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Query: EC:3.2.1.143 (poly(ADP-ribose) glycohydrolase)
 208 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel enzyme that splits a bond between ADP-ribose and histone was discovered and partially purified from rat liver cytosol. The 105,000 X g supernatant of rat liver homogenate was precipitated by 45% saturated ammonium sulfate and then chromatographed on a DEAE-cellulose column. The enzyme activity was eluted in a single peak at about 0.2 M NaCl and clearly separated from poly(ADP-ribose) glycohydrolase which came out at 0.13 M NaCl. In contrast to the latter enzyme, this new enzyme catalyzed the spliting of a linkage between ADP-ribose and a protein portion in mono ADP-ribosylated histone H2B but little, if any, of the glycosidic ribosyl(1"-2') ribose bonds within poly(ADP-ribose). Analysis of the reaction product by paper chromatography and Dowex 1 column chromatography indicated that the split product contained the ADP-ribose moiety but was not exactly identical with ADP-ribose. Available evidence suggested that it was either an altered ADP-ribose molecule produced by a structural rearrangement or ADP-ribose itself linked to an unidentified compound. The enzyme had a pH optimum of about 6.0 and was inhibited by 80-90% in the presence of 5 mM ADP-ribose.
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PMID:Novel enzyme from rat liver that cleaves an ADP-ribosyl histone linkage. 27 65

Histone ADP-ribosylation was studied using two-dimensional gel electrophoresis after cleavage of the nuclear DNA with nucleases. Modified histones carrying different numbers of ADP-ribose groups form a ladder of bands above each variant histone. Cellular lysates containing unfragmented DNA mainly synthesize mono(ADP-ribosylated) histones. Cleavage of the DNA with either DNase I or micrococcal nuclease to fragments of an average size of 10-20 kilobases (kb) dramatically induces the formation of poly(ADP-ribosylated) species of histones in nuclei. As the number of DNA strand breaks produced by either DNase I or micrococcal nuclease increases and a great number of DNA cuts is introduced (fragments of 0.4-0.2 kb), the size of the poly(ADP-ribose) chains on the histones decreases. Finally, in the presence of 10 mM cAMP as an inhibitor of poly(ADP-ribose) glycohydrolase, human lymphoid nuclei synthesize hyper(ADP-ribosylated) histone H2B with at least 40 ADP-ribose groups attached to it. Lateral ladders emanating at precise points of the linear ladder on hypermodified H2B can arise from branching of poly(ADP-ribose) or from multiple monomodifications of glutamic (or aspartic) acid residues. Branching or de novo monomodifications occur after a precise number of ADP-ribose groups have been added to a histone molecule. Poly(ADP-ribosylated) histones thus appear to be intermediates in nuclear processes involving DNA strand breaks.
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PMID:DNA strand breaks alter histone ADP-ribosylation. 272 32

Poly(ADP-ribose) polymerase is a nuclear enzyme that is highly conserved in eucaryotes. Its activity is totally dependent on the presence of DNA containing single or double stranded breaks. We have shown that this activation results in a decondensation of chromatin superstructure in vitro, which is caused mainly by hyper(ADP-ribosy)ation of histone H1. In core particles, the modification of histone H2B leads to a partial dissociation of DNA from core histones. The conformational change of native chromatin by poly(ADP-ribosyl)ation is reversible upon degradation of the histone H1-bound poly(ADP-ribose) by poly(ADP-ribose) glycohydrolase. We propose that cuts produced in vivo on DNA during DNA repair activate poly(ADP-ribose) polymerase, which then synthesizes poly(ADP-ribose) on histone H1, in particular, and contributes to the opening of the 25-nm chromatin fiber, resulting in the increased accessibility of DNA to excision repair enzymes. This mechanism is fast and reversible.
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PMID:Modulation of chromatin structure by poly(ADP-ribosyl)ation. 313 15

Hydrolysis of protein-bound 32P-labelled poly(ADP-ribose) by poly(ADP-ribose) glycohydrolase shows that there is differential accessibility of poly(ADP-ribosyl)ated proteins in chromatin to poly(ADP-ribose) glycohydrolase. The rapid hydrolysis of hyper(ADP-ribosyl)ated forms of histone H1 indicates the absence of an H1 dimer complex of histone molecules. When the pattern of hydrolysis of poly(ADP-ribosyl)ated histones was analyzed it was found that poly(ADP-ribose) attached to histone H2B is more resistant than the polymer attached to histone H1 or H2A or protein A24. Polymer hydrolysis of the acceptors, which had been labelled at high substrate concentrations (greater than or equal to 10 microM), indicate that the only high molecular weight acceptor protein is poly(ADP-ribose) polymerase and that little processing of the enzyme occurs. Finally, electron microscopic evidence shows that hyper(ADP-ribosyl)ated poly(ADP-ribose) polymerase, which is dissociated from its DNA-enzyme complex, binds again to DNA after poly(ADP-ribose) glycohydrolase action.
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PMID:Poly(ADP-ribose) accessibility to poly(ADP-ribose) glycohydrolase activity on poly(ADP-ribosyl)ated nucleosomal proteins. 371

DNA-alkylating agents in combination with poly (ADP-ribose) (PAR) synthesis inhibitors are a promising treatment for cancer. In search of other efficacious alternatives, we hypothesized that the absence of poly(ADP-ribose) glycohydrolase (PARG), which leads to the inhibition of PAR hydrolysis, would lead to increased DNA alkylation after treatment with low doses of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). At a sublethal dose, MNNG shows synergistic cytotoxicity in PARG-null embryonic trophoblast stem (TS) cells. The PAR modifications of histone H1 and histone H2B are much more pronounced in PARG null-TS cells exposed to MNNG, suggesting their relevance in the efficacy of this combination therapy. Because the PAR modification of these chromatin binding proteins leads to chromatin remodeling, a possible mechanism for the observed synergistic effects involves the subsequent decondensation of chromatin, which may cause the genomic DNA to be more accessible to MNNG alkylation. Further analysis demonstrated chromatin decondensation in PARG null-TS cells as visualized by electron microscopy. In addition, treatment with MNNG led to an increase in O6- methylguanine levels in PARG null-TS cells compared to wild-type, which demonstrates increased DNA alkylation in the absence of PARG. Taken together, we provide compelling evidence that the absence of PARG leads to chromatin decondensation, which in turn leads to increased amounts of DNA alkylation and cell death induced by low doses of MNNG. Therefore, combination therapy of PARG inhibition and a DNA- alkylating agent is a potential treatment to induce the death of cancer cells.
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PMID:Synergistic cytotoxicity of N-methyl-N'-nitro-N-nitrosoguanidine and absence of poly(ADP-ribose) glycohydrolase involves chromatin decondensation. 2151 89