Isolation and Characterization of the cDNA Encoding Bovine Poly(ADP-ribose) Glycohydrolase

Lin, Wei Yu; Amé, Jean‐Christophe; Aboul-Ela, Nasreen; Jacobson, Elaine L.; Jacobson, Myron K.

doi:10.1074/jbc.272.18.11895

Cited by 191 publications

(155 citation statements)

References 60 publications

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“…PARG111 (reviewed in [55]). Indeed, larger isolated PARG proteins have been shown repeatedly to be unstable, forming degradation products of 50-65 kDa [5,54,56]. Isolation and purification of endogenous bovine PARG from thymus yielded such short proteins and MALDI-TOF analyses of the obtained fraction indicated the presence of several different PARG proteins in the range of 50-65 kDa (Meyer, R. G. and Jacobson, M. K., unpublished results).…”

Section: Discussionmentioning

confidence: 98%

Two small enzyme isoforms mediate mammalian mitochondrial poly(ADP-ribose) glycohydrolase (PARG) activity

Meyer

Meyer-Ficca

Whatcott

et al. 2007

Experimental Cell Research

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101

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Poly(ADP-ribose)glycohydrolase (PARG) is the major enzyme capable of rapidly hydrolyzing poly (ADP-ribose)(PAR) formed by the diverse members of the PARP enzyme family. This study presents an alternative splice mechanism by which two novel PARG protein isoforms of 60 kDa and 55 kDa are expressed from the human PARG gene, termed hPARG60 and hPARG55, respectively. Homologous forms were found in the mouse (mPARG63 and mPARG58) supporting the hypothesis that expression of small PARG isoforms is conserved among mammals. A PARG protein of ∼60kDa has been described for decades but with its genetic basis unknown, it was hypothesized to be a product of posttranslational cleavage of larger PARG isoforms. While this is not excluded entirely, isolation and expression of cDNA clones from different sources of RNA indicate that alternative splicing leads to expression of a catalytically active hPARG60 in multiple cell compartments. A second enzyme, hPARG55 that can be expressed through alternative translation initiation from hPARG60 transcripts is strictly targeted to the mitochondria. Functional studies of a mitochondrial targeting signal (MTS) in PARG exon IV suggest that hPARG60 may be capable of shuttling between nucleus and mitochondria, which would be in line with a proposed function of PAR in genotoxic stress-dependent, nuclear-mitochondrial crosstalk.

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Section: Discussionmentioning

confidence: 98%

Two small enzyme isoforms mediate mammalian mitochondrial poly(ADP-ribose) glycohydrolase (PARG) activity

Meyer

Meyer-Ficca

Whatcott

et al. 2007

Experimental Cell Research

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101

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“…31 PARG hydrolyses the protein-bound poly(ADP-ribose), thereby generating free oligo-and monomers of ADP-ribose. 30 This indicates that PARP-1 and PARG activities in response to DNA damage are closely coordinated. 29 Using functional efflux assays, we provide evidence that UVB irradiation inhibits the activity of ABC transporters.…”

Section: Discussionmentioning

confidence: 99%

“…Poly(ADP-ribosyl)ation is involved in chromatin decondensation, DNA repair and replication, regulation of telomere function, and apoptosis. 29,30 As soon as the level of poly(ADP-ribose) exceeds a threshold (approximately 5 mM), cytoplasmic PARG is recruited to the nucleus. 31 PARG hydrolyses the protein-bound poly(ADP-ribose), thereby generating free oligo-and monomers of ADP-ribose.…”

Section: Discussionmentioning

confidence: 99%

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UV irradiation inhibits ABC transporters via generation of ADP-ribose by concerted action of poly(ADP-ribose) polymerase-1 and glycohydrolase

et al. 2003

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ATP-binding cassette (ABC) transporters are involved in the transport of multiple substrates across cellular membranes, including metabolites, proteins, and drugs. Employing a functional fluorochrome export assay, we found that UVB irradiation strongly inhibits the activity of ABC transporters. Specific inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) restored the function of ABC transporters in UVB-irradiated cells, and PARP-1-deficient cells did not undergo UVBinduced membrane transport inhibition. These data suggest that PARP-1 activation is necessary for ABC transporter functional downregulation. The hydrolysis of poly(ADPribose) by poly(ADP-ribose) glycohydrolase (PARG) was also required, since specific PARG inhibitors, which limit the production of ADP-ribose molecules, restored the function of ABC transporters. Furthermore, ADP-ribose molecules potently inhibited the activity of the ABC transporter Pglycoprotein. Hence, poly(ADP-ribose) metabolism appears to play a novel role in the regulation of ABC transporters.

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“…In contrast to the abundance of structural and functional data describing PAR synthesis [1][2][3][4] , our present understanding of the PAR-degradation pathway is comparatively poor 5,6 . Canonical PARG is a highly conserved protein found in organisms ranging from protozoa to humans 7 . The disruption of the PARG gene in mouse and Drosophila melanogaster leads to early embryonic lethality 8,9 .…”

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confidence: 99%

Structure and mechanism of a canonical poly(ADP-ribose) glycohydrolase

Dunstan¹,

Barkauskaite

Lafite

et al. 2012

Nat Commun

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Poly(ADP-ribosyl)ation is a reversible post-translational protein modification involved in the regulation of a number of cellular processes including DnA repair, chromatin structure, mitosis, transcription, checkpoint activation, apoptosis and asexual development. The reversion of poly(ADP-ribosyl)ation is catalysed by poly(ADP-ribose) (PAR) glycohydrolase (PARG), which specifically targets the unique PAR (1′′-2′) ribose-ribose bonds. Here we report the structure and mechanism of the first canonical PARG from the protozoan Tetrahymena thermophila. In addition, we reveal the structure of T. thermophila PARG in a complex with a novel rhodaninecontaining mammalian PARG inhibitor RBPI-3. our data demonstrate that the protozoan PARG represents a good model for human PARG and is therefore likely to prove useful in guiding structure-based discovery of new classes of PARG inhibitors.

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Isolation and Characterization of the cDNA Encoding Bovine Poly(ADP-ribose) Glycohydrolase

Abstract: The synthesis and rapid turnover of ADP-ribose polymers is an immediate cellular response to DNA damage. We report here the isolation and characterization of cDNA encoding poly(ADP-ribose) glycohydrolase (PARG), the enzyme responsible for polymer turnover.

Cited by 191 publications

References 60 publications

Two small enzyme isoforms mediate mammalian mitochondrial poly(ADP-ribose) glycohydrolase (PARG) activity

Two small enzyme isoforms mediate mammalian mitochondrial poly(ADP-ribose) glycohydrolase (PARG) activity

UV irradiation inhibits ABC transporters via generation of ADP-ribose by concerted action of poly(ADP-ribose) polymerase-1 and glycohydrolase

Structure and mechanism of a canonical poly(ADP-ribose) glycohydrolase

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