title: BRCA2 localization to the midbody by filamin A regulates cep55 signaling and completion of cytokinesis.
abstract: Disruption of the BRCA2 tumor suppressor is associated with structural and numerical chromosomal defects. The numerical abnormalities in BRCA2-deficient cells may partly result from aberrations in cell division caused by disruption of BRCA2 during cytokinesis. Here we show that BRCA2 is a component of the midbody that is recruited through an interaction with Filamin A actin-binding protein. At the midbody, BRCA2 influences the recruitment of endosomal sorting complex required for transport (ESCRT)-associated proteins, Alix and Tsg101, and formation of CEP55-Alix and CEP55-Tsg101 complexes during abscission. Disruption of these BRCA2 interactions by cancer-associated mutations results in increased cytokinetic defects but has no effect on BRCA2-dependent homologous recombination repair of DNA damage. These findings identify a specific role for BRCA2 in the regulation of midbody structure and function, separate from DNA damage repair, that may explain in part the whole-chromosomal instability in BRCA2-deficient tumors.
authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
authors: Gourish
authors: G
authors: Mondal
authors: Matthew
authors: M
authors: Rowley
authors: Lucia
authors: L
authors: Guidugli
authors: Jianmin
authors: J
authors: Wu
authors: Vernon S
authors: VS
authors: Pankratz
authors: Fergus J
authors: FJ
authors: Couch
mesh_terms: D000818:Animals; D024682:BRCA2 Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D018797:Cell Cycle Proteins / Q000502:physiology*; D003285:Contractile Proteins / Q000502:physiology*; D048749:Cytokinesis / Q000502:physiology*; D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D005260:Female; D064448:Filamins; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008817:Mice, Mutant Strains; D008840:Microfilament Proteins / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology*; D021381:Protein Transport / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors; D000099177:Tsg101 Protein
chemical_list: D024682:BRCA2 Protein; D018797:Cell Cycle Proteins; D003285:Contractile Proteins; D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D064448:Filamins; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D000099177:Tsg101 Protein; C551750:BRCA2 protein, human; C106711:BRCA2 protein, mouse; C505378:Cep55 protein, human