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Molecular and Cellular Biology, August 2009, p. 4116-4129, Vol. 29, No. 15
0270-7306/09/$08.00+0     doi:10.1128/MCB.00121-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

SIRT1 Promotes Cell Survival under Stress by Deacetylation-Dependent Deactivation of Poly(ADP-Ribose) Polymerase 1{triangledown}

Senthilkumar B. Rajamohan,1 Vinodkumar B. Pillai,1 Madhu Gupta,2 Nagalingam R. Sundaresan,1 Konstantin G. Birukov,1 Sadhana Samant,1 Michael O. Hottiger,3 and Mahesh P. Gupta1*

Pritzker School of Medicine, Committee on Molecular and Cellular Physiology, University of Chicago, Chicago, Illinois,1 Department of Physiology and Biophysics, University of Illinois, Chicago, and Hope Children's Hospital, Oak-Lawn, Illinois,2 Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Zurich, Switzerland3

Received 26 January 2009/ Returned for modification 23 February 2009/ Accepted 16 May 2009

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.

* Corresponding author. Mailing address: Department of Surgery, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637. Phone: (773) 834-7811. Fax: (773) 702-4187. E-mail: mgupta{at}surgery.bsd.uchicago.edu

{triangledown} Published ahead of print on 26 May 2009.

Molecular and Cellular Biology, August 2009, p. 4116-4129, Vol. 29, No. 15
0270-7306/09/$08.00+0     doi:10.1128/MCB.00121-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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