BRCA1-Dependent and Independent Recruitment of PALB2-BRCA2-RAD51 in the DNA Damage Response and Cancer

Cancer Res. 2022 Sep 16;82(18):3191-3197. doi: 10.1158/0008-5472.CAN-22-1535.

Abstract

The BRCA1-PALB2-BRCA2 axis plays essential roles in the cellular response to DNA double-strand breaks (DSB), maintenance of genome integrity, and suppression of cancer development. Upon DNA damage, BRCA1 is recruited to DSBs, where it facilitates end resection and recruits PALB2 and its associated BRCA2 to load the central recombination enzyme RAD51 to initiate homologous recombination (HR) repair. In recent years, several BRCA1-independent mechanisms of PALB2 recruitment have also been reported. Collectively, these available data illustrate a series of hierarchical, context-dependent, and cooperating mechanisms of PALB2 recruitment that is critical for HR and therapy response either in the presence or absence of BRCA1. Here, we review these BRCA1-dependent and independent mechanisms and their importance in DSB repair, cancer development, and therapy. As BRCA1-mutant cancer cells regain HR function, for which PALB2 is generally required, and become resistant to targeted therapies, such as PARP inhibitors, targeting BRCA1-independent mechanisms of PALB2 recruitment represents a potential new avenue to improve treatment of BRCA1-mutant tumors.

Publication types

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

MeSH terms

  • BRCA1 Protein / genetics
  • BRCA1 Protein / metabolism
  • BRCA2 Protein / genetics
  • DNA
  • DNA Damage
  • DNA Repair
  • Fanconi Anemia Complementation Group N Protein / genetics
  • Humans
  • Neoplasms* / genetics
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Poly(ADP-ribose) Polymerase Inhibitors* / pharmacology
  • Rad51 Recombinase / genetics
  • Rad51 Recombinase / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism

Substances

  • BRCA1 Protein
  • BRCA1 protein, human
  • BRCA2 Protein
  • BRCA2 protein, human
  • Fanconi Anemia Complementation Group N Protein
  • Nuclear Proteins
  • PALB2 protein, human
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Tumor Suppressor Proteins
  • DNA
  • RAD51 protein, human
  • Rad51 Recombinase