The fission yeast meiotic checkpoint kinase Mek1 regulates nuclear localization of Cdc25 by phosphorylation.
In eukaryotic cells, fidelity in transmission of genetic information during cell division is ensured by the action of cell cycle checkpoints. Checkpoints are surveillance mechanisms that arrest or delay cell cycle progression when critical cellular processes are defective or when the genome is damaged. During meiosis, the so-called meiotic recombination checkpoint blocks entry into meiosis I until recombination has been completed, thus avoiding aberrant chromosome segregation and the formation of aneuploid gametes. One of the key components of the meiotic recombination checkpoint is the meiosis-specific Mek1 kinase, which belongs to the family of Rad53/Cds1/Chk2 checkpoint kinases containing forkhead-associated domains. In fission yeast, several lines of evidence suggest that Mek1 targets the critical cell cycle regulator Cdc25 to delay meiotic cell cycle progression. Here, we investigate in more detail the molecular mechanism of action of the fission yeast Mek1 protein. We demonstrate that Mek1 acts independently of Cds1 to phosphorylate Cdc25, and this phosphorylation is required to trigger cell cycle arrest. Using ectopic overexpression of mek1(+) as a tool to induce in vivo activation of Mek1, we find that Mek1 promotes cytoplasmic accumulation of Cdc25 and results in prolonged phosphorylation of Cdc2 at tyrosine 15. We propose that at least one of the mechanisms contributing to the cell cycle delay when the meiotic recombination checkpoint is activated in fission yeast is the nuclear exclusion of the Cdc25 phosphatase by Mek1-dependent phosphorylation.
Pérez-Hidalgo
Livia
L
Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas and Universidad de Salamanca, Salamanca, Spain.
Moreno
Sergio
S
San-Segundo
Pedro A
PA
D048948:14-3-3 Proteins / Q000378:metabolism; D016203:CDC2 Protein Kinase / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000201:enzymology*; D064447:Checkpoint Kinase 2; D004261:DNA Replication; D004271:DNA, Fungal / Q000378:metabolism; D005656:Fungal Proteins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000378:metabolism*; D008540:Meiosis; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport; D012568:Schizosaccharomyces / Q000166:cytology* / Q000201:enzymology*; D029702:Schizosaccharomyces pombe Proteins / Q000378:metabolism*; D020666:ras-GRF1 / Q000378:metabolism*
D048948:14-3-3 Proteins; D018797:Cell Cycle Proteins; D004271:DNA, Fungal; D005656:Fungal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D029702:Schizosaccharomyces pombe Proteins; C501114:rad24 protein, S pombe; D020666:ras-GRF1; D019000:Phosphotyrosine; D064447:Checkpoint Kinase 2; C119549:Mek1 protein, S pombe; C578636:Cds1 protein, S pombe; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; C469447:cdc2 protein, S pombe; D048369:MAP Kinase Kinase 1