BRCA1/BARD1 orthologs required for DNA repair in Caenorhabditis elegans.
Inherited germline mutations in the tumor suppressor gene BRCA1 predispose individuals to early onset breast and ovarian cancer. BRCA1 together with its structurally related partner BARD1 is required for homologous recombination and DNA double-strand break repair, but how they perform these functions remains elusive. As part of a comprehensive search for DNA repair genes in C. elegans, we identified a BARD1 ortholog. In protein interaction screens, Ce-BRD-1 was found to interact with components of the sumoylation pathway, the TACC domain protein TAC-1, and most importantly, a homolog of mammalian BRCA1. We show that animals depleted for either Ce-brc-1 or Ce-brd-1 display similar abnormalities, including a high incidence of males, elevated levels of p53-dependent germ cell death before and after irradiation, and impaired progeny survival and chromosome fragmentation after irradiation. Furthermore, depletion of ubc-9 and tac-1 leads to radiation sensitivity and a high incidence of males, respectively, potentially linking these genes to the C. elegans BRCA1 pathway. Our findings support a shared role for Ce-BRC-1 and Ce-BRD-1 in C. elegans DNA repair processes, and this role will permit studies of the BRCA1 pathway in an organism amenable to rapid genetic and biochemical analysis.
Boulton
Simon J
SJ
DNA Damage Response Laboratory, Cancer Research UK, The London Research Institute, Clare Hall Laboratories, EN6 3LD, South Mimms, United Kingdom. simon.boulton@cancer.org.uk
Martin
Julie S
JS
Polanowska
Jolanta
J
Hill
David E
DE
Gartner
Anton
A
Vidal
Marc
M
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects; D019313:BRCA1 Protein / Q000235:genetics*; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins / Q000235:genetics*; D017931:DNA Primers; D004260:DNA Repair / Q000235:genetics*; D040461:Gene Components; D006066:Gonads / Q000033:anatomy & histology; D006652:Histological Techniques; D008969:Molecular Sequence Data; D034622:RNA Interference; D016415:Sequence Alignment; D025521:Tumor Suppressor Proteins; D020798:Two-Hybrid System Techniques; D044767:Ubiquitin-Protein Ligases
D019313:BRCA1 Protein; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D017931:DNA Primers; D025521:Tumor Suppressor Proteins; C491164:brd-1 protein, C elegans; D044767:Ubiquitin-Protein Ligases