PARP3 is a sensor of nicked nucleosomes and monoribosylates histone H2BGlu2

Grundy, Gabrielle J.; Polo, Luis Mariano; Zeng, Zhihong; Rulten, Stuart L.; Hoch, Nicolas C.; Paomephan, Pathompong; Xu, Yingqi; Sweet, Steve M. M.; Thorne, Alan W.; Oliver, Antony W.; Matthews, Stephen; Pearl, Laurence H.; Caldecott, Keith W.

doi:10.1038/ncomms12404

Cited by 66 publications

(69 citation statements)

References 44 publications

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“…Interestingly, the ADP-ribosylation of Ku80 by PARP-3 plays an important role in directing DNA repair toward NHEJ rather than homologous recombination (Beck et al 2014a). ADP-ribosylation of histone H2B by PARP-3 is also observed near the sites of DNA damage upon the binding of PARP-3 to the nicked DNA (Grundy et al 2016;Kistemaker et al 2016). PARP-3 may also function synergistically with PARP-1 to potentiate DNA damage repair, as Parp1 and Parp3 double-knockout mice exhibit decreased survival in response to X-ray irradiation as compared with the individual gene knockouts (Boehler et al 2011).…”

Section: Nad + Consumersmentioning

confidence: 96%

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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Section: Nad + Consumersmentioning

confidence: 96%

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

2017

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“…The DNA-dependent PARPs 1, 2 and 3 have DNA binding domains that promote their activation by DNA breaks. These proteins contain a WGR (Trp-Gly-Arg) domain, which upon DNA binding promotes conformational changes in the HD that activate the catalytic domain (Eustermann et al, 2015;Grundy et al, 2016;Obaji et al, 2018).…”

Section: Domain Architecture and Activationmentioning

confidence: 99%

“…Interestingly, PARP1 makes much more extensive contacts with the DNA surrounding the break than at the break site per se, allowing for the recognition of DNA breaks from a variety of sources. In contrast, the WGR domains of both PARP2 and PARP3 (which do not have ZnFs) play a key role in DNA binding and discriminate between different DNA ends by recognising the presence of a 5'phosphate group at the DNA break site (Langelier et al, 2014;Grundy et al, 2016;Obaji et al, 2018).…”

Section: Domain Architecture and Activationmentioning

confidence: 99%

ADP-ribosylation: from molecular mechanisms to human disease

Hoch

Polo

2020

Genet. Mol. Biol.

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Post-translational modification of proteins by ADP-ribosylation, catalysed by poly (ADP-ribose) polymerases (PARPs) using NAD + as a substrate, plays central roles in DNA damage signalling and repair, modulates a range of cellular signalling cascades and initiates programmed cell death by parthanatos. Here, we present mechanistic aspects of ADP-ribose modification, PARP activation and the cellular functions of ADP-ribose signalling, and discuss how this knowledge is uncovering therapeutic avenues for the treatment of increasingly prevalent human diseases such as cancer, ischaemic damage and neurodegeneration.The PARP1 active site is formed between the catalytic domain (ART domain) and the helical domain (HD) Figure 1 -Schematic mechanism of ADP ribosylation reaction and the catalytic domain of DNA-dependant PARPs. A) A simplified overview of the (ADP)-ribosylation reactions catalysed by PARPs. The final products depend on the acceptor residue acting as a nucleophile (Nu, in blue). PARP1 active-site residues interacting with the ribose-nicotinamide moiety of NAD + are illustrated in orange. B) The NAD + (modelled based on the human PARP1 bound to benzamide adenine dinucleotide [PDB: 6BHV], carbon atoms in yellow) in an extended conformation, bound to the catalytic domain of human PARP1 (ART in cartoon, orange, [PDB: 6BHV]). The residues involved in the catalysis are presented as sticks. C) Superposed cartoon view of human PARP-1 ART domain (orange, [PDB: 6BHV]), PARP1 (light blue, [PDB: 5WS1]) and PARP2 (green, [PDB: 3KJD]) showing the structure of the entire catalytic domains (ART and HD). The modelled NAD + (in yellow) denotes the donor site, while a molecule of ADP (modelled by superimposing the structures of chicken PARP1 [PDB: 1A26] to the human PARP1 [PDB: 3KJD]) indicates the acceptor site. Donor loop (D-loop) and acceptor loop are labelled. D) Surface representation of human PARP1 [PDB: 3KJD] with NAD + modelled into the active site. The ribose group to be attacked is exposed to the solvent. ADP-ribose mechanisms and disease 3 ADP-ribose mechanisms and disease 13

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“…PARP3 activity has been shown to accelerate NHEJ rates , yet PARP1, in contrast, can trans‐ribosylate Ku70/Ku80, inhibiting its DNA‐binding activity . ADP‐ribosylation can, therefore, regulate the NHEJ complex in positive and negative ways, but the activation of different PARPs by different DNA substrates, and their different chromatin targets, may explain how some of these interactions could be regulated by PARP activation .…”

Section: How Are Multiple Interactions Regulated In the Nhej Process?mentioning

confidence: 99%

Non‐homologous end joining: Common interaction sites and exchange of multiple factors in the DNA repair process

Rulten

Grundy

2017

BioEssays

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Non-homologous end-joining (NHEJ) is the dominant means of repairing chromosomal DNA double strand breaks (DSBs), and is essential in human cells. Fifteen or more proteins can be involved in the detection, signalling, synapsis, end-processing and ligation events required to repair a DSB, and must be assembled in the confined space around the DNA ends. We review here a number of interaction points between the core NHEJ components (Ku70, Ku80, DNA-PKcs, XRCC4 and Ligase IV) and accessory factors such as kinases, phosphatases, polymerases and structural proteins. Conserved protein-protein interaction sites such as Ku-binding motifs (KBMs), XLF-like motifs (XLMs), FHA and BRCT domains illustrate that different proteins compete for the same binding sites on the core machinery, and must be spatially and temporally regulated. We discuss how post-translational modifications such as phosphorylation, ADP-ribosylation and ubiquitinylation may regulate sequential steps in the NHEJ pathway or control repair at different types of DNA breaks.

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PARP3 is a sensor of nicked nucleosomes and monoribosylates histone H2BGlu2

Cited by 66 publications

References 44 publications

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

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

ADP-ribosylation: from molecular mechanisms to human disease

Non‐homologous end joining: Common interaction sites and exchange of multiple factors in the DNA repair process

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