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Cell. 2019 Apr 18;177(3):622-638.e22. doi: 10.1016/j.cell.2019.03.043.

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

Author information

1
Department of Biology, University of Rochester, Rochester, NY 14627, USA.
2
Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA.
3
Leibniz Institute on Aging - Fritz Lipmann Institute, Beutenbergstra├če 11, Jena D-07745, Germany.
4
School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
5
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
6
Huffington Center on Aging, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
7
Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
8
Ichor Therapeutics, 2521 US-11, Lafayette, NY 13084, USA.
9
Departments of Biochemistry and Physiology, National University Singapore, Singapore; Centre for Healthy Aging, National University Health System, Singapore.
10
Department of Biology, University of Rochester, Rochester, NY 14627, USA. Electronic address: andrei.seluanov@rochester.edu.
11
Department of Biology, University of Rochester, Rochester, NY 14627, USA. Electronic address: vera.gorbunova@rochester.edu.

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.

KEYWORDS:

DNA DSB repair; DNA repair; NER; SIRT6; aging; longevity

PMID:
31002797
PMCID:
PMC6499390
[Available on 2020-04-18]
DOI:
10.1016/j.cell.2019.03.043

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