Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.2.1.143 (poly(ADP-ribose) glycohydrolase)
 208 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rat peritoneal macrophages are known to contain a chymotrypsin-like neutral protease associated with a specific inhibitor. By homogenizing the cells in 0.25 M sucrose (pH 8.0) containing 0.5% Triton X-100, both the protease and the inhibitor were found to be localized in the nuclei, particularly in chromatin. The inhibitory factor in chromatin was then separated from the protease by hydroxylapatite gel chromatography in the presence of 2 M NaCl and 5 M urea. The inhibitor fraction obtained was deproteinized by digestion with Pronase and subsequent extraction with phenol; these treatments did not alter the inhibitory potency. The deproteinized inhibitor fraction had a UV absorption ratio, A280/A260, of 0.61, but it was resistant to digestion with various nucleases, including DNase 1, nuclease P1, and snake venom phosphodiesterase. However, when it was incubated with poly(ADP-ribose) glycohydrolase from calf thymus, the inhibitory potency was markedly decreased. An authentic poly(ADP-ribose), with a mean chain length of approximately 30 ADP-ribose units, produced significant inhibition of the neutral protease isolated from macrophage chromatin. No such inhibition was produced by DNA, single-stranded DNA, RNA, polyadenylate, polyuridylate, polycytidylate, or monomeric ADP-ribose.
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PMID:A chromatin-bound neutral protease and its inhibitor in rat peritoneal macrophages. 71 9

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.
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PMID:Modulation of DNA fragmentation factor 40 nuclease activity by poly(ADP-ribose) polymerase-1. 1570 74