BRCA2 Localization to the Midbody by Filamin A Regulates CEP55 Signaling and Completion of Cytokinesis

• Published in: Developmental cell Vol. 23; no. 1; pp. 137 - 152
• Main Authors: Mondal, Gourish, Rowley, Matthew, Guidugli, Lucia, Wu, Jianmin, Pankratz, Vernon S., Couch, Fergus J.
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 17.07.2012; Cell Press
• Subjects: Animals; Biological and medical sciences; BRCA2 Protein - chemistry; BRCA2 Protein - genetics; BRCA2 Protein - metabolism; BRCA2 Protein - physiology; Cell Cycle Proteins - physiology; Cell cycle, cell proliferation; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Contractile Proteins - physiology; Cytokinesis - physiology; DNA-Binding Proteins; Endosomal Sorting Complexes Required for Transport; Female; Filamins; Fundamental and applied biological sciences. Psychology; HEK293 Cells; HeLa Cells; Humans; Mammary Neoplasms, Animal - metabolism; Mammary Neoplasms, Animal - pathology; Mice; Mice, Mutant Strains; Microfilament Proteins - physiology; Molecular and cellular biology; Nuclear Proteins - physiology; Protein Transport - genetics; Signal Transduction - physiology; Transcription Factors; Regulation(control); BRCA2 gene; Cytodieresis; Cell cycle; Development; Filamin; Localization; Tumor suppressor gene
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2012.05.008

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. ► BRCA2 is recruited to the central spindle and midbody by Filamin A ► Localization of signaling proteins at the midbody is regulated by BRCA2 ► BRCA2 mediates CEP55-associated recruitment of ESCRT complexes to the midbody ► Missense mutations separate the cytokinetic and DNA repair activities of BRCA2 BRCA2-deficient cells exhibit numerous chromosomal abnormalities, suggesting that BRAC2 functions in cell division independent of DNA repair. Mondal et al. show that Filamin A recruits BRCA2 to the spindle midbody during cytokinesis. Once there, BRCA2 interacts with CEP55 and Alix, an ESCRT-associated protein, and promotes terminal stages of abscission.