(CA/TG) Microsatellite Sequences Escape the Inhibition of Recombination by Mismatch Repair in Saccharomyces cerevisiae

Corresponding author: Marie Dutreix, UMR-CNRS 2027, Institut Curie-section de Recherche, Bât 110, Université Paris-Sud, F-91405 Orsay, France., marie.dutreix{at}curie.u-psud.fr (E-mail)

Communicating editor: L. S. SYMINGTON

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

Sequence divergence reduces the frequency of recombination, a process that is dependent on the activity of the mismatch repair system. In the yeast Saccharomyces cerevisiae, repair of mismatches results in gene conversion or restoration, whereas failure to repair mismatches results in postmeiotic segregation (PMS). By examining the conversion and PMS in yeast strains deficient in various MMR genes and heterozygous for large inserts (107 bp) with either a mixed sequence or a 39 (CA/TG) repetitive microsatellite sequence, we demonstrate that: (1) the inhibition of conversion by large inserts depends upon a complex containing both Msh2 and Pms1 proteins; (2) conversion is not inhibited if the single-stranded DNA loop in the heteroduplex is the microsatellite sequence; and (3) large heteroduplex loops with random sequence or repetitive sequence might be repaired by two complexes, containing either Msh2 or Pms1. Our results suggest that inhibition of recombination by heterologous inserts and large loop repair are not processed by the same MMR complexes. We propose that the inhibition of conversion by large inserts is due to recognition by the Msh2/Pms1 complex of mismatches created by intrastrand interactions in the heteroduplex loop.

THE meiotic cell cycle of Saccharomyces cerevisiae is an excellent model for studying homologous recombination mechanisms. Recombination is induced during meiosis, resulting in at least one reciprocal recombination event between each pair of homologous chromosomes. This interaction is thought to be necessary for the proper pairing and segregation of homologous chromosomes during the first meiotic division (PADMORE et al. 1991 ). The resulting recombination events can be easily scored by studying the segregation of markers in yeast ascospores by tetrad analysis.

It has been found that recombination is regulated to prevent interactions between divergent sequences (BAILIS and ROTHSTEIN 1990 ; CHEN and JINKS-ROBERTSON 1999 ; COIC et al. 2000 ). The role of the mismatch repair system (MMR; KOLODNER 1996 ) in regulating recombination was first described in Escherichia coli (RAYSSIGUIER et al. 1989 ; SHEN and HUANG 1989 ). The frequency of homologous recombination was found to be 1000 times greater than that of homeologous recombination (recombination between DNA sequences diverging by up to 10%) in the wild-type strains, whereas these two frequencies were similar in mutS and mutL mutants. Various studies in S. cerevisiae have indicated that the MutS homolog, the Msh2 protein, is also involved in regulating recombination between divergent sequences: Msh2 is a component of all known yeast MMR complexes and it functions as a heterodimer with either Msh3p or Msh6p in mismatch recognition (ALANI et al. 1995 ; JOHNSON et al. 1996 ; MARSISCHKY et al. 1996 ). Pms1p and Mlh1p, the primary yeast MutL homologs in MMR, form heterodimers, and disruption of either of the corresponding genes results in a mutation frequency similar to that in msh2 mutant strains. These observations suggest that MMR is carried out principally by a complex containing a Mlh1p-Pms1p heterodimer and either a Msh2p-Msh3p or a Msh2p-Msh6p heterodimer (KOLODNER 1996 ).

Various models of meiotic recombination have been proposed (SZOSTAK et al. 1983 ; PETES et al. 1991 ; PAQUES and HABER 1999 ). All predict the formation of a heteroduplex due to invasion of the intact duplex by a homologous single-stranded DNA and subsequent branch migration. During recombination between homeologous chromosomes or highly polymorphic repetitive sequences on homologous chromosomes, loop intermediates may result from heteroduplex formation. Their repair results in gene conversion or restoration, whereas a failure to repair results in postmeiotic segregation (PMS). PMS events are characterized by the presence of two genotypes in a single haploid spore (ESPOSITO 1971 ). A recent study with a 26-bp insertion demonstrated that small loops formed during recombination are repaired by DNA-mismatch repair proteins and nucleotide-excision repair proteins (KIRKPATRICK and PETES 1997 ). However, loops formed by a palindromic sequence were poorly repaired as shown by the high rate of PMS observed in MMR-proficient cells (NAG et al. 1989 ). This suggests that the secondary structure of the loop may affect its processing by MMR enzymes during recombination.

