Fission Yeast Mus81·Eme1 Holliday Junction Resolvase Is Required for Meiotic Crossing Over but Not for Gene Conversion

Corresponding author: Gerald R. Smith, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., A1-162, Seattle, WA 98109-1024., gsmith{at}fhcrc.org (E-mail)

Communicating editor: A. P. MITCHELL

	ABSTRACT

TOP ABSTRACT LITERATURE CITED

Most models of homologous recombination invoke cleavage of Holliday junctions to explain crossing over. The Mus81·Eme1 endonuclease from fission yeast and humans cleaves Holliday junctions and other branched DNA structures, leaving its physiological substrate uncertain. We report here that Schizosaccharomyces pombe mus81 mutants have normal or elevated frequencies of gene conversion but 20- to 100-fold reduced frequencies of crossing over. Thus, gene conversion and crossing over can be genetically separated, and Mus81 is required for crossing over, supporting the hypothesis that the fission yeast Mus81·Eme1 protein complex resolves Holliday junctions in meiotic cells.

DURING meiosis, homologous recombination serves at least two purposes—to increase genetic diversity, upon which natural selection can act to further evolution, and to provide physical connections between homologs to aid their reductional segregation critical to forming viable haploid gametes. Two types of homologous recombination occur during meiosis. Gene conversion, or nonreciprocal recombination, is the primary mechanism of recombination of alleles in the same gene, whereas crossing over, or reciprocal recombination, predominates in recombination between genes (for a review see WHITEHOUSE 1982 ).

Models of homologous recombination have usually attempted to explain conversion and crossing over by a single initiating mechanism with alternative outcomes. Central to these models is the observation that convertants have a crossover for flanking markers more frequently than do chromosomes in the total population. This statistical association, which can range from 15 to 80% depending on the genetic interval and organism examined (WHITEHOUSE 1982 ), suggests a mechanistic association that is incorporated into most models. For example, the model of HOLLIDAY 1964 proposed the formation of hybrid DNA, containing one DNA strand from each of the two parental duplexes, and a reciprocal cross-strand connection between homologs, called the Holliday junction, adjacent to the hybrid DNA. If the hybrid DNA covers one or more markers within a gene, appropriate correction of base mismatches would give rise to one but not the reciprocal recombinant type, i.e., conversion. In this model the cross-strand connection could be resolved by appropriate cutting of the Holliday junction, swapping of DNA strand ends, and ligations. This resolution could give rise either to reciprocal recombinants for markers flanking the hybrid DNA and Holliday junction, i.e., crossovers, or to parental arrangements of these markers, i.e., noncrossovers. Either type of resolution could be accompanied by conversion. Many subsequent models, such as those of MESELSON and RADDING 1975 and SZOSTAK et al. 1983 , also employed these features to account for conversion, crossing over, and their association, although the model of SZOSTAK et al. 1983 proposed, in addition, the repair of DNA double-strand gaps to account for conversion.

Support for Holliday junctions and their resolution in recombination came from the identification of enzymes able to resolve such junctions. The first was endonuclease VII of phage T4 (MIZUUCHI et al. 1982 ). Subsequent studies showed, however, that this enzyme can also cleave DNA molecules with a variety of single- and double-strand branches or base mismatches, leaving uncertain its role in recombination (KEMPER 1998 ). The Escherichia coli RuvC enzyme has high specificity for cleavage of Holliday junctions, but mutants lacking RuvC are not strongly deficient in conjugational recombination unless they also lack the branch-migration enzyme RecG (LLOYD 1991 ; BENSON and WEST 1994 ). In eukaryotes, mitochondrial resolvases have been isolated from several species, but where tested they have no significant role in recombination of nuclear genes (KEMPER 1998 ). A nuclear activity from calf testis and human cells has also been described (CONSTANTINOU et al. 2001 , CONSTANTINOU et al. 2002 ), but the identity of the responsible protein(s) has not been reported.

