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J. Biol. Chem., Vol. 280, Issue 15, 15141-15147, April 15, 2005

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Modulation of DNA Fragmentation Factor 40 Nuclease Activity by Poly(ADP-ribose) Polymerase-1^*

James D. West, Chuan Ji, and Lawrence J. Marnett

From the Department of Biochemistry, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology and the Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146

Poly(ADP-ribose) polymerase-1 (PARP-1) influences numerous cellular processes, including DNA repair, transcriptional regulation, and caspase-independent cell death, by utilizing NAD⁺ to synthesize long chains of poly(ADP-ribose) (PAR) on target proteins, including itself. During the apoptotic response, caspases-3 and -7 cleave PARP-1, thereby inhibiting its activity. Here, we have examined the role of PARP-1 activation and cleavage in the latter stages of apoptosis in response to DNA fragmentation. PARP-1 poly(ADP-ribosyl)ation correlated directly with induction of apoptosis by the lipid peroxidation product, 4-hydroxy-2-nonenal. A significant decrease in PAR accumulation was observed upon caspase or DNA fragmentation factor 40 (DFF40) inhibition. Because DNA fragmentation mediated by DFF40 augmented PARP-1 modification status in apoptotic cells, we hypothesized that PARP-1 alters DFF40 function following PAR accumulation. Indeed, PARP-1, in the presence of NAD⁺, significantly decreased DFF40 activity on plasmid substrates. Conversely, PARP-1 enhanced the DNase activity of DFF40 in the absence of NAD⁺. The inhibition of DFF40 activity in the presence of NAD⁺ was reduced by co-incubation with poly(ADP-ribose) glycohydrolase and a PARP inhibitor. Additionally, caspase-cleaved PARP-1, in the presence of NAD⁺, did not inhibit DFF40 activity significantly. Our results suggest that PARP-1 poly(ADP-ribosyl)ation is a terminal event in the apoptotic response that occurs in response to DNA fragmentation and directly influences DFF40 activity.

Received for publication, November 22, 2004 , and in revised form, January 31, 2005.

^* This work was supported by National Institutes of Health Research and Center Grants CA87819, ES00267, and CA68485 and National Institutes of Health Training Grant CA78136 (to J. D. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: 854 Robinson Research Bldg., 23rd Ave. at Pierce, Vanderbilt University School of Medicine, Nashville, TN 37232-0146. Tel.: 615-343-7329; Fax: 615-343-7534; E-mail: larry.marnett{at}vanderbilt.edu.

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