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: 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 Gorbunova, Andrei Seluanov
• Journal: Cell reports (Cell Rep) Vol. 16 Issue 10 Pg. 2641-2650 (09 06 2016) ISSN: 2211-1247 [Electronic] United States
• PMID: 27568560 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Phosphoserine
• Adenosine Diphosphate Ribose
• Poly (ADP-Ribose) Polymerase-1
• Sirt6 protein, mouse
• JNK Mitogen-Activated Protein Kinases
• SIRT6 protein, human
• Sirtuins

Topics

• Adenosine Diphosphate Ribose (metabolism)
• Animals
• DNA Breaks, Double-Stranded
• DNA Repair
• HEK293 Cells
• Humans
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Mice, Knockout
• Models, Biological
• Oxidative Stress
• Phosphorylation
• Phosphoserine (metabolism)
• Poly (ADP-Ribose) Polymerase-1 (metabolism)
• Sirtuins (metabolism)