title: Coordination of Double Strand Break Repair and Meiotic Progression in Yeast by a Mek1-Ndt80 Negative Feedback Loop.
abstract: During meiosis, homologous chromosomes are physically connected by crossovers and sister chromatid cohesion. Interhomolog crossovers are generated by the highly regulated repair of programmed double strand breaks (DSBs). The meiosis-specific kinase Mek1 is critical for this regulation. Mek1 downregulates the mitotic recombinase Rad51, indirectly promoting interhomolog strand invasion by the meiosis-specific recombinase Dmc1. Mek1 also promotes the formation of crossovers that are distributed throughout the genome by interference and is the effector kinase for a meiosis-specific checkpoint that delays entry into Meiosis I until DSBs have been repaired. The target of this checkpoint is a meiosis-specific transcription factor, Ndt80, which is necessary to express the polo-like kinaseCDC5and the cyclinCLB1thereby allowing completion of recombination and meiotic progression. This work shows that Mek1 and Ndt80 negatively feedback on each other such that when DSB levels are high, Ndt80 is inactive due to high levels of Mek1 activity. As DSBs are repaired, chromosomes synapse and Mek1 activity is reduced below a threshold that allows activation of Ndt80. Ndt80 transcription ofCDC5results in degradation of Red1, a meiosis-specific protein required for Mek1 activation, thereby abolishing Mek1 activity completely. Elimination of Mek1 kinase activity allows Rad51-mediated repair of any remaining DSBs. In this way, cells do not enter Meiosis I until recombination is complete and all DSBs are repaired.
authors.affiliation: Department of Biochemistry and Cell Biology, Stony Brook University, New York 11794-5215.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Prugar
authors.affiliation: Department of Biochemistry and Cell Biology, Stony Brook University, New York 11794-5215.
authors.forename: Cameron
authors.initials: C
authors.lastname: Burnett
authors.affiliation: Department of Biochemistry and Cell Biology, Stony Brook University, New York 11794-5215.
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Cell Biology, Stony Brook University, New York 11794-5215 nancy.hollingsworth@stonybrook.edu.
authors.forename: Nancy M
authors.identifier: 0000-0003-3300-6444
authors.initials: NM
authors.lastname: Hollingsworth
mesh_terms: D002842:Chromatids / Q000235:genetics; D023902:Chromosome Pairing; D020090:Chromosome Segregation / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D025461:Feedback, Physiological; D048369:MAP Kinase Kinase 1 / Q000235:genetics*; D008540:Meiosis / Q000235:genetics*; D010766:Phosphorylation; D051135:Rad51 Recombinase / Q000235:genetics*; D011995:Recombination, Genetic; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C097071:NDT80 protein, S cerevisiae; C086673:RED1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D048369:MAP Kinase Kinase 1; D051135:Rad51 Recombinase
keywords: Mek1; Ndt80; checkpoint; meiosis; recombination