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A cancer-associated BRCA2 mutation reveals masked nuclear export signals controlling localization. Jeyasekharan AD, Liu Y, Hattori H, Pisupati V, Jonsdottir AB, Rajendra E, Lee M, Sundaramoorthy E, Schlachter S, Kaminski CF, Rosenfeld Y, Sato K, Savill J, Ayoub N, Venkitaraman AR, Nature Structural & Molecular Biology (2013), 20,1191–1198(2013),  DOI: 10.1038/nsmb.2666 pdf  


Germline missense mutations affecting a single BRCA2 allele predispose humans to cancer. Here we identify a protein-targeting mechanism that is disrupted by the cancer-associated mutation, BRCA2D2723H, and that controls the nuclear localization of BRCA2 and its cargo, the recombination enzyme RAD51. A nuclear export signal (NES) in BRCA2 is masked by its interaction with a partner protein, DSS1, such that point mutations impairing BRCA2-DSS1 1 binding render BRCA2 cytoplasmic. In turn, cytoplasmic mislocalization of mutant BRCA2 inhibits the nuclear retention of RAD51 1 by exposing a similar NES in RAD51 1 that is usually obscured by the BRCA2-RAD51 1 interaction. Thus, a series of NES-masking interactions localizes BRCA2 and RAD51 1 in the nucleus. Notably, BRCA2D2723H decreases RAD51 1 nuclear retention even when wild-type BRCA2 is also present. Our findings suggest a mechanism for the regulation of the nucleocytoplasmic distribution of BRCA2 and RAD51 1 and its impairment by a heterozygous disease-associated mutation.