title: The BRCA1/BARD1 heterodimer modulates ran-dependent mitotic spindle assembly.
abstract: The heterodimeric tumor-suppressor complex BRCA1/BARD1 exhibits E3 ubiquitin ligase activity and participates in cell proliferation and chromosome stability control by incompletely defined mechanisms. Here we show that, in both mammalian cells and Xenopus egg extracts, BRCA1/BARD1 is required for mitotic spindle-pole assembly and for accumulation of TPX2, a major spindle organizer and Ran target, on spindle poles. This function is centrosome independent, operates downstream of Ran GTPase, and depends upon BRCA1/BARD1 E3 ubiquitin ligase activity. Xenopus BRCA1/BARD1 forms endogenous complexes with three spindle-pole proteins, TPX2, NuMA, and XRHAMM--a known TPX2 partner--and specifically attenuates XRHAMM function. These observations reveal a previously unrecognized function of BRCA1/BARD1 in mitotic spindle assembly that likely contributes to its role in chromosome stability control and tumor suppression.
authors.affiliation: Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Joukov
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Groen
authors.forename: Tatyana
authors.initials: T
authors.lastname: Prokhorova
authors.forename: Ruth
authors.initials: R
authors.lastname: Gerson
authors.forename: Erinn
authors.initials: E
authors.lastname: White
authors.forename: Alison
authors.initials: A
authors.lastname: Rodriguez
authors.forename: Johannes C
authors.initials: JC
authors.lastname: Walter
authors.forename: David M
authors.initials: DM
authors.lastname: Livingston
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002457:Cell Extracts / Q000737:chemistry; D019281:Dimerization; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D009865:Oocytes / Q000737:chemistry; D010750:Phosphoproteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D008941:Spindle Apparatus / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D014981:Xenopus; D029867:Xenopus Proteins / Q000378:metabolism; D020931:ran GTP-Binding Protein / Q000378:metabolism*
chemical_list: D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D002457:Cell Extracts; C000623051:Hmmr protein, Xenopus; D008869:Microtubule-Associated Proteins; C489079:NUMA1 protein, Xenopus; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011994:Recombinant Proteins; C486551:TPX2 protein, Xenopus; D025521:Tumor Suppressor Proteins; D029867:Xenopus Proteins; C102449:BARD1 protein, human; D044767:Ubiquitin-Protein Ligases; D020931:ran GTP-Binding Protein