2. Academic Validation
  3. Structural basis for allosteric PARP-1 retention on DNA breaks

Structural basis for allosteric PARP-1 retention on DNA breaks

  • Science. 2020 Apr 3;368(6486):eaax6367. doi: 10.1126/science.aax6367.
Levani Zandarashvili 1,  Marie-France Langelier 2,  Uday Kiran Velagapudi 3,  Mark A Hancock 4,  Jamin D Steffen 5,  Ramya Billur 1,  Zain M Hannan 1,  Andrew J Wicks 6,  Dragomir B Krastev 6,  Stephen J Pettitt 6,  Christopher J Lord 6,  Tanaji T Talele 3,  John M Pascal 7,  Ben E Black 8
Affiliations

Affiliations

  • 1 Department of Biochemistry and Biophysics, Penn Center for Genome Integrity, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 2 Département de Biochimie and Médecine Moléculaire, Faculté de Médecine, Université de Montréal, Montréal, QC H3C 3J7, Canada.
  • 3 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
  • 4 SPR-MS Facility, McGill University, Montréal, Quebec, Canada.
  • 5 Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
  • 6 CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, London SW3 6JB, UK.
  • 7 Département de Biochimie and Médecine Moléculaire, Faculté de Médecine, Université de Montréal, Montréal, QC H3C 3J7, Canada. john.pascal@umontreal.ca blackbe@pennmedicine.upenn.edu.
  • 8 Department of Biochemistry and Biophysics, Penn Center for Genome Integrity, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. john.pascal@umontreal.ca blackbe@pennmedicine.upenn.edu.
PMID: 32241924 DOI: 10.1126/science.aax6367
Abstract

The success of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors (PARPi) to treat Cancer relates to their ability to trap PARP-1 at the site of a DNA break. Although different forms of PARPi all target the catalytic center of the Enzyme, they have variable abilities to trap PARP-1. We found that several structurally distinct PARPi drive PARP-1 allostery to promote release from a DNA break. Other inhibitors drive allostery to retain PARP-1 on a DNA break. Further, we generated a new PARPi compound, converting an allosteric pro-release compound to a pro-retention compound and increasing its ability to kill Cancer cells. These developments are pertinent to clinical applications where PARP-1 trapping is either desirable or undesirable.

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