We tested this hypothesis by assessing the effect of large inserts with various sequences on heteroduplex formation and repair. In a previous work it has been shown that some single-stranded DNA sequences with repetitive sequences do not form secondary structures (BIET et al. 1999 ). For this study we chose a microsatellite sequence containing tracts of CA/TG dinucleotide repeats because the sequences on each strand have been shown to not form secondary structures.

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

Plasmids and strains:
All plasmids are derived from the plasmids L1.1 (DE MASSY and NICOLAS 1993 ). The 2-bp insertion (RV), the microsatellite (MS), and the random (RS) sequences are inserted into the EcoRV site (+262 bp) of the ARG4 gene coding region on only one of the homologous chromosomes (heterozygous situation). The RS1 and RS2 inserts are PCR fragments amplified from the M13mp19 bacteriophage (positions 1030–1137) and pUC18 (positions 304–411), respectively. MS insert is the XbaI-HindIII fragment from the bacteriophage M13mp19 (CA/TG)₃₉ (DUTREIX 1997 ) containing a sequence of 39 (CA/TG) repeats. The modified ARG4 regions were introduced at the ARG4 locus on chromosome VIII of the strains ORD11-4B and ORD17-47C. Sequences of the constructions were checked by PCR amplification and sequencing using an ABI PRISM. The poly (CA/TG) tract was oriented such that the poly(CA) repeats were in the transcribed strand. All the S. cerevisiae strains used in this study have the MGD background (ROCCO et al. 1992 ). They derived from the strains ORD11-4B [MAT arg42060 ura3-52 trp1-289 leu2-3 ade2-101 dup KV(DED82-arg(HpaI)-YSC83)] and ORD17-47C [MATa arg42060 his31 DED82::URA3 ORF83:: TRP1 dupKV(DED82-arg(HpaI)-YSC83)] (LICHTEN et al. 1990 ). DED82::URA3 and YSC83::TRP1 correspond to a 1.5-kb EcoRI TRP1 fragment and a 1.2-kb HindIII URA3 fragment inserted into the DED82 BamHI site and the YSC83 BglII site, respectively. To complement deficiencies created upon disruption of the essential genes DED82 and YSC83, a 12-kb fragment was inserted into ApaI-StuI of the URA3 gene at its normal chromosomal position on chromosome V. This insert, designed dupKV[DED82-arg(HpaI)-YSC83], contains the ApaI-SnaBI fragment of the ARG4 region deleted from a 2-kb fragment from -316 bp to +1745 bp that carries the ARG4 gene (2060). All strains used in this study bear the Poly(I) substitution. The pms1 and msh2 mutations were introduced into various strains by crosses with the strains RKY1939 (MATa ura3-52 trp1-289 ade2 his31 msh2::Tn10LUK7-7 pms1::TRP1) and RKY-1935 (MAT ura3-52 trp1-289 ade2 leu 2-3 msh2::Tn10LUK7-7 pms1::TRP1; ALANI et al. 1994 ). The RKY strain background was also MGD. Because msh2 and pms1 mutants display a mutator phenotype, strains were mated and sporulated after limited growth, as described previously by REENAN and KOLODNER 1992 and ALANI et al. 1994 . At least three crosses between independent haploids were tested for each diploid. Even under these conditions, the pms1 and msh2 mutations resulted in an average 45% decrease in the number of tetrads that contained four viable spores as compared to wild type.

Media, culture conditions, and genetic analysis:
Standard medium (YPD) was used for vegetative growth. Presporulation medium was specific for presporulation (SPS) liquid medium and sporulation was carried out in 1% potassium acetate supplemented with the required amino acids at 30° as described previously (DE MASSY and NICOLAS 1993 ). Tetrads were dissected on YPD plates by standard methods. After 3 days at 30°, the resulting spore clones were replica plated onto various dropout plates. Aberrant segregations were scored 1 day after replica plating. The segregation of ARG4, URA3, TRP1, and at least four additional markers (LEU2, HIS3, ADE2, and the mating type locus MAT) were examined. All tetrads showing sectored colonies were confirmed by streaks on complete medium and replica plating onto Arg drop-out plates.

Statistical analysis:
All results were tested by statistical analysis. Fisher's exact variant of the chi-square test was used for most comparisons and a P value of <0.05 was considered to be statistically significant.

	RESULTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

Lack of conversion inhibition by a large heterologous repetitive sequence:
We introduced various sequences into the ARG4 gene (Fig 1A) at the same position, a locus close to a well-characterized hotspot for meiotic recombination (NICOLAS et al. 1989 ; SUN et al. 1989 ). Two kinds of large inserted sequence, each 107 bp in length, were compared: the MS sequence, which contains a tract of 39 CA/TG dinucleotide repeats, and the RS1 and RS2 sequences, which are two natural sequences with no repeats (GENDREL et al. 2000 ). The two RS sequences tested are capable of intrastrand pairing over short lengths of their sequences (Fig 1B). In contrast, the MS sequence encodes two strands devoid of secondary structure at 32° (BIET et al. 1999 ). We used a construct with a 2-bp insert (RV) as a control. To monitor reciprocal recombination events induced at meiosis, we introduced two genetic markers (URA3 and TRP1) into the flanking regions of ARG4 in some constructs. The genetic markers were located either on the same chromosome as the insert (cis) or on the homologous chromosome, which had no insert (trans; Table 1). The products of meiosis were analyzed by assessing expression of the URA3, TRP1, and ARG4 genes on selective media.

View larger version (21K): In this window In a new window Download PPT slide   Figure 1. (a) Physical map of the ARG4 region located on chromosome VIII. (b) The secondary structures formed by the inserted sequences were determined using the DNA mfold site (http://mfold.wustl.edu/~folder/dna/form.cgi).

Tetrad analysis showed that heterozygous diploids carrying the large repetitive MS insert or the RV allele displayed a high level of gene conversion (15–23% of the tetrads), whereas heterozygous diploids with the large nonrepetitive RS1 and RS2 sequences displayed a low frequency of conversion of the ARG4 region (4–8% of the tetrads; Table 1). A contingency chi-square test indicated that this difference was highly significant (² = 24.6, P < 0.00005). Similar results were obtained with markers in trans (²= 10.5, P < 0.0004). In addition, the two nonrepetitive heterologous RS inserts inhibited conversion, regardless of the sequence to be converted—the insert or the wild-type ARG4 sequence.

The frequency of crossovers is not affected by large heterologous inserts:
During recombination, strands of homologous chromosomes exchange and form Holliday junctions that are resolved by specific resolvases. We assessed the association between conversion events and reciprocal exchange (crossover) of the flanking markers URA3 and TRP1 in diploid strains containing the RV, RS, and MS sequences (Table 1). The total number of crossovers was similar in all strains. Between one-half and one-third of the conversion events were associated with crossovers in the strains containing the large inserts as well as in the RV control strain. However, the large inserts affected the site of crossovers. In the RV strain, crossovers occurred with similar frequency between URA3 and the insert and between the insert and TRP1, whereas in strains containing the RS and MS inserts, more than two-thirds of crossovers occurred in the region between URA3 and the insert, close to the double-strand-break initiation sites (0.02 < P < 0.04; Table 1). These results suggest that, in contrast to the conversion events, the crossovers were similarly affected in heterozygous strains with the MS or the RS inserts.

The low frequency of conversion of RS heterologous sequences is not associated with a high level of PMS:
It has been suggested that conversion and PMS are two alternative fates of mismatches in a heteroduplex. The difference between conversion efficiency of the RS inserts and the MS insert could be due to an efficient repair of the MS loops and a poor repair of the RS loops. The high frequency of conversion and low frequency of postmeiotic segregation for RV and MS reflect a high rate of heteroduplex formation at the ARG4 locus and efficient repair of the resulting loops. Surprisingly, in the RS strains, an excess of PMS did not compensate for the small number of conversions (Table 2). This suggests that either heteroduplexes are not formed or that the loops formed in RS strains are specifically repaired, restoring parental segregation.

Inhibition of conversion by RS heterologies depends upon Msh2 and Pms1 activities:
We tested the repair of the various inserts by analyzing their segregation in msh2 and pms1 mutants defective for mismatch repair. As expected, the number of PMS increased significantly in heterozygous RV diploids deficient in Msh2 or Pms1. In strains with large heterologous inserts, PMS was mainly detected when both MSH2 and PMS1 were mutated. In single msh2 and pms1 mutants carrying the RS insert, the frequency of conversion was restored to the level observed in MS strains. As defects in Msh2 or Pms1 proteins abolish the MMR inhibition of RS conversion, these two proteins presumably act in the same complex to inhibit conversion.

