Cell cycle checkpoint control

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During meiosis, high levels of recombination initiated by DNA double-strand breaks (DSBs) occur only after DNA replication. How DSB formation is coupled to DNA replication is unknown, however. We examined several DNA replication proteins for a role in this coupling in Schizosaccharomyces pombe and now show that ribonucleotide reductase (RNR), the rate-limiting enzyme of deoxyribonucleotide synthesis and the target of the DNA synthesis inhibitor hydroxyurea (HU), is indirectly required for DSB formation linked to DNA replication. In cells in which the function of the DNA replication checkpoint proteins Rad1p, Rad3p, Rad9p, Radl7p, Rad26p, Huslp, or Cdslp was compromised, however, DSB formation occurred at similar frequencies in the absence or presence of HU. The DSBs in the HU-treated mutant cells occurred at normal sites and were associated with recombination. We propose that the sequence of meiotic S phase and initiation of recombination is coordinated by DNA replication checkpoint proteins.The kinase Cdc2p is a central regulator of entry into and progression through nuclear division during mitosis and meiosis in eukaryotes. Cdc2p is activated at the onset of mitosis by dephosphorylation on tyrosine-15, the phosphorylation status of which is determined mainly by the kinase Weel p and the phosphatase Cdc25p. In fission yeast, the forkhead-type transcription factor Mei4p is required for expression of many genes during meiosis, with mei4 mutant cells arresting before meiosis I. The mechanism of cell cycle arrest in mei4 cells has remained unknown, however. We now show that cdc25+ is an important target of Mei4p in control of entry into meiosis I. Forced dephosphorylation of Cdc2p on tyrosine-15 thus induced meiosis I in mei4 mutant cells without a delay, although no spores were formed. We propose that Mei4p acts as a rate-limiting regulator of meiosis I by activating cdc25+ transcription in coordination with other meiotic events.