Abstract
The breast and ovarian tumor suppressor BRCA1 acts as a hub protein that coordinates many cellular pathways to maintain genomic stability. Its major biological functions includes DNA double-strand break repair by homologous recombination and regulation of cell cycle check points, transcription, apoptosis, and centrosome duplication. As a clue to elucidate the mechanisms underlying the BRCA's multiple biological functions we previously discovered that BRCA1 forms a heterodimeric RING-type ubiquitin ligase with BARD1. BRCA1-BARD1 catalyzes untraditional Lys-6-linked polyubiquitin chains that could be a signal for a process other than proteolysis. We reported that Nucleophosmin/B23 (NPM1) is one of substrates of BRCA1 and the NPM1 ubiquitination by BRCA1-BARD1 was abolished by CDK2-Cyclin A or CDK2-Cyclin E. This could be important for the maintenance of genomic stability through regulation of centrosome duplication. In addition we recently identified RPB8, a common subunit of RNA polymerases, as another substrate of BRCA1-BARD1 by a proteomics screen. Interestingly, HeLa cells stably expressing a ubiquitin-resistant form of RPB8 exhibited UV hypersensitivity, a phenotype ascribed to BRCA1 deficiency. Revealing the roles of BRCA1's enzyme activity, including its specific substrates, could translate into the clinic by providing a means to predict the sensitivity of breast cancers to DNA damaging anti-cancer agents or to predict a molecular target for therapeutic strategy.
