SIRT6 promotes DNA repair under stress
by mono-ADP-ribosylating PARP1

Zhiyong Mao1, C. Hine1,2, A. Vaidya1,
M. Feigenson1,2, A. Seluanov1,2,
V. Gorbunova1,2
1Department of Biology, University of Rochester, Rochester NY 14627
2Department of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, NY, 14627

SIRT6 is a mammalian homolog of the yeast Sir2 deacetylase that promotes longevity in yeast and invertebrates. Mice deficient for SIRT6 exhibit premature aging and genome instability. However, the mechanisms of SIRT6 function in genome maintenance and lifespan regulation are unclear. Here we show that in mammalian cells subjected to oxidative stress SIRT6 is recruited to the sites of DNA double-strand breaks (DSBs) and strongly stimulates DSB repair. SIRT6 physically associates with PARP1 and mono-ADP-ribosylates it, leading to stimulation of PARP1 poly-ADP-ribose polymerase activity. Our results suggest that SIRT6 promotes genome stability by stimulating PARP1 and enhancing DSB repair under oxidative stress. We propose that SIRT6 functions as a regulator integrating oxidative stress signaling and DNA damage response. The theory of hormesis proposes that mild doses of stress may have beneficial effects on the organism by stimulating stress and survival pathways. This theory has been explored extensively by biogerontologists, and was also used to explain life extending effects of food restriction. We hypothesize that SIRT6 serves as a mediator of hormetic response, promoting longevity by stimulating DNA repair under stressful conditions.

Homo Sapiens Liberatus Workshop, Moscow State University, May 2010