Revisiting PARP2 and PARP1 trapping through quantitative live-cell imaging

Biochem Soc Trans. 2022 Aug 31;50(4):1169-1177. doi: 10.1042/BST20220366.

Abstract

Poly (ADP-ribose) polymerase-1 (PARP1) and 2 (PARP2) are two DNA damage-induced poly (ADP-ribose) (PAR) polymerases in cells and are the targets of PARP inhibitors used for cancer therapy. Strand breaks recruit and activate PARP1 and 2, which rapidly generate PAR from NAD+. PAR promotes the recruitment of other repair factors, relaxes chromatin, and has a role in DNA repair, transcription regulation, and RNA biology. Four PARP1/2 dual inhibitors are currently used to treat BRCA-deficient breast, ovarian, prostate, and pancreatic cancers. In addition to blocking the enzymatic activity of PARP1 and 2, clinical PARP inhibitors extend the appearance of PARP1 and PARP2 on chromatin after damage, termed trapping. Loss of PARP1 confers resistance to PARP inhibitors, suggesting an essential role of trapping in cancer therapy. Yet, whether the persistent PARP1 and 2 foci at the DNA damage sites are caused by the retention of the same molecules or by the continual exchange of different molecules remains unknown. Here, we discuss recent results from quantitative live-cell imaging studies focusing on PARP1 and PARP2's distinct DNA substrate specificities and modes of recruitment and trapping with implications for cancer therapy and on-target toxicities of PARP inhibitors.

Keywords: DNA damage response; PARP inhibitors; PARP1; PARP2; cancer therapy; live-cell imaging.

Publication types

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

MeSH terms

  • Chromatin
  • DNA Repair
  • Humans
  • Male
  • Neoplasms*
  • Poly (ADP-Ribose) Polymerase-1 / metabolism
  • Poly(ADP-ribose) Polymerase Inhibitors* / pharmacology
  • Poly(ADP-ribose) Polymerases / genetics

Substances

  • Chromatin
  • Poly(ADP-ribose) Polymerase Inhibitors
  • PARP1 protein, human
  • PARP2 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases