1. SIRT6 Is Responsible for More Efficient DNA Double-Strand Break Repair in Long-Lived Species
- Author
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Kitty Zheng, Zhiyong Mao, Aaron J. Wolfe, Kelsey Moody, Jonathan Tam, Adam B. Johnson, Steven Henderson, Janine Steffan, Dirk Bohmann, Matthew Simon, Jiang Nan Yang, Ruiyue Tan, Xiao Tian, Gregory Tombline, Audrey Goldfarb, Brian K. Kennedy, Andrei Seluanov, Lingfeng Luo, Adam Cornwell, Zhengdong D. Zhang, Jan Vijg, Denis Firsanov, Vera Gorbunova, Bruno Manta, Zhihui Zhang, Vadim N. Gladyshev, Yang Cheng, and Weiwei Dang
- Subjects
Male ,SIRT6 ,DNA Repair ,Ultraviolet Rays ,DNA repair ,media_common.quotation_subject ,Longevity ,Mutant ,Rodentia ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Evolution, Molecular ,Gene Knockout Techniques ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Animals ,Humans ,Sirtuins ,DNA Breaks, Double-Stranded ,Amino Acid Sequence ,Phylogeny ,030304 developmental biology ,media_common ,0303 health sciences ,Body Weight ,Fibroblasts ,Phenotype ,Double Strand Break Repair ,Cell biology ,Kinetics ,enzymes and coenzymes (carbohydrates) ,chemistry ,Mutagenesis ,Sequence Alignment ,030217 neurology & neurosurgery ,DNA ,Nucleotide excision repair - Abstract
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.
- Published
- 2019
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