JNK Phosphorylates SIRT6 to Stimulate DNA Double-Strand Break Repair in Response to Oxidative Stress by Recruiting PARP1 to DNA Breaks
Michael Van Meter, Matthew Simon, Gregory Tombline, Alfred May, Timothy D. Morello, Basil P. Hubbard, Katie Bredbenner, Rosa Park, David A. Sinclair, Vilhelm A. Bohr, Vera Gorbunova4, Andrei Seluanov
Model for JNK-Mediated Activation of DSB Repair
Upon oxidative stress JNK phosphorylates SIRT6 on Serine 10. This results in rapid recruitment of SIRT6 to the DSB site and simultaneously stimulates SIRT6 mono-ADP ribosylation of PARP1. PARP1 mono-ADP ribosylation leads to recruitment of PARP1 to DSB site and activates PARP1 poly-ADP ribosylation activity. This sequence of events represents the initial steps in the assembly of repair machinery on a DSB, and it is required for efficient DSB repair under oxidative stress conditions.
• JNK phosphorylates SIRT6 at residue S10 in response to oxidative stress
• SIRT6 S10 phosphorylation is required for the stimulation of DNA break repair
• SIRT6 S10 phosphorylation stimulates SIRT6 mono-ADP ribosylation activity on PARP1
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.
Received: December 28, 2015; Received in revised form: April 6, 2016; Accepted: August 1, 2016; Published: August 25, 2016
© 2016 The Author(s). Published by Elsevier Inc.
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