%0 Journal Article
%T Obesity increases genomic instability at DNA repeat-mediated endogenous mutation hotspots.
%A Kompella P
%A Wang G
%A Durrett RE
%A Lai Y
%A Marin C
%A Liu Y
%A Habib SL
%A DiGiovanni J
%A Vasquez KM
%J Nat Commun
%V 15
%N 1
%D 2024 Jul 23
%M 39043652
%F 17.694
%R 10.1038/s41467-024-50006-8
%X 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.