Recently, a complex containing the Mus81 polypeptide from the fission yeast Schizosaccharomyces pombe (BODDY et al. 2001 ), the budding yeast Saccharomyces cerevisiae (KALIRAMAN et al. 2001 ), and human cells (CHEN et al. 2001 ; CONSTANTINOU et al. 2002 ; CICCIA et al. 2003 ) has been reported to cleave a variety of branched DNA molecules. Endogenous Mus81 complexes from S. pombe and humans readily cleave Holliday junctions, unlike the "recombinant" enzymes synthesized in E. coli and encoded by the S. cerevisiae or human genes mus81 and their partner mms4 or eme1. Recent studies have revealed that the endogenous and recombinant complexes of fission yeast Mus81·Eme1 differ primarily in their ability to make the first cut in a nick-and-counternick mechanism of Holliday junction resolution (GAILLARD et al. 2003 ), suggesting that the recombinant enzymes lack a post-translational modification or additional subunit(s) necessary to initiate cleavage of Holliday junctions.

S. pombe mutants lacking Mus81 or its partner polypeptide Eme1 are severely deficient in meiosis; they form few viable spores and their DNA often remains as a single mass within the meiotic ascus (BODDY et al. 2001 ). These deficiencies are largely overcome by a mutation in rec6 or rec12, which blocks the formation of meiotic double-strand breaks apparently necessary for meiotic recombination (CERVANTES et al. 2000 ; BODDY et al. 2001 ). These observations suggest that Mus81·Eme1 is required for meiotic recombination after the formation of double-strand breaks but before the segregation of homologs. To test this hypothesis, we have assayed S. pombe mus81 mutants for meiotic recombination: if Mus81·Eme1 is required for the resolution of Holliday junctions, these mutants would, within the context of the models above, be deficient for crossing over. They might, however, be proficient for hybrid DNA formation and gene conversion. The data reported here support this hypothesis.

To test the requirement for Mus81 in crossing over, we examined recombination in large intergenic intervals, one on each of the three chromosomes. We conducted standard matings of appropriately marked haploid strains on EMM2 medium, on which cells of opposite mating type mate and undergo meiosis after few or no mitotic divisions (GUTZ et al. 1974 ). Under these conditions almost all recombination occurs during meiosis. Because of the very low spore viability in mus81 mutants, tetrad analysis to verify reciprocality of crossovers was not feasible. However, random spore analysis can be used in S. pombe to assess crossing over because the frequency of gene conversion of most markers is low: the mean conversion frequency of 31 markers other than ade6-M26 is 0.07% per spore (range 0.03% to 0.4%; P. MUNZ, personal communication cited in YOUNG et al. 2002 ). Intergenic recombinant frequencies greater than this therefore reflect primarily crossing over. We converted the observed recombinant frequencies to genetic distances (centimorgans) using the mapping function of HALDANE 1919 , which is appropriate for S. pombe since it does not manifest crossover interference (MUNZ 1994 ). This allowed us to assess quantitatively the degree of reduction of crossing over in the mus81 mutant.

For the his3–ade3 interval the frequency of recombinants was 47.6% in mus81⁺ crosses and 7.5% in the mus81 mutant crosses (Table 1). These data translate to 150 and 8.1 cM, respectively, indicating a reduction of crossing over in the mus81 mutant by a factor of 19. Because the frequency of recombinants in mus81⁺ cells was so close to the theoretical maximum of 50%, the estimate of the his3–ade3 genetic distance is not precise. Since crossover frequencies per unit physical distance appear to be nearly uniform in S. pombe, we estimated the his3–ade3 genetic distance using the physical distance and the genome average of 0.16 cM/kb (WOOD et al. 2002 ; YOUNG et al. 2002 ). This nominal distance of 480 cM in mus81⁺ cells indicates that the mus81 mutation reduces crossing over by a factor of 60.

