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A cancer-associated BRCA2 mutation reveals masked nuclear export signals controlling localization

A. Jeyasekharan,Yang Liu,Hiroyoshi Hattori,V. Pisupati,Á. B. Jónsdóttir,E. Rajendra,Miyoung Lee,Elayanambi Sundaramoorthy,S. Schlachter,C. Kaminski,Yaara Ofir-Rosenfeld,Ko Sato,Jane M. Savill,N. Ayoub,A. Venkitaraman

Published 2013 in Nature Structural &Molecular Biology

ABSTRACT

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 binding render BRCA2 cytoplasmic. In turn, cytoplasmic mislocalization of mutant BRCA2 inhibits the nuclear retention of RAD51 by exposing a similar NES in RAD51 that is usually obscured by the BRCA2-RAD51 interaction. Thus, a series of NES-masking interactions localizes BRCA2 and RAD51 in the nucleus. Notably, BRCA2D2723H decreases RAD51 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 and its impairment by a heterozygous disease-associated mutation.

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