PARP Inhibitor with Selectivity Toward ADP-Ribosyltransferase ARTD3/PARP3

Lindgren, Åsa; Karlberg, T.; Thorsell, A.G.; Hesse, Manfred; Spjut, Sara; Ekblad, T.; Andersson, C. David; Pinto, A.F.; Weigelt, J.; Hottiger, Michael O.; Linusson, Anna; Elofsson, Mikael; Schüler, H.

doi:10.1021/cb4002014

Cited by 51 publications

(58 citation statements)

References 20 publications

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“…We elected to focus on PARP3, as it has druggable catalytic activity19 and is dispensable for murine and cellular viability2021. The PARP family of 17 proteins contains 3 enzymes (PARP1, PARP2 and PARP3) that have been implicated in DNA repair.…”

Section: Resultsmentioning

confidence: 99%

PARP3 is a promoter of chromosomal rearrangements and limits G4 DNA

et al. 2017

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Chromosomal rearrangements are essential events in the pathogenesis of both malignant and nonmalignant disorders, yet the factors affecting their formation are incompletely understood. Here we develop a zinc-finger nuclease translocation reporter and screen for factors that modulate rearrangements in human cells. We identify UBC9 and RAD50 as suppressors and 53BP1, DDB1 and poly(ADP)ribose polymerase 3 (PARP3) as promoters of chromosomal rearrangements across human cell types. We focus on PARP3 as it is dispensable for murine viability and has druggable catalytic activity. We find that PARP3 regulates G quadruplex (G4) DNA in response to DNA damage, which suppresses repair by nonhomologous end-joining and homologous recombination. Chemical stabilization of G4 DNA in PARP3−/− cells leads to widespread DNA double-strand breaks and synthetic lethality. We propose a model in which PARP3 suppresses G4 DNA and facilitates DNA repair by multiple pathways.

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Section: Resultsmentioning

confidence: 99%

PARP3 is a promoter of chromosomal rearrangements and limits G4 DNA

et al. 2017

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“…Furthermore, our findings may inspire the development of PARP3-specific inhibitors in therapeutic strategies aimed to potentialize the cytotoxic action of clastogenic drugs generating high amounts of DSB. Clearly, recent and ongoing structural and screening studies aimed to identify PARP3-specific inhibitors will be valuable in exploring such strategies (84,93). …”

Section: Discussionmentioning

confidence: 99%

PARP3 affects the relative contribution of homologous recombination and nonhomologous end-joining pathways

Beck

Boehler

Guirouilh‐Barbat

et al. 2014

Nucleic Acids Research

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The repair of toxic double-strand breaks (DSB) is critical for the maintenance of genome integrity. The major mechanisms that cope with DSB are: homologous recombination (HR) and classical or alternative nonhomologous end joining (C-NHEJ versus A-EJ). Because these pathways compete for the repair of DSB, the choice of the appropriate repair pathway is pivotal. Among the mechanisms that influence this choice, deoxyribonucleic acid (DNA) end resection plays a critical role by driving cells to HR, while accurate C-NHEJ is suppressed. Furthermore, end resection promotes error-prone A-EJ. Increasing evidence define Poly(ADP-ribose) polymerase 3 (PARP3, also known as ARTD3) as an important player in cellular response to DSB. In this work, we reveal a specific feature of PARP3 that together with Ku80 limits DNA end resection and thereby helps in making the choice between HR and NHEJ pathways. PARP3 interacts with and PARylates Ku70/Ku80. The depletion of PARP3 impairs the recruitment of YFP-Ku80 to laser-induced DNA damage sites and induces an imbalance between BRCA1 and 53BP1. Both events result in compromised accurate C-NHEJ and a concomitant increase in DNA end resection. Nevertheless, HR is significantly reduced upon PARP3 silencing while the enhanced end resection causes mutagenic deletions during A-EJ. As a result, the absence of PARP3 confers hypersensitivity to anti-tumoral drugs generating DSB.

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“…The PARP1 D-loop has been described as a relatively rigid structure, unlike the flexible counterpart in other PARP superfamily proteins (Wahlberg et al, 2012). However, recently determined PARP1 inhibitor cocrystal structures (PDB IDs: 4HHY, 4HHZ, and 4GV7) (Lindgren et al, 2013;Ye et al, 2013) reveal that the Tyr889 side chain on the D-loop can adopt multiple rotameric positions among noncrystallographic symmetry-related molecules (Fig. 3C).…”

Section: Structural Basis For Parp-dna Trappingmentioning

confidence: 99%

“…(C) Superpositions of the 33 PARP1 CAT domain structures from PDB indicate that the D-loop residue, Tyr889, can assume multiple side-chain conformations. Binding of a rigid stereospecific inhibitor (e.g., talazoparib) may sterically restrict the side-chain flexibility (PDB IDs: 4PJT, 4GV7, 4HHY, 4HHZ, 4L6S, 4DQY, 3GN7, 3L3L, 3L3M, 3GJW, 2RD6, 1WOK, 1UK0, and 1UK1) Kinoshita et al, 2004;Iwashita et al, 2005;Miyashiro et al, 2009;Gandhi et al, 2010;Penning et al, 2010;Langelier et al, 2012;Gangloff et al, 2013;Lindgren et al, 2013;Ye et al, 2013;Aoyagi-Scharber et al, 2014). (Ruf et al, 1998) and well characterized as a sequence-diverse element in the PARP superfamily Papeo et al, 2013;Steffen et al, 2013), may also contribute to the protein dynamics of the CAT domain that are implicated in the putative inhibitor-induced reverse-allosteric signaling.…”

Section: Structural Basis For Parp-dna Trappingmentioning

confidence: 99%

Trapping Poly(ADP-Ribose) Polymerase

Shen

Aoyagi-Scharber

Wang

2015

J Pharmacol Exp Ther

181

188

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Recent findings indicate that a major mechanism by which poly (ADP-ribose) polymerase (PARP) inhibitors kill cancer cells is by trapping PARP1 and PARP2 to the sites of DNA damage. The PARP enzyme-inhibitor complex "locks" onto damaged DNA and prevents DNA repair, replication, and transcription, leading to cell death. Several clinical-stage PARP inhibitors, including veliparib, rucaparib, olaparib, niraparib, and talazoparib, have been evaluated for their PARP-trapping activity. Although they display similar capacity to inhibit PARP catalytic activity, their relative abilities to trap PARP differ by several orders of magnitude, with the ability to trap PARP closely correlating with each drug's ability to kill cancer cells. In this article, we review the available data on molecular interactions between these clinical-stage PARP inhibitors and PARP proteins, and discuss how their biologic differences might be explained by the trapping mechanism. We also discuss how to use the PARP-trapping mechanism to guide the development of PARP inhibitors as a new class of cancer therapy, both for singleagent and combination treatments.

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PARP Inhibitor with Selectivity Toward ADP-Ribosyltransferase ARTD3/PARP3

Cited by 51 publications

References 20 publications

PARP3 is a promoter of chromosomal rearrangements and limits G4 DNA

PARP3 is a promoter of chromosomal rearrangements and limits G4 DNA

PARP3 affects the relative contribution of homologous recombination and nonhomologous end-joining pathways

Trapping Poly(ADP-Ribose) Polymerase

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