title: Identification of a non-canonical nuclear localization signal (NLS) in BRCA1 that could mediate nuclear localization of splice variants lacking the classical NLS.
abstract: The breast cancer type 1 susceptibility gene (BRCA1) is a tumor suppressor gene, mutations or loss of which lead to genomic instability and breast cancer. BRCA1 protein is part of a large multi-protein complex involved in a variety of DNA repair and transcription regulatory functions. At least four splice variants have been described and these differ in their function and tissue and spatio-temporal expression patterns. Structural analysis has revealed the presence of two nuclear localization signals (NLS) located in exon 11 of BRCA1. Interestingly, a splice variant of the protein that lacks both of the known NLS still manages to gain entry to the nucleus. While there is experimental proof for the translocation of these proteins by binding to other established nuclear proteins, we examined the possibility of a hitherto unidentified NLS in this particular variant. In this paper, we present evidence for the existence of a previously unreported non-canonical NLS contained within the first 39 amino acids of exon 11. A fusion protein with this 39mer and a reporter green fluorescent protein translocated into the nucleus when it was expressed in breast epithelial cells. We demonstrate the presence of a hitherto unreported noncanonical NLS in exon 11a of BRCA1. This NLS might aid proteins that were encoded by splice variants and lack the canonical NLS to localize to the nucleus.
authors.affiliation: Division of Molecular Medicine, St. John's Research Institute (SJRI), Bangalore, India. aruna@sjri.res.in
authors.forename: Aruna
authors.initials: A
authors.lastname: Korlimarla
authors.forename: Lekhana
authors.initials: L
authors.lastname: Bhandary
authors.forename: Jyothi S
authors.initials: JS
authors.lastname: Prabhu
authors.forename: Hema
authors.initials: H
authors.lastname: Shankar
authors.forename: Hari
authors.initials: H
authors.lastname: Sankaranarayanan
authors.forename: Pravin
authors.initials: P
authors.lastname: Kumar
authors.forename: Jose
authors.initials: J
authors.lastname: Remacle
authors.forename: Dipa
authors.initials: D
authors.lastname: Natarajan
authors.forename: T S
authors.initials: TS
authors.lastname: Sridhar
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000595:Amino Acid Sequence; D019313:BRCA1 Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D005091:Exons / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D019913:Nuclear Localization Signals / Q000737:chemistry / Q000378:metabolism*; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D019313:BRCA1 Protein; D019913:Nuclear Localization Signals; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins