Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating homologous recombination

By R. Buisson, Anne-Marie Dion-Côté, Yan Coulombe, H. Launay, Hong Cai, A. Stasiak, A. Stasiak, B. Xia, J. Masson. 2010

318 citations recorded by the source corpus.

Inherited mutations in human PALB2 are associated with a predisposition to breast and pancreatic cancers. PALB2′s tumor-suppressing effect is thought to be based on its ability to facilitate BRCA2′s function in homologous recombination. However, the biochemical properties of PALB2 are unknown. Here we show that human PALB2 binds DNA, preferentially D-loop structures, and directly interacts with the RAD51 recombinase to stimulate strand invasion, a vital step of homologous recombination. This stimulation occurs through reinforcing biochemical mechanisms, as PALB2 alleviates inhibition by RPA and stabilizes the RAD51 filament. Moreover, PALB2 can function synergistically with a BRCA2 chimera (termed piccolo, or piBRCA2) to further promote strand invasion. Finally, we show that PALB2-deficient cells are sensitive to PARP inhibitors. Our studies provide the first biochemical insights into PALB2′s function with piBRCA2 as a mediator of homologous recombination in DNA double-strand break repair.

Subfields: Molecular Biology, Oncology

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Citations in the corpus

EgoNet: identification of human disease ego-network modules (2014, background): “The RAD51 protein has been demonstrated to interact with the ssDNA-binding protein BRCA2, a well-known breast cancer susceptibility gene [40].”
A framework to rank genomic alterations as targets for cancer precision medicine: the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) (2018, background): “FANCN) is a protein that interacts with BRCA2, and PALB2 loss impairs DNA repair through a similar mechanism as BRCA2 loss-of-function [37].”
Homologous recombination and human health: the roles of BRCA1, BRCA2 and associated proteins (2015, background): “Biochemical studies have shown that purified PALB2 binds DNA and RAD51, and is able to stimulate RAD51-dependent strand invasion, including synergistically with a BRCA2 peptide (Buisson et al. 2010; Dray et al. 2010).”
Homologous recombination and its regulation (2012, background): “Additionally, it also binds to and cooperates with RAD51AP1 (described below) to enhance RAD51-mediated recombination activities, suggesting a role after the assembly of presynaptic filaments (201,202).”