SIRT6 Is Responsible for More Efficient DNA Double-Strand Break Repair in Long-Lived Species
SIRT6 Is Responsible for More Efficient DNA Double-Strand Break Repair in Long-Lived Species
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DOI：
10.1016/j.cell.2019.03.043
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发表时间：
2019-04-18
期刊：
影响因子：
64.5
通讯作者：
Gorbunova, Vera
中科院分区：
文献类型：
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作者：
Tian, Xiao;Firsanov, Denis;Gorbunova, Vera
DNA修复被认为是长寿的决定因素，但它的证据主要是基于DNA修复突变体的加速老化表型。在这里，使用一组18种不同寿命的啮齿动物物种，我们表明，更强大的DNA双链断裂（DSB）修复，而不是核苷酸切除修复（NER），与长寿共同进化。与DSB不同，NER的演变主要由阳光照射形成。我们进一步表明，SIRT6蛋白促进DSB修复的能力占短寿命和长寿命物种之间DSB修复功效变化的主要部分。我们剖析了弱（小鼠）和强（海狸）SIRT6蛋白之间的分子差异，并确定了五个氨基酸残基，完全负责其差异活动。我们的研究结果表明，DSB修复和SIRT6在长寿的进化过程中得到了优化，这为抗衰老干预提供了新的目标。
DNA repair has been hypothesized to be a longevity determinant, but the evidence for it is based largely on accelerated aging phenotypes of DNA repair mutants. Here, using a panel of 18 rodent species with diverse lifespans, we show that more robust DNA double-strand break (DSB) repair, but not nucleotide excision repair (NER), coevolves with longevity. Evolution of NER, unlike DSB, is shaped primarily by sunlight exposure. We further show that the capacity of the SIRT6 protein to promote DSB repair accounts for a major part of the variation in DSB repair efficacy between short-and long-lived species. We dissected the molecular differences between a weak (mouse) and a strong (beaver) SIRT6 protein and identified five amino acid residues that are fully responsible for their differential activities. Our findings demonstrate that DSB repair and SIRT6 have been optimized during the evolution of longevity, which provides new targets for anti-aging interventions.