Control of AIF-mediated Cell Death by the Functional Interplay of SIRT1 and PARP-1 in Response to DNA Damage

• Published in: Cell cycle (Georgetown, Tex.) Vol. 5; no. 8; pp. 873 - 877
• Main Authors: Kolthur-Seetharam, Ullas, Dantzer, Françoise, McBurney, Michael W., Murcia1, Gilbert de, Sassone-Corsi, Paolo
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 15.04.2006
• Subjects: Animals; Apoptosis Inducing Factor - physiology; Binding; Biology; Bioscience; Calcium; Cancer; Cell; Cell Death; Cell Line; Cycle; DNA Damage; Enzyme Inhibitors - pharmacology; Gene Expression Regulation; Humans; Landes; Mice; Models, Biological; Organogenesis; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases - metabolism; Poly(ADP-ribose) Polymerases - physiology; Proteins; Sirtuin 1; Sirtuins - physiology; Stilbenes - pharmacology
• ISSN: 1538-4101; 1551-4005
• DOI: 10.4161/cc.5.8.2690

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.