SIRT6 Is Responsible for More Efficient DNA Double-Strand Break Repair in Long-Lived Species

被引：210

作者：

Tian, Xiao ^{[1
]}

Firsanov, Denis ^{[1
]}

Zhang, Zhihui ^{[1
]}

Cheng, Yang ^{[2
]}

Luo, Lingfeng ^{[1
]}

Tombline, Gregory ^{[1
]}

Tan, Ruiyue ^{[1
]}

Simon, Matthew ^{[1
]}

Henderson, Steven ^{[1
]}

Steffan, Janine ^{[1
]}

Goldfarb, Audrey ^{[1
]}

Tam, Jonathan ^{[1
]}

Zheng, Kitty ^{[1
]}

Cornwell, Adam ^{[1
]}

Johnson, Adam ^{[1
]}

Yang, Jiang-Nan ^{[3
]}

Mao, Zhiyong ^{[4
]}

Manta, Bruno ^{[5
]}

Dang, Weiwei ^{[6
]}

Zhang, Zhengdong ^{[7
]}

Vijg, Jan ^{[7
]}

Wolfe, Aaron ^{[8
]}

Moody, Kelsey ^{[8
]}

Kennedy, Brian K. ^{[9
,10
,11
]}

Bohmann, Dirk ^{[2
]}

Gladyshev, Vadim N. ^{[5
]}

Seluanov, Andrei ^{[1
]}

Gorbunova, Vera ^{[1
]}

机构：

[1] Univ Rochester, Dept Biol, Rochester, NY 14627 USA

[2] Univ Rochester, Med Ctr, Dept Biomed Genet, Rochester, NY 14642 USA

[3] Fritz Lipmann Inst, Leibniz Inst Aging, Beutenbergstr 11, D-07745 Jena, Germany

[4] Tongji Univ, Sch Life Sci & Technol, Shanghai 200092, Peoples R China

[5] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA

[6] Baylor Coll Med, Huffington Ctr Aging, Dept Mol & Human Genet, Houston, TX 77030 USA

[7] Albert Einstein Coll Med, Dept Genet, Bronx, NY 10467 USA

[8] Ichor Therapeut, 2521 US-11, La Fayette, NY 13084 USA

[9] Natl Univ Singapore, Dept Biochem, Singapore, Singapore

[10] Natl Univ Singapore, Dept Physiol, Singapore, Singapore

[11] Natl Univ Hlth Syst, Ctr Hlth Aging, Singapore, Singapore

来源：

CELL | 2019年 / 177卷 / 03期

基金：

美国国家卫生研究院;

关键词：

LIFE-SPAN; SEASONAL ACTIVITY; CHINCHILLA-LANIGERA; GENOMIC INSTABILITY; EXCISION-REPAIR; CELLS; MOUSE; CHROMATIN; BIOLOGY; DEACETYLASE;

D O I：

10.1016/j.cell.2019.03.043

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：622 / +

页数：39

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