The diverse biological roles of mammalian PARPS, a small but powerful family of poly-ADP-ribose polymerases

Paul, Oindrila

doi:10.2741/2909

Cited by 520 publications

(490 citation statements)

References 370 publications

(579 reference statements)

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“…Our results are in agreement with the previously reported data in the murine model, showing that regions of chromosomes known to be CFS in the mouse genome, are not more prone to DNA rearrangements in the absence of both PARP-1 and the Werner syndrome protein [55]. PARP-1, the principal member of a large family of PARPs, catalyzes the synthesis of ADP-ribose polymers using NAD + as a substrate [21]. Poly(ADP-ribosyl)ation of proteins represents one of the earliest responses to DNA damage, modifying chromatin structure in proximity of DNA damage; thus favouring the recruitment of DNA repair machineries, such as the base excision repair that is devoted to the correction of abasic sites and single strand breaks.…”

Section: Discussionsupporting

confidence: 93%

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Common fragile sites in colon cancer cell lines: Role of mismatch repair, RAD51 and poly(ADP-ribose) polymerase-1

Vernole

Muzi

Volpi

et al. 2011

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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t r a c tCommon fragile sites (CFS) are specific chromosomal areas prone to form gaps and breaks when cells are exposed to stresses that affect DNA synthesis, such as exposure to aphidicolin (APC), an inhibitor of DNA polymerases. The APC-induced DNA damage is repaired primarily by homologous recombination (HR), and RAD51, one of the key players in HR, participates to CFS stability. Since another DNA repair pathway, the mismatch repair (MMR), is known to control HR, we examined the influence of both the MMR and HR DNA repair pathways on the extent of chromosomal damage and distribution of CFS provoked by APC and/or by RAD51 silencing in MMR-deficient and -proficient colon cancer cell lines (i.e., HCT-15 and HCT-15 transfected with hMSH6, or HCT-116 and HCT-116/3+6, in which a part of a chromosome 3 containing the wild-type hMLH1 allele was inserted). Here, we show that MMR-deficient cells are more sensitive to APC-induced chromosomal damage particularly at the CFS as compared to MMR-proficient cells, indicating an involvement of MMR in the control of CFS stability. The most expressed CFS is FRA16D in 16q23, an area containing the tumour suppressor gene WWOX often mutated in colon cancer. We also show that silencing of RAD51 provokes a higher number of breaks in MMR-proficient cells with respect to their MMR-deficient counterparts, likely as a consequence of the combined inhibitory effects of RAD51 silencing on HR and MMR-mediated suppression of HR. The RAD51 silencing causes a broader distribution of breaks at CFS than that observed with APC. Treatment with APC of RAD51-silenced cells further increases DNA breaks in MMR-proficient cells. The RNAi-mediated silencing of PARP-1 does not cause chromosomal breaks or affect the expression/distribution of CFS induced by APC. Our results indicate that MMR modulates colon cancer sensitivity to chromosomal breaks and CFS induced by APC and RAD51 silencing.

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Section: Discussionsupporting

confidence: 93%

“…Moreover, since poly(ADP-ribose) polymerase (PARP)-1 is involved in NHEJ-mediated repair of DSBs and ensures regulation of replication fork progression by HR on damaged DNA [21][22][23], we analyzed also the sensitivity to APC of colon cancer cell lines stably silenced for PARP-1 expression.…”

Section: Introductionmentioning

confidence: 99%

Common fragile sites in colon cancer cell lines: Role of mismatch repair, RAD51 and poly(ADP-ribose) polymerase-1

Vernole

Muzi

Volpi

et al. 2011

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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“…PARPs are found in all groups of eukaryotes and are characterized by the catalytic site, a b-a-loop-B-a NAD + fold, also called the PARP signature (Ruf et al, 1996;Oliver et al, 2004). This family has been best characterized in humans, where there are 18 family members with diverse functional domains outside of the PARP signature Schreiber et al, 2006;Hassa and Hottiger, 2008). It is postulated that different PARPs participate in diverse events through these domains.…”

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confidence: 99%

“…PARPs have been implicated to be involved in DNA damage repair, cell death pathways, transcription, and chromatin modification/remodeling (for review, see Kim et al, 2005;Schreiber et al, 2006;Hassa and Hottiger, 2008). Human PARPs have been placed into five classes according to their functions: DNA-dependent PARPs, tankyrases, CCCH-type PARPs, macroPARPs, and a diverse orphan group with no known functions (Schreiber et al, 2006).…”

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confidence: 99%

The Paralogous GenesRADICAL-INDUCED CELL DEATH1andSIMILAR TO RCD ONE1Have Partially Redundant Functions during Arabidopsis Development

