title: Loss of Caenorhabditis elegans BRCA1 promotes genome stability during replication in smc-5 mutants.
abstract: DNA damage by ultraviolet (UV) light poses a risk for mutagenesis and a potential hindrance for cell cycle progression. Cells cope with UV-induced DNA damage through two general strategies to repair the damaged nucleotides and to promote cell cycle progression in the presence of UV-damaged DNA. Defining the genetic pathways and understanding how they function together to enable effective tolerance to UV remains an important area of research. The structural maintenance of chromosomes (SMC) proteins form distinct complexes that maintain genome stability during chromosome segregation, homologous recombination, and DNA replication. Using a forward genetic screen, we identified two alleles of smc-5 that exacerbate UV sensitivity in Caenorhabditis elegans. Germ cells of smc-5-defective animals show reduced proliferation, sensitivity to perturbed replication, chromatin bridge formation, and accumulation of RAD-51 foci that indicate the activation of homologous recombination at DNA double-strand breaks. Mutations in the translesion synthesis polymerase polh-1 act synergistically with smc-5 mutations in provoking genome instability after UV-induced DNA damage. In contrast, the DNA damage accumulation and sensitivity of smc-5 mutant strains to replication impediments are suppressed by mutations in the C. elegans BRCA1/BARD1 homologs, brc-1 and brd-1. We propose that SMC-5/6 promotes replication fork stability and facilitates recombination-dependent repair when the BRC-1/BRD-1 complex initiates homologous recombination at stalled replication forks. Our data suggest that BRC-1/BRD-1 can both promote and antagonize genome stability depending on whether homologous recombination is initiated during DNA double-strand break repair or during replication stalling.
authors.affiliation: Institute for Genome Stability in Ageing and Disease, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Wolters
authors.forename: Maria A
authors.initials: MA
authors.lastname: Ermolaeva
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Bickel
authors.forename: Jaclyn M
authors.initials: JM
authors.lastname: Fingerhut
authors.forename: Jayshree
authors.initials: J
authors.lastname: Khanikar
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Chan
authors.forename: Björn
authors.initials: B
authors.lastname: Schumacher
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D004261:DNA Replication / Q000528:radiation effects; D018509:DNA, Helminth; D049751:Genome, Helminth; D042822:Genomic Instability / Q000528:radiation effects; D005854:Germ Cells / Q000378:metabolism; D009154:Mutation; D051135:Rad51 Recombinase / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: C528463:BRC-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D018797:Cell Cycle Proteins; D018509:DNA, Helminth; C000594909:SMC-5 protein, C elegans; C000594910:SMC-6 protein, C elegans; D025521:Tumor Suppressor Proteins; C491164:brd-1 protein, C elegans; D044767:Ubiquitin-Protein Ligases; D051135:Rad51 Recombinase; C495148:rad-51 protein, C elegans
keywords: BRCA1; Caenorhabditis elegans; DNA repair; DNA replication; SMC5/6