title: A cancer-associated BRCA2 mutation reveals masked nuclear export signals controlling localization.
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.
authors.affiliation: The Medical Research Council (MRC) Cancer Unit, University of Cambridge, Hutchison-MRC Research Centre, Cambridge, UK.
authors.forename: Anand D
authors.initials: AD
authors.lastname: Jeyasekharan
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Hattori
authors.forename: Venkat
authors.initials: V
authors.lastname: Pisupati
authors.forename: Asta Bjork
authors.initials: AB
authors.lastname: Jonsdottir
authors.forename: Eeson
authors.initials: E
authors.lastname: Rajendra
authors.forename: Miyoung
authors.initials: M
authors.lastname: Lee
authors.forename: Elayanambi
authors.initials: E
authors.lastname: Sundaramoorthy
authors.forename: Simon
authors.initials: S
authors.lastname: Schlachter
authors.forename: Clemens F
authors.initials: CF
authors.lastname: Kaminski
authors.forename: Yaara
authors.initials: Y
authors.lastname: Ofir-Rosenfeld
authors.forename: Ko
authors.initials: K
authors.lastname: Sato
authors.forename: Jane
authors.initials: J
authors.lastname: Savill
authors.forename: Nabieh
authors.initials: N
authors.lastname: Ayoub
authors.forename: Ashok R
authors.initials: AR
authors.lastname: Venkitaraman
mesh_terms: D000595:Amino Acid Sequence; D002467:Cell Nucleus / Q000378:metabolism; D024522:Genes, BRCA2; D006801:Humans; D008969:Molecular Sequence Data; D049790:Nuclear Export Signals; D017354:Point Mutation; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D051135:Rad51 Recombinase / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: D049790:Nuclear Export Signals; C484606:SEM1 protein, human; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D046988:Proteasome Endopeptidase Complex