SIRT1 promotes cell survival under stress by deacetylation-dependent deactivation of poly(ADP-ribose) polymerase 1.
Poly(ADP-ribose) polymerase 1 (PARP1) and SIRT1 deacetylase are two NAD-dependent enzymes which play major roles in the decision of a cell to live or to die in a stress situation. Because of the dependence of both enzymes on NAD, cross talk between them has been suggested. Here, we show that PARP1 is acetylated after stress of cardiomyocytes, resulting in the activation of PARP1, which is independent of DNA damage. SIRT1 physically binds to and deacetylates PARP1. Increased acetylation of PARP1 was also detected in hearts of SIRT1(-/-) mice, compared to that detected in the hearts of SIRT1(+/+) mice, confirming a role of SIRT1 in regulating the PARP1 acetylation in vivo. SIRT1-dependent deacetylation blocks PARP1 activity, and it protects cells from PARP1-mediated cell death. We also show that SIRT1 negatively regulates the activity of the PARP1 gene promoter, thus suggesting that the deacetylase controls the PARP1 activity at the transcriptional level as well. These data demonstrate that the activity of PARP1 is under the control of SIRT1, which is necessary for survival of cells under stress conditions.
Rajamohan
Senthilkumar B
SB
Department of Surgery, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA.
Pillai
Vinodkumar B
VB
Gupta
Madhu
M
Sundaresan
Nagalingam R
NR
Birukov
Konstantin G
KG
Samant
Sadhana
S
Hottiger
Michael O
MO
Gupta
Mahesh P
MP
D000107:Acetylation / Q000187:drug effects; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D019556:COS Cells; D002470:Cell Survival; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D034622:RNA Interference; D051381:Rats; D056564:Sirtuin 1; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D013314:Stress, Mechanical
D009243:NAD; D000804:Angiotensin II; D010656:Phenylephrine; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C470545:Sirt1 protein, mouse; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D037761:Sirtuins