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. Epub 2016 Aug 25.


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.

MeSH terms

  • 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*


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