In the msh2 pms1 double mutant, the significant increase of PMS for large inserts indicated that large loops can be repaired by MMR complexes. However, the nature of the mismatch repair complex differs for small and large inserts. The low number of PMS and the high level of conversion in single MMR mutants with a large heterologous insert indicate that either of the Msh2 and Pms1 activities alone is sufficient to repair large MS and RS loops, whereas both activities are required for RV heteroduplex repair. Our results suggest that both Pms1 and Msh2 proteins are involved in the repair of large loops, but as part of two different repair complexes, each able to compensate for a lack of activity of the other.

In the msh2 pms1 double mutant, we observed a slight increase in the 3:5 class of aberrant events. The disparity of 5:3 and 3:5 events was significant only for the MS strain (² = 2.3, P < 0.03). It could indicate a preferential initiation on the chromosome carrying the MS insert. However, in this hypothesis, a similar disparity in the frequency of the conversion events would be expected and yet was not found. The disparity we observed in PMS events reflects preferentially the loss of the wild-type sequence during recombination initiation. This result could be due to preferential replication of the insert-containing strand after strand invasion, according to the double-strand-break repair model (SZOSTAK et al. 1983 ). In our experiments, the disparity was detected only in tetrads in which no correction had occurred, suggesting that this preferential replication of the strand containing the MS repetitive sequence would not be favored in mismatch repair-proficient cells.

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

Several conclusions may be drawn from this study. The first is that, in some situations, DNA sequence plays a major role in the regulation of recombination. Similar conclusions were drawn from studies using heterologous palindromic sequences (NAG et al. 1989 ; MOORE et al. 1999 ) and homozygous repetitive sequences (GENDREL et al. 2000 ). In our experiments, DNA sequence seemed to affect two different steps of recombination: heteroduplex formation and loop repair. In both cases, the recognition of DNA by MMR proteins was the step sensitive to the sequence.

Our results indicate that the S. cerevisiae Msh2/Pms1 complex inhibits RS heteroduplex formation. This has been suggested by ALANI et al. 1994 from the observation that Msh2/Pms1 proteins regulate heteroduplex DNA tract length. Consistent with this model, the MutS/MutL protein E. coli analog inhibits the strand exchange promoted by the RecA protein (WORTH et al. 1998 ). Two MMR complexes, which bind to base-base mismatches (Msh2p-Msh6p) and a small loop insertion (Msh2p-Msh3p), have been found to interact with Holliday junctions (MARSISCHKY et al. 1999 ) and recombination intermediates (EVANS et al. 2000 ). We found that RS large heterologous inserts inhibited conversion. Two models could explain these observations. One is that mismatch repair recognizes intermediates that are formed and destroys them or restores parental segregation as a by-product of repair. The heterozygous region would bias the resolution of recombination intermediates toward restoring the sequence of the invaded duplex rather than copying the invading strand. In this hypothesis we would expect that the total number of recombinant tetrads (PMS and conversions) would increase in MMR-deficient strains since heteroduplex would be detected as PMS. In fact, we observed no significant difference in the frequency of recombinant tetrads in single MMR mutants, which can repair loops, and double mutants, which cannot. Alternatively, some combination of MMR enzymes could recognize the formation of the loop and block the formation of the mature recombination intermediate. In this hypothesis, the inhibitory effect would be due to binding of MMR proteins to the heteroduplex loops.

We found that RS sequences inhibited conversion whereas MS sequences did not. The difference between RS and MS sequences might be due to the poor recognition of repetitive loops by MMR proteins. Two hypotheses can account for the poor binding of MMR proteins to MS loops. Repetitive DNA can adopt Z-DNA structure and has been shown to modify the binding affinity of recombination proteins (BIET et al. 1999 ). However, the observation that defects in mismatch repair strongly increase microsatellite instability suggests that some MMR proteins bind to repetitive sequences. Since we demonstrated that the MMR complex involved in large loop repair is different from the complex involved in conversion inhibition, we cannot reject the possibility that the MMR complex involved in conversion inhibition does not bind efficiently to a loop with repetitive sequence and thus does not promote conversion inhibition of the microsatellite insert. Alternatively, because RS secondary structures are a mixture of single-stranded regions and a short duplex with "mismatched" regions, they could be recognized by MMR proteins (Fig 1B). Such structures are very likely to form on single-stranded DNA with random sequences as long as 107 bp but have been shown to not form in CA or TG dinucleotide repeat tracts (BIET et al. 1999 ). A mixture of single-stranded regions and a short duplex in the heteroduplex could be sufficient for the observed inhibition. In that case, the lack of recombination inhibition by large repetitive MS loops would be due to the poor binding of MMR proteins on single-stranded DNA with repetitive sequence. Actually, in the two models discussed above, primary binding to the single-stranded DNA in the loop would trigger the secondary binding to the junction. We rather favor this last hypothesis since recombination was not inhibited by the 26-bp insert forming a perfect palindrome, but was reduced twofold when mismatches were present in the palindromic structure (NAG et al. 1989 ). The fact that the decrease of recombination by heterologous inserts in our study was slightly higher may be due to the larger size of the insert (107 bp instead of 26 bp) or to differences between recombination at ARG4 and HIS4 loci.

