RRC ID 45885
著者 Wolters S, Ermolaeva MA, Bickel JS, Fingerhut JM, Khanikar J, Chan RC, Schumacher B.
タイトル Loss of Caenorhabditis elegans BRCA1 promotes genome stability during replication in smc-5 mutants.
ジャーナル Genetics
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.
巻・号 196(4)
ページ 985-99
公開日 2014-4-1
DOI 10.1534/genetics.113.158295
PII genetics.113.158295
PMID 24424777
PMC PMC3982690
MeSH Animals Caenorhabditis elegans / genetics Caenorhabditis elegans / growth & development* Caenorhabditis elegans Proteins / genetics* Caenorhabditis elegans Proteins / metabolism* Cell Cycle Proteins / genetics* Cell Cycle Proteins / metabolism DNA Damage DNA Replication / radiation effects DNA, Helminth Genome, Helminth Genomic Instability* / radiation effects Germ Cells / metabolism Mutation Rad51 Recombinase / metabolism Tumor Suppressor Proteins / genetics Tumor Suppressor Proteins / metabolism* Ubiquitin-Protein Ligases / genetics Ubiquitin-Protein Ligases / metabolism*
IF 4.015
引用数 19
WOS 分野 GENETICS & HEREDITY
リソース情報
線虫 tm3886 tm1145