The Tumor Suppressor BRCA1 in IP3R Calcium Signaling and Apoptosis

The inositol 1,4,5-trisphosphate receptor (IP3R) is a ubiquitously expressed endoplasmic-reticulum (ER)-resident calcium channel. Calcium release mediated by IP3Rs influence many signaling pathways including those regulating apoptosis. IP3R activity is regulated by protein-protein interactions, including binding to proto-oncogenes and tumor suppressors to regulate cell death. Here we show that the IP3R binds to the tumor suppressor BRCA1. BRCA1 binds directly to the IP3R and causes destabilization of the IP3R closed state resulting in an increased open probability and increased calcium release. BRCA1 is recruited to the ER during apoptosis in an IP3R-dependent manner, and in addition, a pool of BRCA1 protein is constitutively associated with the ER under non-apoptotic conditions. This is likely mediated by a novel lipid binding activity of the first BRCT (BRCA1 C-Terminus) domain of BRCA1. Lastly, phosphatidic acid, which is was identified in a lipid binding screen, is produced at the ER during apoptosis suggesting a mechanism for apoptotic recruitment of BRCA1 to the ER. These findings provide a mechanistic explanation by which BRCA1 can act as a pro-apoptotic protein.