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

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.