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肥胖增加了DNA重复介导内源突变热点的基因组不稳定性

Pallavi Kompella¹, Guliang Wang¹, Russell E Durrett²

¹Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, Austin, TX, USA.

Nature communications

|July 23, 2024

概括

肥胖会增加癌症风险,因为它会增加特定热点的DNA损伤和突变. 这项研究揭示了肥胖小鼠的DNA修复效率降低,为肥胖驱动的癌症机制提供了新的见解.

科学领域:

遗传学和基因组学遗传学和基因组学
癌症生物学癌症生物学
代谢性疾病研究研究

背景情况:

肥胖是众所周知的各种癌症的风险因素,但精确的分子机制尚未完全理解.
基因组不稳定性,通常是由代谢和细胞通路的干扰驱动的,是肥胖相关癌症的标志.
形成像H-DNA这样的替代结构的重复性DNA序列与癌症基因组内的突变热点有关.

研究的目的:

为了调查肥胖是否影响内源突变热点通过DNA重复介导.
确定肥胖对DNA损伤和H-DNA形成序列的突变频率的影响.
评估肥胖者与正常体重模型的DNA修复效率.

主要方法:

使用了具有B-DNA或H-DNA形成序列的转基因记者小鼠 (来源于c-MYC转位热点).
肥胖和正常体重小鼠之间的突变频率和DNA损伤水平的比较.
在两组中评估了特定组织的DNA修复效率.

主要成果:

肥胖显著提高H-DNA诱导的DNA损伤和突变频率以特定组织的方式.
与对照小鼠相比,肥胖小鼠的DNA修复效率明显下降.
这些发现强调了肥胖与特定基因组部位内源突变增加之间的直接联系.

结论:

肥胖会加剧DNA损伤和H-DNA形成热点的突变,导致基因组不稳定.
肥胖症中DNA修复能力的降低在癌症发展中起着机械作用.
这项研究提供了关于肥胖如何通过内源性突变性过程促进癌症的关键见解.

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