Luther Davis and Gerald R.Smith*

Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, A1–162, Seattle, WA 98109–1024

In most organisms homologous recombination is vital for the proper segregation of chromosomes during meiosis, the formation of haploid sex cells from diploid precursors. This review compares meiotic recombination and chromosome segregation in the fission yeast Schizosaccharomyces pombe and the distantly related budding yeast Saccharomyces cerevisiae, two especially tractable microorganisms. Certain features, such as the occurrence of DNA breaks associated with recombination, appear similar, suggesting that these features may be common in eukaryotes. Other features, such as the role of these breaks and the ability of chromosomes to segregate faithfully in the absence of recombination, appear different, suggesting multiple solutions to the problems faced in meiosis.

The cardinal feature of meiosis is the generation of haploid gametes from diploid precursor cells by the proper segregation of chromosomes. In most species this crucial event is intimately associated with homologous recombination and the generation of genetic diversity. The faithful segregation of homologous chromosomes at the first (reductional) division of meiosis generally requires recombination. In this case meiotic recombination is vital: in its absence homologs missegregate and the resulting aneuploid gametes give rise to defective or inviable progeny. Recombination between homologs during meiosis also generates genetic diversity among the gametes and resultant progeny. Such diversity may be vital to the long-term survival of the species.

In the conventional view of meiosis, chromosome segregation at the first meiotic division (MI) depends on recombination in the following way (Fig. 1) (reviewed in ref. 1). After replication, a chromatid of one homolog recombines with a chromatid of the other homolog, thereby precisely joining homologous chromosomes. As the centromeres of the homologs are pulled to opposite sides of the cell by the spindle apparatus, tension between the recombined homologs signals that homologs are oriented for proper segregation. Without recombination homologs are not joined, tension is not generated, and homologs eventually move to the poles at random. The second meiotic division (MII) is not preceded by replication, and the sister chromatids separate equationally. Thus, in meiosis one diploid cell produces four haploid cells, which then differentiate into specialized gametes—eggs and sperm in animals, ovules and pollen in plants, or spores in fungi.

An especially tractable organism for the study of meiotic recombination and chromosome segregation is the fission yeast Schizosaccharomyces pombe (2). Like other ascomycetes it encloses the four haploid products of each meiosis (spores) in a sac, called an ascus. Analysis of these four spores reveals the recombinational and segregational fate of each of the four chromatids (Fig. 1). After germination the spores can be propagated indefinitely as haploid cells, or these haploids can be mated to form stable diploids, which also multiply indefinitely. Having only three chromosomes, S. pombe forms a substantial number of viable spores in the absence of recombination, thereby facilitating studies of meiotic recombination-deficient (Rec⁻) mutants. Biochemical analyses are aided by a mutant, described below, that undergoes rapid, synchronous meiosis when the temperature is raised. Finally, the nucleotide sequence of the S. pombe genome is essentially complete (www.sanger.ac.uk/projects/S_pombe), and the near isogenicity of the commonly used S. pombe strains aids comparisons between different studies.

S. pombe is only distantly related to the budding yeast Saccharomyces cerevisiae, in which meiosis also has been extensively studied (1–3). Some features of meiosis are the same in the two yeasts, suggesting that they may be common among eukaryotes. Other features, however, appear to be distinctly different and illustrate the diversity of meiosis. In this review we shall emphasize some of these similarities and differences. To place meiotic recombination and chromosome segregation in context, we briefly discuss the changes in physiology, gene expression, and DNA replication during meiosis.

Haploid S. pombe cells of opposite mating type, designated mat1-P (or h⁺) and mat1-M (or h⁻), mate only upon starvation, and normally the diploid zygotes directly undergo meiosis. But upon return to a growth medium, the zygotes resume mitotic divisions as diploids, which undergo meiosis when subsequently starved.

Starvation and mat1 heterozygosity, a sign of diploidy, activate two key regulators of meiosis, Ste11 and Mei2, via three interacting pathways (Fig. 2; reviewed in ref. 4). First, starvation activates the “stress”-induced Wis1-Spc1 protein kinase cascade to phosphorylate the transcription factor Atf1·Pcr1. Second, starvation lowers the cAMP level, which inactivates the protein kinase Pka1. These two changes induce ste11 transcription. Third, Ste11 in conjunction with a pheromone signaling pathway induces expression of the heterozygous mat1-P and mat1-M genes; together, their products induce Mei3, an inhibitor of the critical protein kinase Pat1. Ste11 also induces other meiotic genes, including Mei2, which activates multiple meiotic events.

In the absence of starvation and mat1 heterozygosity, active Pat1 kinase prevents meiosis by inhibiting Ste11 and Mei2. Thermal inactivation of the Pat1–114 temperature-sensitive mutant protein leads to synchronous meiosis even in haploids: premeiotic DNA replication begins at ~2 h, MI occurs at ~5 h, and spores appear at ~7 h. Meiotic events are similar in thermally induced haploid or diploid pat1–114 mutants and in starvation-induced pat1⁺ diploids, except that only ~2% of the