RRC ID 46178
Author Rosu S, Zawadzki KA, Stamper EL, Libuda DE, Reese AL, Dernburg AF, Villeneuve AM.
Title The C. elegans DSB-2 protein reveals a regulatory network that controls competence for meiotic DSB formation and promotes crossover assurance.
Journal PLoS Genet.
Abstract For most organisms, chromosome segregation during meiosis relies on deliberate induction of DNA double-strand breaks (DSBs) and repair of a subset of these DSBs as inter-homolog crossovers (COs). However, timing and levels of DSB formation must be tightly controlled to avoid jeopardizing genome integrity. Here we identify the DSB-2 protein, which is required for efficient DSB formation during C. elegans meiosis but is dispensable for later steps of meiotic recombination. DSB-2 localizes to chromatin during the time of DSB formation, and its disappearance coincides with a decline in RAD-51 foci marking early recombination intermediates and precedes appearance of COSA-1 foci marking CO-designated sites. These and other data suggest that DSB-2 and its paralog DSB-1 promote competence for DSB formation. Further, immunofluorescence analyses of wild-type gonads and various meiotic mutants reveal that association of DSB-2 with chromatin is coordinated with multiple distinct aspects of the meiotic program, including the phosphorylation state of nuclear envelope protein SUN-1 and dependence on RAD-50 to load the RAD-51 recombinase at DSB sites. Moreover, association of DSB-2 with chromatin is prolonged in mutants impaired for either DSB formation or formation of downstream CO intermediates. These and other data suggest that association of DSB-2 with chromatin is an indicator of competence for DSB formation, and that cells respond to a deficit of CO-competent recombination intermediates by prolonging the DSB-competent state. In the context of this model, we propose that formation of sufficient CO-competent intermediates engages a negative feedback response that leads to cessation of DSB formation as part of a major coordinated transition in meiotic prophase progression. The proposed negative feedback regulation of DSB formation simultaneously (1) ensures that sufficient DSBs are made to guarantee CO formation and (2) prevents excessive DSB levels that could have deleterious effects.
Volume 9(8)
Pages e1003674
Published 2013
DOI 10.1371/journal.pgen.1003674
PII PGENETICS-D-13-00681
PMID 23950729
PMC PMC3738457
MeSH Animals Caenorhabditis elegans / genetics Caenorhabditis elegans Proteins / genetics* Caenorhabditis elegans Proteins / metabolism Chromosomal Proteins, Non-Histone / genetics* Chromosome Segregation / genetics* Crossing Over, Genetic* DNA Breaks, Double-Stranded* DNA Repair / genetics* Gene Regulatory Networks Homologous Recombination / genetics Meiosis / genetics* Rad51 Recombinase / genetics Rad51 Recombinase / metabolism Receptors, Cytoplasmic and Nuclear / genetics Receptors, Cytoplasmic and Nuclear / metabolism
IF 5.54
Times Cited 30
WOS Category GENETICS & HEREDITY
Resource
C.elegans tm3298