PDF(Pubmed)
Abstract：
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.
摘要：
肥胖与癌症风险增加有关，然而，潜在的机制仍然难以捉摸。肥胖相关癌症涉及代谢和细胞通路的破坏，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）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影响DNA重复介导的内源性突变热点.我们通过测量携带对照人B-DNA-或H-DNA形成序列（来自伯基特淋巴瘤中c-MYC的易位热点）的肥胖和正常体重转基因报告小鼠的突变频率来解决这一差距。这里,我们发现H-DNA诱导的DNA损伤和突变以组织特异性的方式升高，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癌症相关内源性突变热点的影响。提供对肥胖和癌症之间联系的机械洞察。
