Control of AIF-mediated cell death by the functional interplay of SIRT1 and PARP-1 in response to DNA damage.
Cell survival after genotoxic stress is determined by a counterbalance of pro- and anti-death factors. Sirtuins (SIRTs) are deacetylases that promote cell survival whereas poly(ADP-ribose) polymerases (PARPs) can act both as survival and death inducing factor and the two protein families are strictly dependent on NAD(+) for their activities. Here we report that SIRT1 modulates PARP-1 activity upon DNA damage. Activation of SIRT1 by resveratrol leads to reduced PARP-1 activity and there is a drastic increase in PAR synthesis in sirt1-null cells. The unbalanced regulation of PARP-1 in the absence of SIRT1 results in AIF (apoptosis inducing factor)-mediated cell death. Our findings establish a functional link between the two NAD+-dependent enzyme systems and provide a physiological interpretation for the mechanism of death in cells lacking SIRT1.
Kolthur-Seetharam
Ullas
U
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, Inserm, Université Louis Pasteur, Strasbourg, France.
Dantzer
Françoise
F
McBurney
Michael W
MW
de Murcia
Gilbert
G
Sassone-Corsi
Paolo
P
D000818:Animals; D051033:Apoptosis Inducing Factor / Q000502:physiology*; D016923:Cell Death; D002460:Cell Line; D004249:DNA Damage; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008954:Models, Biological; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism / Q000502:physiology*; D000077185:Resveratrol; D056564:Sirtuin 1; D037761:Sirtuins / Q000502:physiology*; D013267:Stilbenes / Q000494:pharmacology
D051033:Apoptosis Inducing Factor; D004791:Enzyme Inhibitors; D013267:Stilbenes; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins; D000077185:Resveratrol