PARP1: Structural insights and pharmacological targets for inhibition

DNA Repair (Amst). 2021 Jul;103:103125. doi: 10.1016/j.dnarep.2021.103125. Epub 2021 Apr 14.

Abstract

Poly(ADP-ribose) polymerase 1 (PARP1, also known as ADPRT1) is a multifunctional human ADP-ribosyltransferase. It plays a role in multiple DNA repair pathways, including the base excision repair (BER), non-homologous end joining (NHEJ), homologous recombination (HR), and Okazaki-fragment processing pathways. In response to DNA strand breaks, PARP1 covalently attaches ADP-ribose moieties to arginine, glutamate, aspartate, cysteine, lysine, and serine acceptor sites on both itself and other proteins. This signal recruits DNA repair proteins to the site of DNA damage. PARP1 binding to these sites enhances ADP-ribosylation via allosteric communication between the distant DNA binding and catalytic domains. In this review, we provide a general overview of PARP1 and emphasize novel potential approaches for pharmacological inhibition. Clinical PARP1 inhibitors bind the catalytic pocket, where they directly interfere with ADP-ribosylation. Some inhibitors may further enhance potency by "trapping" PARP1 on DNA via an allosteric mechanism, though this proposed mode of action remains controversial. PARP1 inhibitors are used clinically to treat some cancers, but resistance is common, so novel pharmacological approaches are urgently needed. One approach may be to design novel small molecules that bind at inter-domain interfaces that are essential for PARP1 allostery. To illustrate these points, this review also includes instructive videos showing PARP1 structures and mechanisms.

Keywords: Cancer; Chemotherapy; DNA repair; Drug resistance; PARP1; Review.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • DNA / metabolism
  • DNA Damage
  • DNA Repair*
  • Drug Resistance, Neoplasm
  • Humans
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology
  • Neoplasms / physiopathology
  • Poly (ADP-Ribose) Polymerase-1 / antagonists & inhibitors
  • Poly (ADP-Ribose) Polymerase-1 / metabolism*
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
  • Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use
  • Protein Conformation

Substances

  • Poly(ADP-ribose) Polymerase Inhibitors
  • DNA
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1