title: COM-1 promotes homologous recombination during Caenorhabditis elegans meiosis by antagonizing Ku-mediated non-homologous end joining.
abstract: Successful completion of meiosis requires the induction and faithful repair of DNA double-strand breaks (DSBs). DSBs can be repaired via homologous recombination (HR) or non-homologous end joining (NHEJ), yet only repair via HR can generate the interhomolog crossovers (COs) needed for meiotic chromosome segregation. Here we identify COM-1, the homolog of CtIP/Sae2/Ctp1, as a crucial regulator of DSB repair pathway choice during Caenorhabditis elegans gametogenesis. COM-1-deficient germ cells repair meiotic DSBs via the error-prone pathway NHEJ, resulting in a lack of COs, extensive chromosomal aggregation, and near-complete embryonic lethality. In contrast to its yeast counterparts, COM-1 is not required for Spo11 removal and initiation of meiotic DSB repair, but instead promotes meiotic recombination by counteracting the NHEJ complex Ku. In fact, animals defective for both COM-1 and Ku are viable and proficient in CO formation. Further genetic dissection revealed that COM-1 acts parallel to the nuclease EXO-1 to promote interhomolog HR at early pachytene stage of meiotic prophase and thereby safeguards timely CO formation. Both of these nucleases, however, are dispensable for RAD-51 recruitment at late pachytene stage, when homolog-independent repair pathways predominate, suggesting further redundancy and/or temporal regulation of DNA end resection during meiotic prophase. Collectively, our results uncover the potentially lethal properties of NHEJ during meiosis and identify a critical role for COM-1 in NHEJ inhibition and CO assurance in germ cells.
authors: Department of Toxicogenetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
authors: Bennie B L G
authors: BB
authors: Lemmens
authors: Nicholas M
authors: NM
authors: Johnson
authors: Marcel
authors: M
authors: Tijsterman
mesh_terms: D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics*; D020090:Chromosome Segregation / Q000235:genetics; D003434:Crossing Over, Genetic; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004706:Endodeoxyribonucleases / Q000235:genetics / Q000378:metabolism; D005854:Germ Cells / Q000378:metabolism; D059765:Homologous Recombination / Q000235:genetics*; D000072200:Ku Autoantigen; D008540:Meiosis / Q000235:genetics*; D049471:Pachytene Stage / Q000235:genetics; D000099257:Meiotic Recombination Protein SPO11
chemical_list: D034961:Antigens, Nuclear; D029742:Caenorhabditis elegans Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004706:Endodeoxyribonucleases; D000072200:Ku Autoantigen; D000099257:Meiotic Recombination Protein SPO11; C581620:COM-1 protein, C elegans