co-immunoprecipitation experiments to demonstrate its ability to characterize the mechanism by which MUTYH mutants are defective at DNA repair.<\/jats:p>","DOI":"10.1093\/nar\/gkaf037","type":"journal-article","created":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T19:13:33Z","timestamp":1743448413000},"source":"Crossref","is-referenced-by-count":7,"title":["Precision genome editing and in-cell measurements of oxidative DNA damage repair enable functional and mechanistic characterization of cancer-associated <i>MUTYH<\/i> variants"],"prefix":"10.1093","volume":"53","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1965-8457","authenticated-orcid":false,"given":"Carlos\u00a0A","family":"Vasquez","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of California San Diego , La Jolla , CA 92093 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1481-6903","authenticated-orcid":false,"given":"Nicola\u00a0R B","family":"Osgood","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of California San Diego , La Jolla , CA 92093 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9494-6113","authenticated-orcid":false,"given":"Marcanthony\u00a0U","family":"Zepeda","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of California San Diego , La Jolla , CA 92093 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7851-6066","authenticated-orcid":false,"given":"Dominika\u00a0K","family":"Sandel","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of California San Diego , La Jolla , CA 92093 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8697-8178","authenticated-orcid":false,"given":"Quinn\u00a0T","family":"Cowan","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of California San Diego , La Jolla , CA 92093 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malalage\u00a0N","family":"Peiris","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of California San Diego , La Jolla , CA 92093 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4546-2175","authenticated-orcid":false,"given":"Daniel\u00a0J","family":"Donoghue","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of California San Diego , La Jolla , CA 92093 ,","place":["United States"]},{"name":"Moores UCSD Cancer Center, University of California San Diego , La Jolla, San Diego , CA 92093 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5043-0998","authenticated-orcid":false,"given":"Alexis\u00a0C","family":"Komor","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of California San Diego , La Jolla , CA 92093 ,","place":["United States"]},{"name":"Moores UCSD Cancer Center, University of California San Diego , La Jolla, San Diego , CA 92093 ,","place":["United States"]},{"name":"Sanford Stem Cell Institute, University of California San Diego , La Jolla , CA 92037 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,3,28]]},"reference":[{"key":"2025041601023017200_B1","doi-asserted-by":"publisher","first-page":"1478","DOI":"10.1126\/science.aaa9119","article-title":"The origins, determinants, and consequences of human mutations","volume":"349","author":"Shendure","year":"2015","journal-title":"Science"},{"key":"2025041601023017200_B2","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1126\/science.1219240","article-title":"Evolution and functional impact of rare coding variation from deep sequencing of human exomes","volume":"337","author":"Tennessen","year":"2012","journal-title":"Science"},{"key":"2025041601023017200_B3","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1111\/cts.12440","article-title":"High-throughput assays to assess the functional impact of genetic variants: a road towards genomic-driven medicine","volume":"10","author":"Ipe","year":"2017","journal-title":"Clin. 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