Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, Austin, TX, USA.
Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA.
Nat Commun. 2024 Jul 23;15(1):6213. doi: 10.1038/s41467-024-50006-8.
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.
肥胖与癌症风险增加有关，但潜在机制仍难以捉摸。与肥胖相关的癌症涉及代谢和细胞途径的中断，这可能导致基因组不稳定。能够采用替代 DNA 结构的重复 DNA 序列（例如 H-DNA）会刺激突变，并在人类癌症基因组中的突变热点处富集。然而，目前尚不清楚肥胖是否会影响 DNA 重复介导的内源性突变热点。我们通过测量携带控制人类 B-DNA 或 H-DNA 形成序列（来自 Burkitt 淋巴瘤中 c-MYC 的易位热点）的肥胖和正常体重转基因报告小鼠中的突变频率来解决这一差距。在这里，我们发现 H-DNA 诱导的 DNA 损伤和突变以组织特异性方式升高，并且与对照饮食相比，肥胖小鼠的 DNA 修复效率降低。这些发现阐明了肥胖对与癌症相关的内源性突变热点的影响，为肥胖与癌症之间的联系提供了机制上的见解。
