PARP-1 Activation Requires Local Unfolding of an Autoinhibitory Domain

Dawicki-McKenna, Jennine M.; Langelier, Marie-France; DeNizio, Jamie E.; Riccio, Amanda A.; Cheng, Chao; Karch, Kelly R.; McCauley, Michael; Steffen, Jamin D.; Black, Ben E.; Pascal, John M.

doi:10.1016/j.molcel.2015.10.013

Cited by 281 publications

(349 citation statements)

References 59 publications

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“…As PARP-1 participates in DNA damage repair, the single application of a PARP-1 inhibitor treatment or a DNA damage drug combination may promote apoptosis (21). A previous study has demonstrated that drug inhibition or gene knockout PARP-1 may not only cause the avoidance of tissue damage caused by oxidative stress, but may also improve the prognosis of patients with cancer (22). Additionally, in the present study, HCPT effectively activated the PARP-1 protein expression of human osteosarcoma MG-63 cells.…”

Section: Discussionmentioning

confidence: 99%

Anticancer effects of 10-hydroxycamptothecin induce apoptosis of human osteosarcoma through activating caspase-3, p53 and cytochromeï¿½c pathways

Xiong

Han

et al. 2017

Oncol Lett

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Abstract. In order to evaluate the anticancer effect of 10-hydroxycamptothecin (HCPT) in terms of inducing the apoptosis of human osteosarcoma cells, its apoptosis-inducing molecular mechanisms were investigated. In the present study, the anticancer effects of HCPT were revealed to result in suppressed cell viability, increased cytotoxicity, the induction of apoptosis and an augmented apoptotic nucleolus of human osteosarcoma cells. MG-63 cells were cultured with HCPT (0, 20, 40 and 80 nM) for 24 and 48 h. An MTT assay and a lactate dehydrogenase assay were used to analyze the anticancer effect of HCPT on cell viability and cytotoxicity in MG-63 cells. MG-63 cell apoptosis, and caspase-9 and caspase-3 activity levels were evaluated using flow cytometry and an ELISA. Western blot analysis was used to detect the protein expression levels of p53, poly (ADP-ribose) polymerase-1 (PARP-1), cytochrome c and B cell lymphoma-2 (Bcl-2) in MG-63 cells. The anticancer effects of HCPT were demonstrated to significantly activate the protein expression of p53, PARP-1 and cytochrome c, and suppress Bcl-2 protein expression and promote the activity of caspase-9 and caspase-3 in human osteosarcoma cells. In conclusion, the anticancer effects of HCPT appear to induce the apoptosis of human osteosarcoma cells through the activation of the caspase-3, p53 and cytochrome c pathways.

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Section: Discussionmentioning

confidence: 99%

Anticancer effects of 10-hydroxycamptothecin induce apoptosis of human osteosarcoma through activating caspase-3, p53 and cytochromeï¿½c pathways

Xiong

Han

et al. 2017

Oncol Lett

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“…Upon association of PARP-1 with a break site, these protein domains are refolded to promote extensive interdomain contacts that facilitate PARP-1 catalytic activity (Langelier et al 2012). Moreover, DNA binding induces unfolding of an autoinhibitory helical domain (HD), which then allows for NAD + binding and activation of PARP-1 (Dawicki-McKenna et al 2015;Steffen et al 2016). The recognition of single-stranded breaks by Zn1 and Zn2 promotes the folding of other PARP-1 domains and subsequent allosteric activation (Eustermann et al 2015).…”

