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Identification of a non-canonical nuclear localization signal (NLS) in BRCA1 that could mediate nuclear localization of splice variants lacking the classical NLS


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.



BRCA1-associated RING domain


breast cancer type 1 susceptibility protein




enhanced green fluorescent protein


green fluorescent protein


human breast carcinoma cell line


human embryonic kidney 293 cells


nuclear localization signals


ubiquitin-conjugating enzyme 9


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Correspondence to Aruna Korlimarla.

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These authors contributed equally to this manuscript

Visiting Scientist, SJRI

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Korlimarla, A., Bhandary, L., Prabhu, J.S. et al. Identification of a non-canonical nuclear localization signal (NLS) in BRCA1 that could mediate nuclear localization of splice variants lacking the classical NLS. Cell Mol Biol Lett 18, 284–296 (2013).

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Key words

  • Breast cancer
  • BRCA1
  • Splice variants
  • Nuclear localization
  • Importin alpha
  • Green fluorescent protein