Differential trapping of PARP1 and PARP2 by clinical PARP inhibitors

By J. Murai, Shar-yin N. Huang, B. Das, Amélie Renaud, Yiping Zhang, J. Doroshow, J. Ji, S. Takeda, Yves Pommier. Cancer Research, 2012

1,883 citations recorded by the source corpus.

Small molecule inhibitors of polyADP-ribose polymerase (PARP) are thought to mediate their antitumor effects as catalytic inhibitors that block repair of DNA single strand breaks. However, the mechanism of action of PARP inhibitors with regard to their effects in cancer cells is not fully understood. In this study we demonstrate that PARP inhibitors trap the PARP1 and PARP2 enzymes at damaged DNA. Trapped PARP-DNA complexes were more cytotoxic than unrepaired single-strand breaks caused by PARP inactivation, arguing that PARP inhibitors act in part as poisons that trap PARP enzyme on DNA. Moreover, the potency in trapping PARP differed markedly among inhibitors with MK-4827 > olaparib (AZD-2281) ≫ veliparib (ABT-888), a pattern not correlated with the catalytic inhibitory properties for each drug. We also analyzed repair pathways for PARP-DNA complexes using 30 genetically altered avian DT40 cell lines with pre-established deletions in specific DNA repair genes. This analysis revealed that, in addition to its function in homologous recombination, PARP also functions in post-replication repair and the Fanconi anemia pathway, and that polymerase β and FEN1 were critical for repairing trapped PARP-DNA complexes. In summary, our study provides a new mechanistic foundation for the rational application of PARP inhibitors in cancer therapy.

Subfields: Electrical and Electronic Engineering, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/e573d959ed1d8f231c3d4154ee1cac839c065548

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4. G. Shapiro
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Citations in the corpus

• A decade of clinical development of PARP inhibitors in perspective (2019, background): “Although the precise mechanisms that explain PARP1 trapping are still unclear, two have been proposed: (i) PARPi either prevents the release of PARP1 from DNA by inhibiting autoPARylation [11] or (ii) PARPi binding to the catalytic site causes allosteric changes in the PARP1 structure enhancing DNA ”
• Homologous recombination deficiency: Exploiting the fundamental vulnerability of ovarian cancer (2015, background): “Accordingly, recent studies have demonstrated that PARPimediated trapping of PARP1–DNA complexes showed higher cytotoxicity than unrepaired SSBs caused by knockdown of PARP1 (89).”
• PARP Inhibitors: The First Synthetic Lethal Targeted Therapy (2017, background): “These differences in PARP1 trapping, rather than simply the ability to inhibit PARylation, may be a better predictor of in vitro cytotoxicity in BRCA mutant cells, with talazoparib having the most profound cytotoxic effects (10, 22, 23).”
• Olaparib Monotherapy in Patients With Advanced Cancer and a Germline BRCA1/2 Mutation (2014, background): “Jaspers JE, Kersbergen A, Boon U, et al: Loss of 53BP1 causes PARP inhibitor resistance in Brca1mutated mouse mammary tumors.”