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
  • 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. [email protected] [email protected].
  • 8. Department of Biochemistry and Biophysics, Penn Center for Genome Integrity, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. [email protected] [email protected].
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.