{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T20:33:18Z","timestamp":1770755598152,"version":"3.50.0"},"reference-count":40,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,11,16]],"date-time":"2024-11-16T00:00:00Z","timestamp":1731715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH\/NCI","award":["R01CA093729"],"award-info":[{"award-number":["R01CA093729"]}]},{"name":"PhRMA Foundation Predoctoral Fellowship in Drug Discovery","award":["R01CA093729"],"award-info":[{"award-number":["R01CA093729"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Aging constitutes complex and dynamic alterations in molecular and physiological processes and is associated with numerous disorders, in part due to increased genetic instability. The aging population is projected to double by 2050, underscoring the urgent need to better understand the relationships between aging and age-related disorders. Repetitive DNA elements are intrinsic sources of genetic instability and have been found to co-localize with mutation hotspots in human cancer genomes. In this study, we explored the relationship between aging and DNA repeat-mediated genetic instability in vivo using an H-DNA-forming mirror-repeat sequence from the cancer-associated human c-MYC gene. Utilizing a unique mutation-reporter mouse model, we observed tissue-specific effects of aging on H-DNA-induced genetic instability, with mutation frequencies increasing in spleen tissues and remaining unchanged in testis tissues. Analysis of the mutation spectra revealed large deletion mutations as the primary contributor to increasing H-DNA-induced mutations, supported by increased cleavage activity of H-DNA structures in aged spleen tissues. Our findings demonstrate that aging has distinct tissue-specific effects on repeat-mediated, cancer-associated mutations, providing insights into the complex relationship between aging and cancer.<\/jats:p>","DOI":"10.3390\/biom14111453","type":"journal-article","created":{"date-parts":[[2024,11,18]],"date-time":"2024-11-18T05:36:45Z","timestamp":1731908205000},"page":"1453","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Tissue-Specific Effects of Aging on Repeat-Mediated Mutation Hotspots In Vivo"],"prefix":"10.3390","volume":"14","author":[{"given":"Alexandra M.","family":"D\u2019Amico","sequence":"first","affiliation":[{"name":"Division of Pharmacology and Toxicology, Dell Pediatric Research Institute, College of Pharmacy, The University of Texas at Austin, 1400 Barbara Jordan Blvd., Austin, TX 78723, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6355-2185","authenticated-orcid":false,"given":"Tonia T.","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Toxicology, Dell Pediatric Research Institute, College of Pharmacy, The University of Texas at Austin, 1400 Barbara Jordan Blvd., Austin, TX 78723, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6958-5073","authenticated-orcid":false,"given":"Karen M.","family":"Vasquez","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Toxicology, Dell Pediatric Research Institute, College of Pharmacy, The University of Texas at Austin, 1400 Barbara Jordan Blvd., Austin, TX 78723, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,16]]},"reference":[{"key":"ref_1","unstructured":"U.S. Census Bureau (2020). 65 and Older Population Grows Rapidly as Baby Boomers Age."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1016\/j.cell.2013.05.039","article-title":"The hallmarks of aging","volume":"153","author":"Blasco","year":"2013","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1038\/171737a0","article-title":"Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid","volume":"171","author":"Watson","year":"1953","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"13448","DOI":"10.1073\/pnas.0405116101","article-title":"Naturally occurring H-DNA-forming sequences are mutagenic in mammalian cells","volume":"101","author":"Wang","year":"2004","journal-title":"Proc. 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