Section: Structural Analyses Of Parps In Dna Repairmentioning

confidence: 99%

PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes

2017

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The discovery of poly(ADP-ribose) >50 years ago opened a new field, leading the way for the discovery of the poly(ADP-ribose) polymerase (PARP) family of enzymes and the ADP-ribosylation reactions that they catalyze. Although the field was initially focused primarily on the biochemistry and molecular biology of PARP-1 in DNA damage detection and repair, the mechanistic and functional understanding of the role of PARPs in different biological processes has grown considerably of late. This has been accompanied by a shift of focus from enzymology to a search for substrates as well as the first attempts to determine the functional consequences of site-specific ADP-ribosylation on those substrates. Supporting these advances is a host of methodological approaches from chemical biology, proteomics, genomics, cell biology, and genetics that have propelled new discoveries in the field. New findings on the diverse roles of PARPs in chromatin regulation, transcription, RNA biology, and DNA repair have been complemented by recent advances that link ADP-ribosylation to stress responses, metabolism, viral infections, and cancer. These studies have begun to reveal the promising ways in which PARPs may be targeted therapeutically for the treatment of disease. In this review, we discuss these topics and relate them to the future directions of the field.ADP-ribosylation is a reversible post-translational modification (PTM) of proteins resulting in the covalent attachment of a single ADP-ribose unit [i.e., mono(ADP-ribose) (MAR)] or polymers of ADP-ribose units [i.e., poly(ADP-ribose) (PAR)] on a variety of amino acid residues on target proteins (Gibson and Kraus 2012;Daniels et al. 2015a). This modification is mediated by a diverse group of ADPribosyl transferase (ADPRT) enzymes that use ADP-ribose units derived from β-NAD + to catalyze the ADP-ribosylation reaction. These enzymes include bacterial ADPRTs (e.g., cholera toxin and diphtheria toxin) as well as members of three different protein families in yeast and animals: (1) arginine-specific ecto-enzymes (ARTCs), (2) sirtuins, and (3) PAR polymerases (PARPs) . Surprisingly, a recent study showed that the bacterial toxin DarTG can ADP-ribosylate DNA . How this fits into the broader picture of cellular ADP-ribosylation has yet to be determined.In this review, we focus on the mono(ADP-ribosyl)ation (MARylation) and poly(ADP-ribosyl)ation (PARylation) of glutamate, aspartate, and lysine residues by PARP family members. While many reviews have been written on PARPs in the past decade, we highlight the current trends and ideas in the field, in particular those discoveries that have been published in the past 2-3 years.

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“…PARP1 is a multi-domain protein composed of six distinct modules including two N-terminal zinc finger domains (Zn1 and Zn2) responsible for initial binding to altered DNA structures; the third zinc-binding domain (Zn3) and tryptophan-glycine-arginine (WGR) domain participating in DNA binding and formation of a network of interdomain contacts critical for activation of the C-terminal catalytic (CAT) domain resulting in NAD + cleavage and formation of PAR polymer; and a central auto-modification domain containing a cluster of glutamic acid residues serving as ADP-ribose acceptor sites: a BRCA1 C-terminal (BRCT) motif (16–18). Both PARP1 and PARP2 have WGR and CAT domains and the overall three-dimensional structures of theirs CAT domains are similar (19).…”

Section: Introductionmentioning

confidence: 99%

Poly(ADP-ribose) polymerases covalently modify strand break termini in DNA fragmentsin vitro

Talhaoui¹,

Лебедева²,

Zarkovic³

et al. 2016

Nucleic Acids Res

101

170

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Poly(ADP-ribose) polymerases (PARPs/ARTDs) use nicotinamide adenine dinucleotide (NAD+) to catalyse the synthesis of a long branched poly(ADP-ribose) polymer (PAR) attached to the acceptor amino acid residues of nuclear proteins. PARPs act on single- and double-stranded DNA breaks by recruiting DNA repair factors. Here, in in vitro biochemical experiments, we found that the mammalian PARP1 and PARP2 proteins can directly ADP-ribosylate the termini of DNA oligonucleotides. PARP1 preferentially catalysed covalent attachment of ADP-ribose units to the ends of recessed DNA duplexes containing 3′-cordycepin, 5′- and 3′-phosphate and also to 5′-phosphate of a single-stranded oligonucleotide. PARP2 preferentially ADP-ribosylated the nicked/gapped DNA duplexes containing 5′-phosphate at the double-stranded termini. PAR glycohydrolase (PARG) restored native DNA structure by hydrolysing PAR-DNA adducts generated by PARP1 and PARP2. Biochemical and mass spectrometry analyses of the adducts suggested that PARPs utilise DNA termini as an alternative to 2′-hydroxyl of ADP-ribose and protein acceptor residues to catalyse PAR chain initiation either via the 2′,1″-O-glycosidic ribose-ribose bond or via phosphodiester bond formation between C1′ of ADP-ribose and the phosphate of a terminal deoxyribonucleotide. This new type of post-replicative modification of DNA provides novel insights into the molecular mechanisms underlying biological phenomena of ADP-ribosylation mediated by PARPs.

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PARP-1 Activation Requires Local Unfolding of an Autoinhibitory Domain

Cited by 281 publications

References 59 publications

Anticancer effects of 10-hydroxycamptothecin induce apoptosis of human osteosarcoma through activating caspase-3, p53 and cytochromeï¿½c pathways

Anticancer effects of 10-hydroxycamptothecin induce apoptosis of human osteosarcoma through activating caspase-3, p53 and cytochromeï¿½c pathways

PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes

Poly(ADP-ribose) polymerases covalently modify strand break termini in DNA fragmentsin vitro

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