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Obesity-associated cancers involve disruptions in metabolic and cellular pathways, which can lead to genomic instability. Repetitive DNA sequences capable of adopting alternative DNA structures (e.g., H-DNA) stimulate mutations and are enriched at mutation hotspots in human cancer genomes. However, it is not known if obesity impacts DNA repeat-mediated endogenous mutation hotspots. We address this gap by measuring mutation frequencies in obese and normal-weight transgenic reporter mice carrying either a control human B-DNA- or an H-DNA-forming sequence (from a translocation hotspot in <jats:italic>c-MYC<\/jats:italic> in Burkitt lymphoma). Here, we discover that H-DNA-induced DNA damage and mutations are elevated in a tissue-specific manner, and DNA repair efficiency is reduced in obese mice compared to those on the control diet. These findings elucidate the impact of obesity on cancer-associated endogenous mutation hotspots, providing mechanistic insight into the link between obesity and cancer.<\/jats:p>","DOI":"10.1038\/s41467-024-50006-8","type":"journal-article","created":{"date-parts":[[2024,7,23]],"date-time":"2024-07-23T17:02:28Z","timestamp":1721754148000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Obesity increases genomic instability at DNA repeat-mediated endogenous mutation hotspots"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9508-5603","authenticated-orcid":false,"given":"Pallavi","family":"Kompella","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6871-7540","authenticated-orcid":false,"given":"Guliang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell E.","family":"Durrett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8903-069X","authenticated-orcid":false,"given":"Yanhao","family":"Lai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celeste","family":"Marin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4797-6396","authenticated-orcid":false,"given":"Yuan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samy L.","family":"Habib","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4233-6728","authenticated-orcid":false,"given":"John","family":"DiGiovanni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6958-5073","authenticated-orcid":false,"given":"Karen M.","family":"Vasquez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,7,23]]},"reference":[{"key":"50006_CR1","unstructured":"Mannar M., Micha R. 2020 Global Nutrition Report: Action On Equity To End Malnutrition (Development Initiatives, 2020)."},{"key":"50006_CR2","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1111\/j.1753-4887.2011.00456.x","volume":"70","author":"BM Popkin","year":"2012","unstructured":"Popkin, B. 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