Modulation of DNA fragmentation factor 40 nuclease activity by poly(ADP-ribose) polymerase-1.

West JD, Ji C, Marnett LJ
J Biol Chem. 2005 280 (15): 15141-7

PMID: 15703174 · DOI:10.1074/jbc.M413147200

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.

MeSH Terms (29)

Animals Apoptosis Blotting, Western Caspase 3 Caspase 7 Caspases Cell Line Cell Line, Tumor Deoxyribonucleases DNA Fragmentation DNA Repair Enzyme Activation Epitopes Genetic Vectors Glycoside Hydrolases Humans Immunoprecipitation Lipid Peroxidation Mice Models, Biological Models, Molecular Plasmids Poly(ADP-ribose) Polymerases Poly-ADP-Ribose Binding Proteins Poly Adenosine Diphosphate Ribose Protein Binding Time Factors Transcription, Genetic Transfection

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