Structural Basis for Inhibitor Specificity in Human Poly(ADP-ribose) Polymerase-3

Lehtiö, L.; Jemth, Ann-Sofie; Collins, R.; Loseva, Olga; Johansson, Anders; Markova, Natalia; Hammarstrom, M.; Flores, Alex F. C.; Holmberg-Schiavone, L.; Weigelt, J.; Helleday, Thomas; Schüler, H.; Karlberg, T.

doi:10.1021/jm900052j

Cited by 89 publications

(81 citation statements)

References 22 publications

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“…Although recent studies have provided insights into the biochemical and structural properties of PARP3 (7,8), its physiological functions are unknown. In this study, we provide in vivo evidence for two distinct roles of PARP3 in genome maintenance and mitotic progression.…”

Section: Discussionmentioning

confidence: 99%

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Poly(ADP-ribose) polymerase 3 (PARP3), a newcomer in cellular response to DNA damage and mitotic progression

Boehler

Gauthier

Mortusewicz

et al. 2011

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

234

263

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The ADP ribosyl transferase [poly(ADP-ribose) polymerase] ARTD3 (PARP3) is a newly characterized member of the ARTD(PARP) family that catalyzes the reaction of ADP ribosylation, a key posttranslational modification of proteins involved in different signaling pathways from DNA damage to energy metabolism and organismal memory. This enzyme shares high structural similarities with the DNA repair enzymes PARP1 and PARP2 and accordingly has been found to catalyse poly(ADP ribose) synthesis. However, relatively little is known about its in vivo cellular properties. By combining biochemical studies with the generation and characterization of loss-of-function human and mouse models, we describe PARP3 as a newcomer in genome integrity and mitotic progression. We report a particular role of PARP3 in cellular response to doublestrand breaks, most likely in concert with PARP1. We identify PARP3 as a critical player in the stabilization of the mitotic spindle and in telomere integrity notably by associating and regulating the mitotic components NuMA and tankyrase 1. Both functions open stimulating prospects for specifically targeting PARP3 in cancer therapy. mitotic division | poly(ADP ribosyl)ation | double-strand break repair P oly(ADP ribosyl)ation is a posttranslational modification of proteins mediated by poly(ADP ribose) polymerases (PARPs). PARPs catalyze the transfer and polymerization of ADP ribose units from NAD + to form branched polymers of ADP ribose covalently linked to heterologous acceptor proteins or PARPs themselves. PARP1, the founding and best-studied member of the PARP family, was for a long time considered to be the only enzyme that could generate poly(ADP ribose) polymers. However,

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Section: Discussionmentioning

confidence: 99%

“…Recently, efforts have been developed to define the biochemical and structural properties of PARP3 (7,8). These studies describe PARP3 as a poly(ADP ribosyl)transferase that shares high degree of structural similarities of the PARP catalytic domains and a conserved catalytic glutamate residue with PARP1 and PARP2.…”

mentioning

confidence: 99%

Poly(ADP-ribose) polymerase 3 (PARP3), a newcomer in cellular response to DNA damage and mitotic progression

Boehler

Gauthier

Mortusewicz

et al. 2011

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

234

263

View full text Add to dashboard Cite

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“…References ), (B) ARTD3 (PDB id. 3FHB (Lehtiö et al, 2009)), (C) ARTD6 (PDB id. 3U9H ), (D) ARTD12 (PDB id.…”

Section: Conflict Of Interestmentioning

confidence: 99%

Small-Molecule Chemical Probe Rescues Cells from Mono-ADP-Ribosyltransferase ARTD10/PARP10-Induced Apoptosis and Sensitizes Cancer Cells to DNA Damage

Venkannagari

Verheugd

Koivunen

et al. 2016

Cell Chemical Biology

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SUMMARYMembers of the human diphtheria toxin-likeADP-ribosyltransferase (ARTD or PARP) family play important roles in regulating biological activities by mediating either a mono-ADP-ribosylation MARylation) of a substrate or a poly-ADP-ribosylation (PARylation). ARTD10/PARP10 belongs to the MARylating ARTDs (mARTDs) subfamily, and plays important roles in biological processes that range from cellular signaling, DNA repair, and cell proliferation to immune response. Despite their biological and disease relevance, no selective inhibitors for mARTDs are available. Here we describe a small-molecule ARTD10 inhibitor, OUL35, a selective and potent inhibitor for this enzyme. We characterize its selectivity profile, model its binding, and demonstrate activity in HeLa cells where OUL35 rescued cells from ARTD10 induced cell death. Using OUL35 as a cell biology tool we show that ARTD10 inhibition sensitizes the cells to the hydroxyurea-induced genotoxic stress. Our study supports the proposed role of ARTD10 in DNA-damage repair and provides a tool compound for selective inhibition of ARTD10-mediated MARylation.3

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“…Each compound was identified as its ZINC database ID, experimental binding affinities (IC 50 ) [45][46][47][48][49][50][51][52] , and estimated docking scores were reported for individual compounds. While docking results showed higher (absolute) docking scores for PARP-1 active inhibitors, inactive PARP-1 molecules showed lower docking scores (Table 1).…”

Section: Molecular Dockingmentioning

confidence: 99%

In silicoinvestigation of PARP-1 catalytic domains inholoandapostates for the design of high-affinity PARP-1 inhibitors

Salmas

Ünlü

Yurtsever

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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The rational design of high-affinity inhibitors of poly-ADP-ribose polymerase-1 (PARP-1) is at the heart of modern anti-cancer drug design. While relevance of enzyme to DNA repair processes in cellular environment is firmly established, the structural and functional understanding of the main determinants for high-affinity ligands controlling PARP-1 activity is still lacking. The conserved active site of PARP-1 represents an ideal target for inhibitors and may offer a novel target at the treatment of breast cancer. To fill the gap in the structural knowledge, we report on the combination of molecular dynamics (MD) simulations, principal component analysis (PCA), and conformational analysis that analyzes in great details novel binding mode for a number of inhibitors at the PARP-1. While optimization of the binding affinity for original target is an important goal in the drug design, many of the promising molecules for treatment of the breast cancer are plagued by significant cardiotoxicity. One of the most common side-effects reported for a number of polymerase inhibitors is its off-target interactions with cardiac ion channels and hERG1 channel, in particular. Thus, selected candidate PARP-1 inhibitors were also screened in silico at the central cavities of hERG1 potassium ion channel.

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Structural Basis for Inhibitor Specificity in Human Poly(ADP-ribose) Polymerase-3

Cited by 89 publications

References 22 publications

Poly(ADP-ribose) polymerase 3 (PARP3), a newcomer in cellular response to DNA damage and mitotic progression

Poly(ADP-ribose) polymerase 3 (PARP3), a newcomer in cellular response to DNA damage and mitotic progression

Small-Molecule Chemical Probe Rescues Cells from Mono-ADP-Ribosyltransferase ARTD10/PARP10-Induced Apoptosis and Sensitizes Cancer Cells to DNA Damage

In silicoinvestigation of PARP-1 catalytic domains inholoandapostates for the design of high-affinity PARP-1 inhibitors

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