title: Dot1-dependent histone H3K79 methylation promotes activation of the Mek1 meiotic checkpoint effector kinase by regulating the Hop1 adaptor.
abstract: During meiosis, accurate chromosome segregation relies on the proper interaction between homologous chromosomes, including synapsis and recombination. The meiotic recombination checkpoint is a quality control mechanism that monitors those crucial events. In response to defects in synapsis and/or recombination, this checkpoint blocks or delays progression of meiosis, preventing the formation of aberrant gametes. Meiotic recombination occurs in the context of chromatin and histone modifications, which play crucial roles in the maintenance of genomic integrity. Here, we unveil the role of Dot1-dependent histone H3 methylation at lysine 79 (H3K79me) in this meiotic surveillance mechanism. We demonstrate that the meiotic checkpoint function of Dot1 relies on H3K79me because, like the dot1 deletion, H3-K79A or H3-K79R mutations suppress the checkpoint-imposed meiotic delay of a synapsis-defective zip1 mutant. Moreover, by genetically manipulating Dot1 catalytic activity, we find that the status of H3K79me modulates the meiotic checkpoint response. We also define the phosphorylation events involving activation of the meiotic checkpoint effector Mek1 kinase. Dot1 is required for Mek1 autophosphorylation, but not for its Mec1/Tel1-dependent phosphorylation. Dot1-dependent H3K79me also promotes Hop1 activation and its proper distribution along zip1 meiotic chromosomes, at least in part, by regulating Pch2 localization. Furthermore, HOP1 overexpression bypasses the Dot1 requirement for checkpoint activation. We propose that chromatin remodeling resulting from unrepaired meiotic DSBs and/or faulty interhomolog interactions allows Dot1-mediated H3K79-me to exclude Pch2 from the chromosomes, thus driving localization of Hop1 along chromosome axes and enabling Mek1 full activation to trigger downstream responses, such as meiotic arrest.
authors: Instituto de Biología Funcional y Genómica, Consejo Superior de Investigaciones Científicas and University of Salamanca, Salamanca, Spain.
authors: David
authors: D
authors: Ontoso
authors: Isabel
authors: I
authors: Acosta
authors: Fred
authors: F
authors: van Leeuwen
authors: Raimundo
authors: R
authors: Freire
authors: Pedro A
authors: PA
authors: San-Segundo
mesh_terms: D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D008239:Lysine / Q000235:genetics; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D008540:Meiosis / Q000235:genetics*; D008745:Methylation; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C086672:HOP1 protein, S cerevisiae; D006657:Histones; D009687:Nuclear Proteins; C528119:Pch2 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C090118:Zip1 protein, S cerevisiae; C416235:Dot1 protein, S cerevisiae; D011495:Histone-Lysine N-Methyltransferase; D048369:MAP Kinase Kinase 1; D008239:Lysine
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