Exploiting replication gaps for cancer therapy

Mol Cell. 2022 Jul 7;82(13):2363-2369. doi: 10.1016/j.molcel.2022.04.023. Epub 2022 May 13.

Abstract

Defects in DNA double-strand break repair are thought to render BRCA1 or BRCA2 (BRCA) mutant tumors selectively sensitive to PARP inhibitors (PARPis). Challenging this framework, BRCA and PARP1 share functions in DNA synthesis on the lagging strand. Thus, BRCA deficiency or "BRCAness" could reflect an inherent lagging strand problem that is vulnerable to drugs such as PARPi that also target the lagging strand, a combination that generates a toxic accumulation of replication gaps.

Keywords: BRCA cancer; PARP inhibitor; cancer therapy; chemoresistance; single-stranded DNA; synthetic lethality.

Publication types

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

MeSH terms

  • BRCA1 Protein* / genetics
  • BRCA2 Protein* / genetics
  • DNA
  • DNA Breaks, Double-Stranded*
  • DNA Repair* / genetics
  • Humans
  • Neoplasms* / drug therapy
  • Neoplasms* / genetics
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use

Substances

  • BRCA1 Protein
  • BRCA2 Protein
  • Poly(ADP-ribose) Polymerase Inhibitors
  • DNA