Obesity increases genomic instability at DNA repeat-mediated endogenous mutation hotspots.

Autor: Kompella P; Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, Austin, TX, USA., Wang G; Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, Austin, TX, USA., Durrett RE; Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA., Lai Y; Department of Chemistry and Biochemistry, Florida International University, Miami, FL, USA., Marin C; Department of Chemistry and Biochemistry, Florida International University, Miami, FL, USA., Liu Y; Department of Chemistry and Biochemistry, Florida International University, Miami, FL, USA., Habib SL; South Texas Veterans Health Care System, San Antonio, TX, USA., DiGiovanni J; Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, Austin, TX, USA., Vasquez KM; Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, Austin, TX, USA. karen.vasquez@austin.utexas.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Jul 23; Vol. 15 (1), pp. 6213. Date of Electronic Publication: 2024 Jul 23.
DOI: 10.1038/s41467-024-50006-8
Abstrakt: Obesity is associated with increased cancer risk, yet the underlying mechanisms remain elusive. 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 c-MYC 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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