Structural Basis for Allosteric PARP-1 Retention on DNA Breaks

Science. 2020 Apr 3;368(6486):eaax6367. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / drug effects*
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology
  • Cell Line, Tumor
  • DNA Breaks / drug effects*
  • DNA Damage / drug effects*
  • Humans
  • Isoindoles / chemistry
  • Isoindoles / pharmacology
  • Neoplasms / enzymology*
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Poly (ADP-Ribose) Polymerase-1 / chemistry*
  • Poly(ADP-ribose) Polymerase Inhibitors / chemistry*
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • Protein Domains

Substances

  • Benzimidazoles
  • EB-47
  • Isoindoles
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • veliparib
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1