BRCA1-mediated ubiquitylation.

The BRCA1 tumour suppressor and its heterodimeric partner BARD1 play crucial roles in coordinating cellular responses to DNA damage. Evidence also implicates these proteins in transcriptional regulation, cell cycle progression and meiotic sex chromosome inactivation, but their mode of action remains elusive. The demonstration that the BRCA1/BARD1 heterodimer constitutes an E3-ubiquitin (Ub) ligase raises the possibility that ubiquitylation of specific targets may allow BRCA1/BARD1 to impact on diverse cellular processes. It is clear that the E3-Ub ligase activity of BRCA1/BARD1 is of critical functional importance as tumour-derived BRCA1 mutations have been identified that eliminate this activity. Recent work and data presented here indicates that BRCA1/BARD1 function is largely conserved in C. elegans. Indeed, studies in C. elegans and human cells have illuminated how the E3-ubiquitin (Ub) ligase activity is regulated in response to DNA damage. However, bone fide targets for BRCA1-dependent ubiquitylation are not known and their identification remains critical to the understanding of the role of BRCA1 in tumorigenesis.