(NAS Colloquium) Links Between Recombination and Replication: Vital Roles of Recombination

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Colloquium on Links Between Recombination and Replication: Vital Roles of Recombination

Fig. 1. Segregation of recombined chromosomes during the two meiotic divisions. Black and white lines represent homologous chromosomes. Gray circles represent cohesin; open circles represent kinetechores. Arrows represent the meiotic spindle. See text for explanation.

spores from pat1–114 haploids are viable, due to insufficient copies of the chromosomes (5, 6).

Control of Meiotic rec Gene Expression

Among the many genes induced in meiosis are those whose products promote recombination (rec genes and others described below). This induction is responsible, at least in part, for the high level of meiotic recombination. Induction of many analyzed rec genes requires Rep1(Rec16), perhaps in a complex with Cdc10, a transcriptional activator that regulates the mitotic cell cycle (Fig. 2; refs. 7 and 8). The rep1(rec16) gene was first identified by a strong meiotic Rec⁻ mutation rec16–125 (9) and later as a high-copy suppressor (rep1⁺) of a cdc10 mutation (8, 10). Several such high-copy suppressors have been identified, and two (Res1 and Res2) form complexes with Cdc10 (11). Rep1(Rec16) also may complex with Cdc10 to form a meiosis-specific transcriptional activator that induces the other analyzed rec genes and genes required for meiotic replication. The rec6, 7, 8, 10, 11, 12, and 15 genes have nearby MluI sites (5′-ACGCGT-3′; MCB or MluI cell cycle box) or closely related sequences, to which Cdc10 complexes bind (12–17). Induction of rep1(rec16) by Ste11 early in meiosis renders the putative Cdc10·Rep1 complex meiosis-specific (10). In addition, Ste11 appears to directly activate some meiotic recombination genes, such as dmc1 (18).

Fig. 2. Control of the entry into meiosis. “Stress” includes starvation, DNA damage, high osmolarity, or heat shock, each of which can activate Atf1·Pcr1. Arrowheads indicate activation of the indicated protein or its gene or process; straight lines indicate inhibition or repression. See text for explanation.

Rep1(Rec16) Links Meiotic Replication and Recombination

That these two processes are closely connected is manifest by the phenotype of rep1(rec16) mutations. The rec16–125 mutation delays meiotic replication by about 2 h and only about half of the cells complete replication; this mutation reduces recombination by a factor of about 50 (7, 9). The rep1::ura4⁺ null allele essentially abolishes both meiotic replication and recombination (8, 10). These observations led to the proposal that these two events are mechanistically connected, as in prokaryotes (7, 19, 20). The connection via Rep 1 (Rep 16) is most simply explained, however, by Rep1(Rec16) inducing two sets of meiotic genes: one for replication and one for recombination (ref. 8; Fig. 2). Recent evidence, however, indicates that DNA replication is a necessary prelude to meiotic DNA breakage in S. cerevisiae (21).

Gene Products Required for Meiotic Recombination

The products of more than two dozen identified genes are required for meiotic recombination in S. pombe (Table 1 and references therein). Mutations in these genes confer a wide range of deficiencies in recombination, from a modest reduction (~3-fold) to near abolition (>1,000-fold reduction), suggesting that some steps are more critical than others or that there are redundant means for some steps. Some of these mutations are specific for meiotic recombination; others affect additional meiotic or mitotic events, suggesting a close interrelation between recombination and other events such as meiotic replication and chromosome segregation or mitotic DNA repair.

Meiotic Rec⁻ mutants were identified in multiple ways. A direct screen for such mutants revealed 16 complementation groups, rec6–rec21, 10 of which have been assigned to sequenced genes (Table 1). Certain mutants identified on another basis subsequently were found to be Rec⁻; these include the radiation-sensitive mutant rad32 and the mating type switching-defective mutant swi5. Some meiotically induced genes, such as dmc1 and meu13, were found to be Rec⁻ when mutated. A search for biochemical activities relevant to recombination revealed the M26 hotspot-activating protein Atf1·Pcr1 and the mismatch repair exonuclease ExoI.

The rec8, rec10, and rec11 mutants display an unusual regional specificity (22–24). Recombination in some intervals of the genome is reduced as much as 100- to 300-fold, whereas in other intervals the reduction is ~3-fold or less. The strongly affected intervals are in the central regions of the chromosomes (encompassing the centromeres), and those less affected are nearer the ends. Rec8 and Rec11 encode meiosis-specific sister chromatid cohesins, which may be predominantly localized in the central

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