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.
Anand D Jeyasekharan1*, Yang Liu1, Hiroyoshi Hattori1,3, Venkat Pisupati1,3, Asta Bjork Jonsdottir1, Eeson Rajendra1, Miyoung Lee1, Elayanambi Sundaramoorthy1, Simon Schlachter2, Clemens F Kaminski2, Yaara Rosenfeld1, Ko Sato1, Jane Savill1, Nabieh Ayoub1 & Ashok R Venkitaraman1
1The Medical Research Council (MRC) Cancer Unit, University of Cambridge, Hutchison–MRC Research Centre, Cambridge, UK.
2Department of Chemical Engineering, University of Cambridge, Cambridge, UK.
3These authors contributed equally to this work.
*The author is currently a Principal Associate at the Cancer Science Institute of Singapore