Studying PAR-Dependent Chromatin Remodeling to Tackle PARPi Resistance

Trends Mol Med. 2021 Jul;27(7):630-642. doi: 10.1016/j.molmed.2021.04.010. Epub 2021 May 21.

Abstract

Histone eviction and chromatin relaxation are important processes for efficient DNA repair. Poly(ADP) ribose (PAR) polymerase 1 (PARP1) is a key mediator of this process, and disruption of PARP1 activity has a direct impact on chromatin structure. PARP inhibitors (PARPis) have been established as a treatment for BRCA1- or BRCA2-deficient tumors. Unfortunately, PARPi resistance occurs in many patients and the underlying mechanisms are not fully understood. In particular, it remains unclear how chromatin remodelers and histone chaperones compensate for the loss of the PARylation signal. In this Opinion article, we summarize currently known mechanisms of PARPi resistance. We discuss how the study of PARP1-mediated chromatin remodeling may help in further understanding PARPi resistance and finding new therapeutic approaches to overcome it.

Keywords: DNA damage response; PARP inhibition; chromatin remodeling; drug resistance; poly(ADP) ribosylation polymerase.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Chromatin Assembly and Disassembly*
  • DNA Damage
  • DNA Repair
  • Drug Resistance, Neoplasm*
  • Histones / genetics
  • Histones / metabolism*
  • Humans
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Poly (ADP-Ribose) Polymerase-1 / antagonists & inhibitors*
  • Poly (ADP-Ribose) Polymerase-1 / genetics
  • Poly (ADP-Ribose) Polymerase-1 / metabolism
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*

Substances

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