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Nat Struct Mol Biol. 2013 Oct;20(10):1191-8. doi: 10.1038/nsmb.2666. Epub 2013 Sep 8.

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

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1
The Medical Research Council (MRC) Cancer Unit, University of Cambridge, Hutchison-MRC Research Centre, Cambridge, UK.

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, BRCA2(D2723H), 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, BRCA2(D2723H) 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.

PMID:
24013206
PMCID:
PMC3796201
DOI:
10.1038/nsmb.2666
[Indexed for MEDLINE]
Free PMC Article
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