Targeting PARP-1 allosteric regulation offers therapeutic potential against cancer

Jamin D. Steffen, Renee M. Tholey, Marie France Langelier, Jamie L. Planck, Matthew J. Schiewer, Shruti Lal, Nikolai A. Bildzukewicz, Charles J. Yeo, Karen E. Knudsen, Jonathan R. Brody, John M. Pascal

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

PARP-1 is a nuclear protein that has important roles in maintenance of genomic integrity. During genotoxic stress, PARP-1 recruits to sites of DNA damage where PARP-1 domain architecture initiates catalytic activation and subsequent poly(ADP-ribose)-dependent DNA repair. PARP-1 inhibition is a promising new way to selectively target cancers harboring DNA repair deficiencies. However, current inhibitors target other PARPs, raising important questions about long-term off-target effects. Here, we propose a new strategy that targets PARP- 1 allosteric regulation as a selective way of inhibiting PARP-1. We found that disruption of PARP-1 domain-domain contacts through mutagenesis held no cellular consequences on recruitment to DNA damage or a model system of transcriptional regulation, but prevented DNA-damage-dependent catalytic activation. Furthermore, PARP-1 mutant overexpression in a pancreatic cancer cell line (MIA PaCa-2) increased sensitivity to platinumbased anticancer agents. These results not only highlight the potential of a synergistic drug combination of allosteric PARP inhibitors with DNA-damaging agents in genomically unstable cancer cells (regardless of homologous recombination status), but also signify important applications of selective PARP-1 inhibition. Finally, the development of a high-throughput PARP-1 assay is described as a tool to promote discovery of novel PARP-1 selective inhibitors.

Original languageEnglish (US)
Pages (from-to)31-37
Number of pages7
JournalCancer Research
Volume74
Issue number1
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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