JNK Phosphorylates SIRT6 to Stimulate DNA Double-Strand Break Repair in Response to Oxidative Stress by Recruiting PARP1 to DNA Breaks

  • Cell Rep. 2016 Sep 6;16(10):2641-2650. doi: 10.1016/j.celrep.2016.08.006.
Michael Van Meter  1 ,  Matthew Simon  1 ,  Gregory Tombline  1 ,  Alfred May  2 ,  Timothy D Morello  1 ,  Basil P Hubbard  3 ,  Katie Bredbenner  1 ,  Rosa Park  1 ,  David A Sinclair  3 ,  Vilhelm A Bohr  2 ,  Vera Gorbunova  4 ,  Andrei Seluanov  5
Affiliations
  • 1. Department of Biology, University of Rochester, Rochester, NY 14627, USA.
  • 2. Laboratory of Molecular Gerontology, National Institute on Aging, Baltimore, MD 21224, USA.
  • 3. Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
  • 4. Department of Biology, University of Rochester, Rochester, NY 14627, USA. Electronic address: [email protected].
  • 5. Department of Biology, University of Rochester, Rochester, NY 14627, USA. Electronic address: [email protected].
PMID: 27568560 DOI: 10.1016/j.celrep.2016.08.006
Abstract

The accumulation of damage caused by oxidative stress has been linked to aging and to the etiology of numerous age-related diseases. The longevity gene, Sirtuin 6 (SIRT6), promotes genome stability by facilitating DNA repair, especially under oxidative stress conditions. Here we uncover the mechanism by which SIRT6 is activated by oxidative stress to promote DNA double-strand break (DSB) repair. We show that the stress-activated protein kinase, c-Jun N-terminal kinase (JNK), phosphorylates SIRT6 on serine 10 in response to oxidative stress. This post-translational modification facilitates the mobilization of SIRT6 to DNA damage sites and is required for efficient recruitment of poly (ADP-ribose) polymerase 1 (PARP1) to DNA break sites and for efficient repair of DSBs. Our results demonstrate a post-translational mechanism regulating SIRT6, and they provide the link between oxidative stress signaling and DNA repair pathways that may be critical for hormetic response and longevity assurance.