Similar reductions of crossing over by the mus81 mutation were seen in other intervals. For the ade7–leu1 interval the reduction was a factor of 52, on the basis of the observed mus81⁺ recombinant frequency, or 80, on the basis of the physical distance and nominal genetic distance. For the ade6–arg1 interval the factors of reduction were 90, on the basis of the observed frequency, or 64, on the basis of the nominal genetic distance. Thus, crossing over is strongly reduced in the mus81 mutant.

Two meiotic phenotypes of the mus81 mutation—low viable spore yield and faulty DNA segregation—are suppressed by the E. coli RusA protein, which resolves Holliday junctions with high specificity (CHAN et al. 1997 ; BODDY et al. 2001 ; BOLT and LLOYD 2002 ). To determine if the low frequency of crossing over was also suppressed, we conducted crosses in mus81 mutants expressing the rusA gene under the control of the S. pombe nmt1 promoter (BODDY et al. 2001 ). The ade6–arg1 crossover frequency was increased from 0.75% in the absence of RusA to 26% in its presence (Table 1). The genetic distance was increased to >50% of that in mus81⁺ cells. The suppression might be greater than this, since S. pombe plasmids are lost at high frequency even under selection (HEYER et al. 1986 ). Thus, the Holliday junction resolvase RusA largely and perhaps completely overcame the defect in crossing over in mus81 mutants.

Although our genetic analysis allowed us to examine crossing over only in viable spores, we suppose that the dead spores also are deficient in crossing over. It is difficult to understand how the dead spores could complete an important step of meiosis, crossing over, but the live spores do not. The single mass of DNA seen in many asci, most of which give rise to dead spores (BODDY et al. 2001 ), indicates that the chromosomes are held together, we presume by Holliday junctions. It is possible, however, that the dead spores complete crossing over but the chromosomes are held together by another feature, such as sister chromatid cohesion. In this case Mus81 would be implicated in the release of sister chromatid cohesion, but this possibility is not supported by the known endonuclease activity of Mus81 and the suppression of the low viable spore yield in mus81 mutants by a rec12 mutation (BODDY et al. 2001 ; GAILLARD et al. 2003 ).

To test the requirement for Mus81 in gene conversion, we examined recombination at the ade6 locus, at which intragenic recombinants arise almost exclusively by gene conversion, not crossing over (GUTZ 1971 ). We used the hotspot allele ade6-M26 (G1010T) to increase the frequency of gene conversion so that recombination could be reliably measured in the low yield of viable spores from mus81 mutants. In crosses with ade6-469 (C2342T) the Ade⁺ recombinant frequency in the mus81 mutant was slightly increased, from 3.7 x 10^-3 in mus81⁺ cells to 5.8 x 10^-3 in the mus81 mutant, at the standard temperature for meiosis (25°), and slightly decreased, from 7.8 x 10^-3 to 4.6 x 10^-3, at 34° (Table 2). Thus, gene conversion with the hotspot allele ade6-M26 is only slightly altered, if at all, by the mus81 mutation.

Gene conversion with the nonhotspot allele ade6-M375 (G1007T) was too low for accurate measurements in mus81 mutants, but from the few Ade⁺ spores obtained, the recombinant frequency did not seem to be lower than that in mus81⁺ strains (Table 2 and data not shown). We noted in other experiments that the viable spore yield of mus81 mutants was 50 times higher at 34° than at 25°; the viable spore yields of mus81 mutants at these temperatures were, respectively, 0.75 and 0.013% of those of mus81⁺ cells. The reason for this difference is unclear, but it allowed us to measure gene conversion with the nonhotspot allele ade6-M375. At 34° the recombinant frequency in crosses between ade6-M375 and ade6-469 was about twice as high in mus81 mutants as in mus81⁺ strains (Table 2). We conclude that Mus81 is not required for gene conversion; the conversion frequency in mus81 mutants is as high as that in mus81⁺ cells and perhaps even higher.

