Investigating the functional conservation of BRCA1/BARD1 in Caenorhabditis elegans
Vahrenkamp, Russell Lloyd
Master of Science
Breast cancer susceptibility gene 1 (BRCA1) and its partner BARD1 function in genomic stability by regulating DNA repair, cell-cycle checkpoints, and transcriptional regulation. Mutations in these genes expose individuals to a higher risk of breast and ovarian cancer. The Caenorhabditis elegans orthologs, BRC-1 and BRD-1, also regulate DNA repair and cell-cycle checkpoints. Yet, how these proteins regulate gene transcription is unknown. Previous work shows that the worm orthologs function in a homologous manner to their human counterparts forming a heterodimeric complex (CeBCBD) that acts as an E3 ligase. We hypothesize that this CeBCBD complex ubiquitinates histone H2A resulting in epigenetic transcriptional regulation in C. elegans. Using biochemical ubiquitylation assays, we show that mutations in the CeBCBD complex inhibit ubiquitination of H2A in nucleosomes. These mutations are analogous to inhibitory and loss-of-function mutations in the human proteins. Our results suggest that transcriptional regulation is a conserved function of BRC-1 and BRD-1.