Control of BRCA2 Cellular and Clinical Functions by a Nuclear Partner, PALB2

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.

Minding the gap: The underground functions of BRCA1 and BRCA2 at stalled replication forks

“…BRCA2 interacts stoichiometrically with a newly identified protein, PALB2, which is required for accumulation of BRCA2/Rad51 at DSBs induced in partial nuclear volumes in vivo [92]. Consistent with this, certain point mutations in BRCA2 that disrupt its interaction with PALB2 are also implicated in breast/ovarian cancer predisposition.…”

“…It is not clear whether DSG repair entails any kind of processing of the dsDNA-ssDNA iunction. In the limited studies that have been performed so far on different BRCA alleles, there appears to be a correlation between defective tumor suppressor function and loss of HR/DSBR function [90][91][92], suggesting that the HR functions of BRCA1 and BRCA2 contribute to tumor suppression.…”

Mammalian BTBD12/SLX4 Assembles A Holliday Junction Resolvase and Is Required for DNA Repair

“…To examine this question, we employed U2OS cells carrying a DR-GFP substrate (Xia et al, 2006). This substrate contains 2 nonfunctional GFP open reading frames, including one GFP coding sequence that is interrupted by a recognition site for the ISceI endonuclease (SceGFP).…”

“…This substrate contains 2 nonfunctional GFP open reading frames, including one GFP coding sequence that is interrupted by a recognition site for the ISceI endonuclease (SceGFP). Expression of I-SceI leads to formation of a DSB in the SceGFP allele, which is repaired by HDR using a nearby iGFP lacking N-and C-terminal GFP sequences, thereby producing functional GFP (Xia et al, 2006). HDR-reporter cells expressing a control firefly luciferase shRNA displayed robust production of GFP-positive cells after ISceI expression and this was reduced by ∼25% upon shRNA-mediated depletion of SLX4 ( Figure 7K) in a manner that correlated with the extent of depletion seen with these vectors ( Figure 3B).…”

PALB2/FANCN, acteur dans la prédisposition au cancer du sein ?

“…D'autres gènes participant à ce processus constituent donc des cibles potentielles pour des mutations prédisposant au développement du cancer du sein. Le gène PALB2, situé dans la région 16p12.1, a été récemment identifié en tant que partenaire du gène BRCA2 et est nécessaire à l'ancrage de BRCA2 aux structures nucléaires, permettant ainsi à BRCA2 de jouer son rôle dans le processus de réparation de l'ADN double-brin par recombinaison homologue [2]. Par ailleurs, des études récentes montrent que les mutations bialléliques dans PALB2, également appelé FANCN, causent l'anémie de Fanconi et produisent un phénotype très similaire à celui résultant des mutations bialléliques dans BRCA2 [3,4].…”