The properties of S. pombe and S. cerevisiae mus81 mutants differ. S. cerevisiae mutants lacking Mus81 or its partner Mms4 have higher spore viability (10–50%, depending on the strain used), have higher frequencies of crossing over (40–180% of MUS81 strains, depending on the interval measured and the strain used), and are delayed or arrested at the pachytene stage of meiosis; these phenotypes are not noticeably suppressed by RusA (INTERTHAL and HEYER 2000 ; DE LOS SANTOS et al. 2001 2003 ; MULLEN et al. 2001 ). In all strains tested, however, viable spore yields are strongly reduced relative to wild type, indicating that Mus81 plays a vital role in meiosis in both S. cerevisiae and S. pombe. In both organisms, mutants lacking Mus81 or its partner are sensitive to methyl methanesulfonate and UV during mitotic growth and have nearly wild-type frequencies of meiotic gene conversion (Table 2; BODDY et al. 2000 2001 ; INTERTHAL and HEYER 2000 ; DE LOS SANTOS et al. 2001 2003 ). These results indicate that some but not all functions of Mus81 differ in the two yeasts. DE LOS SANTOS et al. (2003) concluded that there are two pathways of meiotic recombination in S. cerevisiae: one requires Mus81·Mms4 and shows no interference between closely spaced crossovers and the other shows interference but is Mus81·Mms4 independent. They proposed that S. pombe has only the former pathway. This proposal is consonant with our observation of the near lack of crossovers in S. pombe mus81 mutants (Table 1) and the lack of crossover interference in S. pombe (MUNZ 1994 ).

The results presented here show that S. pombe Mus81 is required for crossing over but not for gene conversion. A similar but less dramatic separation of the two types of recombination is seen in S. cerevisiae and Drosophila melanogaster: mutations in several genes reduce crossing over by a factor of 10 or less but have less effect on conversion (CARPENTER 1982 ; ROEDER 1997 ). In S. pombe, S. cerevisiae, and D. melanogaster both types of recombination require a set of proteins, including Rec12 (Spo11 or Mei-W68), that is also required or presumably required for meiotic DNA double-strand break formation (ROEDER 1997 ; MCKIM and HAYASHI-HAGIHARA 1998 ; MCKIM et al. 1998 ; DAVIS and SMITH 2001 ). Thus, both types of recombination appear to stem from a common precursor, whose transformation into crossovers or convertants requires different sets of proteins. This view is embodied in most models of recombination.

A basic question still unanswered is the point at which the pathways for conversion and crossing over diverge. The models of HOLLIDAY 1964 and most others propose that they diverge at the final step, the resolution of the Holliday junction. ROMAN and FABRE 1983 , CARPENTER 1987 , and others have suggested, however, that conversion and crossing over are not so closely related. Recent data show that hybrid DNA with crossover configuration and that with noncrossover configuration in S. cerevisiae can be both temporally and genetically separated (ALLERS and LICHTEN 2001 ; HUNTER and KLECKNER 2001 ). The strong separation of crossing over and conversion reported here also argues against the simple view that crossing over and conversion differ only by the mode of Holliday junction resolution. Convertants arise without Mus81·Eme1 endonuclease and, we argue, without resolution of Holliday junctions and perhaps without their formation. Further studies of S. pombe mus81 mutants may help elucidate the step at which the pathways for conversion and crossing over diverge.

	ACKNOWLEDGMENTS

We thank Sue Amundsen, Gareth Cromie, Luther Davis, Joe Farah, and Walter Steiner for comments on the manuscript. This research was supported by research grants GM-32194 to G.R.S. and GM-59447 to P.R. from the National Institutes of Health; M.N.B. is a Research Special Fellow of the Leukemia and Lymphoma Society.

Manuscript received August 14, 2003; Accepted for publication September 2, 2003.

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	NOTE ADDED IN PROOF

OSMAN et al. (2003, Mol. Cell 12: 761–774) also have recently reported that crossing over, but not gene conversion, is strongly reduced in S. pombe mus81 mutants.

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