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.
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We thank E. Dray, P. Sung, S. Richard, I. Brodeur, E. Paquet, M. Tishkowitz and J. Vignard for helpful discussions, G. Hamel for technical help and I. Brodeur, J. Birraux and A. Rodrigue for critical reading of the manuscript. R.B. is supported by a doctoral scholarship from Le Fonds Québécois de la Recherche sur la Nature et les Technologies. This work was supported by funds from the Swiss National Science Foundation (grant 3103A-116275 to A.S.), the Cancer Institute of New Jersey (B.X.), the US National Cancer Institute (R01CA138804 to B.X.) and the Cancer Research Society (J.-Y.M.). B.X. is an American Cancer Society Research Scholar, and J.-Y.M. is a Fonds de la Recherche en Santé du Québec Senior II investigator.
The authors declare no competing financial interests.
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Buisson, R., Dion-Côté, A., Coulombe, Y. et al. Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating homologous recombination. Nat Struct Mol Biol 17, 1247–1254 (2010). https://doi.org/10.1038/nsmb.1915
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