Subcellular localization of poly(ADP-ribose) glycohydrolase in mammalian cells

Ohashi, Sayaka; Kanai, Masayuki; Hanai, Shuji; Uchiumi, Fumiaki; Maruta, Hidenori; Tanuma, Sei Ichi; Misawa, Miwa

doi:10.1016/s0006-291x(03)01272-5

Cited by 64 publications

(49 citation statements)

References 28 publications

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“…The failure to remove PAR from either covalently modified proteins or noncovalently bound PAR may lead to growth arrest and cell death, because many PAR-modified proteins are important for cell survival and DNA processing͞repair (37)(38)(39)(40)(41). Recent evidence suggests that poly-(ADP-ribosyl)ation regulates transcription (5) and that the failure to degrade PAR polymer may lead to transcriptional dysregulation.…”

Section: Discussionmentioning

confidence: 99%

Failure to degrade poly(ADP-ribose) causes increased sensitivity to cytotoxicity and early embryonic lethality

Koh

Lawler

Poitras

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

292

288

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The metabolism of poly(ADP-ribose) (PAR) is critical for genomic stability in multicellular eukaryotes. Here, we show that the failure to degrade PAR by means of disruption of the murine poly(ADPribose) glycohydrolase (PARG) gene unexpectedly causes early embryonic lethality and enhanced sensitivity to genotoxic stress. This lethality results from the failure to hydrolyze PAR, because PARG null embryonic day (E) 3.5 blastocysts accumulate PAR and concurrently undergo apoptosis. Moreover, embryonic trophoblast stem cell lines established from early PARG null embryos are viable only when cultured in medium containing the poly(ADPribose) polymerase inhibitor benzamide. Cells lacking PARG also show reduced growth, accumulation of PAR, and increased sensitivity to cytotoxicity induced by N-methyl-N -nitro-N-nitrosoguanidine and menadione after benzamide withdrawal. These results provide compelling evidence that the failure to degrade PAR has deleterious consequences. Further, they define a role for PARG in embryonic development and a protective role in the response to genotoxic stress.poly(ADP-ribose) glycohydrolase ͉ poly(ADP-ribose) polymerase ͉ apoptosis

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Section: Discussionmentioning

confidence: 99%

Failure to degrade poly(ADP-ribose) causes increased sensitivity to cytotoxicity and early embryonic lethality

Koh

Lawler

Poitras

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

292

288

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“…(iii) Both, hPARG60 and hPARG55 are associated with the mitochondria, making them potentially important factors in the nuclear-mitochondrial crosstalk involving PAR metabolism. While PARG111 is a nuclear enzyme carrying a nuclear localization signal (NLS) in exon I near the N-terminus [8], PARG 102 and PARG 99 are mainly extranuclear proteins [7,47] carrying putative nuclear export signals (NES), [43,48] in the N-terminal A-domain. The presence of the bulk of PARG activity in the cytoplasm remains puzzling as the vast majority of PAR synthesis following genotoxic stress is catalyzed by the predominantly nuclear enzymes PARP-1 and PARP-2 and PAR is therefore detectable mainly in the nucleus after DNA damage.…”

Section: Discussionmentioning

confidence: 99%

“…: 610-925-6148, Fax: 610-925-8121 E-Mail: meyerg@vet.upenn.edu synthesizing poly(ADP-ribose) (PAR) [3][4][5], and, so far, ten of them have been shown to be catalytically active. In contrast, only three human poly(ADP-ribose) glycohydrolase (PARG) proteins, PARG111, PARG102 and PARG99 have been described, which are all expressed from one single PARG gene by alternative splicing [6][7][8] . PARG proteins have been the only enzymes known to efficiently catalyze hydrolysis of poly(ADP-ribose) (PAR) produced by enzymes of the poly(ADP-ribose) polymerase (PARP) family [9] until recently a novel gene encoding a 39 kDa enzyme with low poly(ADP-ribose) glycohydrolase activity has been discovered [10][11][12] .…”

Section: Introductionmentioning

confidence: 99%

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

Meyer

Meyer-Ficca

Whatcott

et al. 2007

Experimental Cell Research

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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“…The shuttling of PARG 110 between the cytoplasm and nucleus appears to ensure a dynamic control of the turnover of PAR moieties. 11,12 However, PARG might not be the only antagonist to PARPs, since it has been suggested that the macro domain of a large variety of proteins, such as macroH2A, harbours a phosphoesterase activity that may include the ADP-ribose (or PAR) moiety as a target. 13 The presence of the macro domain in a large range of proteins hints at the possibility that the turnover of the PAR chains is more complex than hitherto believed.…”

Section: Poly(adp-ribosyl)ation: the Game And The Playersmentioning

confidence: 99%