Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2

Mol Cell. 2006 Jun 23;22(6):719-29. doi: 10.1016/j.molcel.2006.05.022.

Abstract

BRCA2 mutations predispose carriers to breast and ovarian cancer and can also cause other cancers and Fanconi anemia. BRCA2 acts as a "caretaker" of genome integrity by enabling homologous recombination (HR)-based, error-free DNA double-strand break repair (DSBR) and intra-S phase DNA damage checkpoint control. Described here is the identification of PALB2, a BRCA2 binding protein. PALB2 colocalizes with BRCA2 in nuclear foci, promotes its localization and stability in key nuclear structures (e.g., chromatin and nuclear matrix), and enables its recombinational repair and checkpoint functions. In addition, multiple, germline BRCA2 missense mutations identified in breast cancer patients but of heretofore unknown biological/clinical consequence appear to disrupt PALB2 binding and disable BRCA2 HR/DSBR function. Thus, PALB2 licenses key cellular biochemical properties of BRCA2 and ensures its tumor suppression function.

Publication types

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

MeSH terms

  • BRCA2 Protein / genetics
  • BRCA2 Protein / metabolism*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Chromatin / genetics
  • Chromatin / metabolism
  • DNA Damage* / genetics
  • DNA Repair* / genetics
  • Fanconi Anemia Complementation Group N Protein
  • Female
  • Genetic Predisposition to Disease
  • Germ-Line Mutation
  • HeLa Cells
  • Humans
  • Mutation, Missense
  • Nuclear Matrix / genetics
  • Nuclear Matrix / metabolism
  • Nuclear Proteins / metabolism*
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism
  • Protein Binding
  • Recombination, Genetic* / genetics
  • S Phase* / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • BRCA2 Protein
  • Chromatin
  • Fanconi Anemia Complementation Group N Protein
  • Nuclear Proteins
  • PALB2 protein, human
  • Tumor Suppressor Proteins