title: JNK Phosphorylates SIRT6 to Stimulate DNA Double-Strand Break Repair in Response to Oxidative Stress by Recruiting PARP1 to DNA Breaks.
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.
authors: Department of Biology, University of Rochester, Rochester, NY 14627, USA.
authors: Michael
authors: M
authors: Van Meter
authors: Department of Biology, University of Rochester, Rochester, NY 14627, USA.
authors: Matthew
authors: M
authors: Simon
authors: Department of Biology, University of Rochester, Rochester, NY 14627, USA.
authors: Gregory
authors: G
authors: Tombline
authors: Laboratory of Molecular Gerontology, National Institute on Aging, Baltimore, MD 21224, USA.
authors: Alfred
authors: A
authors: May
authors: Department of Biology, University of Rochester, Rochester, NY 14627, USA.
authors: Timothy D
authors: TD
authors: Morello
authors: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors: Basil P
authors: BP
authors: Hubbard
authors: Department of Biology, University of Rochester, Rochester, NY 14627, USA.
authors: Katie
authors: K
authors: Bredbenner
authors: Department of Biology, University of Rochester, Rochester, NY 14627, USA.
authors: Rosa
authors: R
authors: Park
authors: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors: David A
authors: DA
authors: Sinclair
authors: Laboratory of Molecular Gerontology, National Institute on Aging, Baltimore, MD 21224, USA.
authors: Vilhelm A
authors: VA
authors: Bohr
authors: Department of Biology, University of Rochester, Rochester, NY 14627, USA. Electronic address: vera.gorbunova@rochester.edu.
authors: Vera
authors: V
authors: Gorbunova
authors: Department of Biology, University of Rochester, Rochester, NY 14627, USA. Electronic address: andrei.seluanov@rochester.edu.
authors: Andrei
authors: A
authors: Seluanov
mesh_terms: D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D000818:Animals; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D057809:HEK293 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018345:Mice, Knockout; D008954:Models, Biological; D018384:Oxidative Stress; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism*; D037761:Sirtuins / Q000378:metabolism*
chemical_list: D010768:Phosphoserine; D000246:Adenosine Diphosphate Ribose; D000071137:Poly (ADP-Ribose) Polymerase-1; C501860:Sirt6 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; C516592:SIRT6 protein, human; D037761:Sirtuins