2009

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RADICAL-INDUCED CELL DEATH1 (RCD1) and SIMILAR TO RCD ONE1 (SRO1) are the only two proteins encoded in the Arabidopsis (Arabidopsis thaliana) genome containing both a putative poly(ADP-ribose) polymerase catalytic domain and a WWE protein-protein interaction domain, although similar proteins have been found in other eukaryotes. Poly(ADP-ribose) polymerases mediate the attachment of ADP-ribose units from donor NAD + molecules to target proteins and have been implicated in a number of processes, including DNA repair, apoptosis, transcription, and chromatin remodeling. We have isolated mutants in both RCD1 and SRO1, rcd1-3 and sro1-1, respectively. rcd1-3 plants display phenotypic defects as reported for previously isolated alleles, most notably reduced stature. In addition, rcd1-3 mutants display a number of additional developmental defects in root architecture and maintenance of reproductive development. While single mutant sro1-1 plants are relatively normal, loss of a single dose of SRO1 in the rcd1-3 background increases the severity of several developmental defects, implying that these genes do share some functions. However, rcd1-3 and sro1-1 mutants behave differently in several developmental events and abiotic stress responses, suggesting that they also have distinct functions. Remarkably, rcd1-3; sro1-1 double mutants display severe defects in embryogenesis and postembryonic development. This study shows that RCD1 and SRO1 are at least partially redundant and that they are essential genes for plant development.

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“…1). PolyADP-ribosylation is catalyzed by poly-ADP-ribosylpolymerases (PARPs) that extend the linked ADPribose by attachment of additional moieties to the 2Ј-carbon atom on either the adenosine or the flanking ribose resulting in elongated or branched poly-ADP-ribosylation, respectively (11). Two classes of enzymes perform the reverse reaction, de-ADP-ribosylation, ADP-ribosyl hydrolases (ARHs) and poly-(ADP-ribose) glycohydrolases (PARGs) cleave the amino acid linked ADP-ribose or the O-glycosidic bond between moieties in poly-ADP-ribose (1, 2, 12) (Fig.…”

mentioning

confidence: 99%

Mechanism of ADP-ribosylation removal revealed by the structure and ligand complexes of the dimanganese mono-ADP-ribosylhydrolase DraG

Berthold

Wang²,

Nordlund³

et al. 2009

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

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ADP-ribosylation is a ubiquitous regulatory posttranslational modification involved in numerous key processes such as DNA repair, transcription, cell differentiation, apoptosis, and the pathogenic mechanism of certain bacterial toxins. Despite the importance of this reversible process, very little is known about the structure and mechanism of the hydrolases that catalyze removal of the ADP-ribose moiety. In the phototrophic bacterium Rhodospirillum rubrum, dinitrogenase reductase-activating glycohydrolase (DraG), a dimanganese enzyme that reversibly associates with the cell membrane, is a key player in the regulation of nitrogenase activity. DraG has long served as a model protein for ADP-ribosylhydrolases. Here, we present the crystal structure of DraG in the holo and ADP-ribose bound forms. We also present the structure of a reaction intermediate analogue and propose a detailed catalytic mechanism for protein de-ADP-ribosylation involving ring opening of the substrate ribose. In addition, the particular manganese coordination in DraG suggests a rationale for the enzyme's preference for manganese over magnesium, although not requiring a redox active metal for the reaction.binuclear dinuclear ͉ bioinorganic chemistry ͉ covalent modification ͉ nitrogen fixation ͉ posttranslational modifications P osttranslational modification of proteins by the attachment of chemical groups is used by cells from all kingdoms of life and occurs in several forms. Through the reversible covalent modification of specific amino acid side chains, enzyme activity, or protein function can be switched on and off as a rapid response to environmental stimuli. ADP-ribosylation is a posttranslational modification existing in two distinct forms, mono-and poly-ADPribosylation, resulting from the attachment of a single ADP-ribose moiety or a polymeric ADP-ribose chain structure, respectively, to the protein (1, 2).Mono-ADP-ribosylation was first discovered as a process used in the action of several bacterial toxins, including cholera-, diphtheria-, and pertussis toxin (3, 4). The pathogenesis of these diseases involves ADP-ribosylation of specific human proteins, catalyzed by the toxins, thereby affecting the activity of the modified proteins. In human physiology, mono-ADP-ribosylation is found in the regulation of cell-cell and cell-matrix interactions, as well as part of immune function (5, 6). Poly-ADP-ribosylation is involved in many fundamental processes such as DNA repair, transcription and cell differentiation, and is also implicated in carcinogenesis (6-8). Poly-ADP-ribosylation inhibitors are currently in phase II clinical trials for treatment of breast and ovarian cancer (9).Mono-ADP-ribosylation is catalyzed by ADP-ribosyltransferases (ARTs) and is specifically targeted to amino acids residues such as Arg, Asn, Glu, Asp, Cys, diphthamide, or phosphoserine. The reaction is stereospecific, using ␤-NAD ϩ as a substrate, forming the ␣-anomer of the ADP-ribosylated amino acid and releasing nicotinamide (10) (Fig. 1). PolyADP-ribosylation i...

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The diverse biological roles of mammalian PARPS, a small but powerful family of poly-ADP-ribose polymerases

Cited by 520 publications

References 370 publications

Common fragile sites in colon cancer cell lines: Role of mismatch repair, RAD51 and poly(ADP-ribose) polymerase-1

Common fragile sites in colon cancer cell lines: Role of mismatch repair, RAD51 and poly(ADP-ribose) polymerase-1

The Paralogous GenesRADICAL-INDUCED CELL DEATH1andSIMILAR TO RCD ONE1Have Partially Redundant Functions during Arabidopsis Development

Mechanism of ADP-ribosylation removal revealed by the structure and ligand complexes of the dimanganese mono-ADP-ribosylhydrolase DraG

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