title: Gradual implementation of the meiotic recombination program via checkpoint pathways controlled by global DSB levels.
abstract: During meiosis, Spo11-induced double-strand breaks (DSBs) are processed into crossovers, ensuring segregation of homologous chromosomes (homologs). Meiotic DSB processing entails 5' end resection and preferred strand exchange with the homolog rather than the sister chromatid (homolog bias). In many organisms, DSBs appear gradually along the genome. Here we report unexpected effects of global DSB levels on local recombination events. Early-occurring, low-abundance "scout" DSBs lack homolog bias. Their resection and interhomolog processing are controlled by the conserved checkpoint proteins Tel1(ATM) kinase and Pch2(TRIP13) ATPase. Processing pathways controlled by Mec1(ATR) kinase take over these functions only above a distinct DSB threshold, resulting in progressive strengthening of the homolog bias. We conclude that Tel1(ATM)/Pch2 and Mec1(ATR) DNA damage response pathways are sequentially activated during wild-type meiosis because of their distinct sensitivities to global DSB levels. Moreover, relative DSB order controls the DSB repair pathway choice and, ultimately, recombination outcome.
authors: Center for Gene Regulation in Health and Disease and Department of Biological Sciences, Cleveland State University, Cleveland, OH 44115, USA.
authors: Neeraj
authors: N
authors: Joshi
authors: Department of Molecular Genetics and Cell Biology, University of Chicago, Cummings Life Science Center, Chicago, IL 60637, USA; Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA.
authors: M Scott
authors: MS
authors: Brown
authors: Department of Molecular Genetics and Cell Biology, University of Chicago, Cummings Life Science Center, Chicago, IL 60637, USA; Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA; Committee on Genetics, University of Chicago, Chicago, IL 60637, USA.
authors: Douglas K
authors: DK
authors: Bishop
authors: Center for Gene Regulation in Health and Disease and Department of Biological Sciences, Cleveland State University, Cleveland, OH 44115, USA; Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA. Electronic address: g.boerner@csuohio.edu.
authors: G Valentin
authors: GV
authors: Börner
mesh_terms: D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004706:Endodeoxyribonucleases / Q000235:genetics / Q000378:metabolism; D059765:Homologous Recombination / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008540:Meiosis / Q000235:genetics*; D008957:Models, Genetic; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D013997:Time Factors; D000099257:Meiotic Recombination Protein SPO11
chemical_list: D045643:DNA Repair Enzymes; D004706:Endodeoxyribonucleases; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D051135:Rad51 Recombinase; D029701:Saccharomyces cerevisiae Proteins; C528119:Pch2 protein, S cerevisiae; C088937:MEC1 protein, S cerevisiae; C513623:TEL1 protein, S cerevisiae; C495151:RAD51 protein, S cerevisiae; C518938:Spo11 protein, S cerevisiae; D000099257:Meiotic Recombination Protein SPO11