A cancer-associated BRCA2 mutation reveals masked nuclear export signals controlling localization.
Nat Struct Mol Biol
; 20(10): 1191-8, 2013 Oct.
Article
em En
| MEDLINE
| ID: mdl-24013206
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Mutação Puntual
/
Genes BRCA2
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Sinais de Exportação Nuclear
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article