The observation that msh2 mutations greatly increased repetitive sequence instability demonstrates that Msh2p complexes bind to dinucleotide repetitive loops formed by DNA polymerase slippage (SIA et al. 1997 ). Two of the most common types of trinucleotide repeats associated with large expansions in several human diseases are poorly corrected when located in heteroduplexes formed during yeast meiotic recombination. This inefficient correction has been proposed to reflect the ability of the tested repetitive sequences to form hairpin secondary structures within the loop (MOORE et al. 1999 ). This hypothesis is in agreement with the observation that palindromic sequences in heteroduplex DNA are poorly repaired (NAG et al. 1989 ). Our results confirm that loops with repetitive sequences can be efficiently repaired as long as they do not form hairpins.

We demonstrate that RS and MS large loops are similarly recognized and repaired by at least two different MMR complexes (Fig 2). The efficient repair of large loops was suggested by the lack of PMS in all MMR-proficient strains. Similar observations have been reported by others, using larger inserts (FINK and STYLES 1974 ; FOGEL et al. 1981 ). We demonstrated that this repair involved MMR proteins, using msh2 pms1 double mutants. We found that the repair of large loops was not sequence sensitive and was almost as efficient as repair of the 2-bp RV mismatch (Table 2). However, the MMR complexes involved in the repair of large loops and of RV mismatch were different. Two complexes, containing either Pms1 or Msh2, are capable of repairing large loops. In contrast, the RV mismatch correction requires the activity of both Msh2 and Pms1, probably present in a single complex (KOLODNER and MARSISCHKY 1999 ). It is not clear how MMR complexes interact with large loops to repair it since none of the proteins has been found to bind to these structures. The simplest explanation would be that the MMR complexes would recognize DNA structures formed at the junction of homologous and heterologous duplex. Actually, it has been suggested that Msh2/Msh3 complexes could bind to branched DNA structures (SUGAWARA et al. 1997 ).

View larger version (20K): In this window In a new window Download PPT slide   Figure 2. A summary of the various interactions of Msh2 and Pms1 proteins during recombination and heteroduplex repair.

Numerous experiments have shown that MMR inhibits mitotic recombination between homeologous sequences (BAILIS and ROTHSTEIN 1990 ; SELVA et al. 1995 ; DATTA et al. 1997 ; COIC et al. 2000 ). Inhibition of meiotic recombination between homeologous chromosomes was also reported (CHAMBERS et al. 1996 ). However, the results were contradictory concerning the involvement of the PMS1 mismatch repair gene. For example, pms1 mutation had no effect on recombination between 23% diverged sequences, but increased 11-fold in recombination between 10% diverged sequences (DATTA et al. 1997 ). It consistently inhibited recombination to a lesser degree than did msh2. On the other hand, pms1 mutation was reported to increase the frequency of recombination between chromosomes from closely related species (S. cerevisiae and S. paradoxus), the genomes of which were estimated to have diverged by 8–20% (CHAMBERS et al. 1996 ). In our experiments, pms1 and msh2 mutations seem to have a similar effect on inhibition of recombination. In the experiments with homeologous DNAs, all kinds of heteroduplexes were probably formed during recombination, containing high or low density of mismatches, small and large loops with palindromic sequences, and repetitive sequences. Since the recognition by mismatch repair of these different structures seems to involve different protein complexes, the effect of the MMR mutations on the different strains probably reflects the distribution of the different kinds of mismatches that can be formed during recombination.

Our results suggest that different MMR complexes act in the recombination process and in heteroduplex repair (Fig 2). The complex formed by Msh2 and Pms1, together with other proteins, probably recognizes small mismatches and repairs them. In the case of large single-stranded DNA loops included in the heteroduplex, the binding of the complex is likely to inhibit conversion of the region. The correction of the large loop heteroduplex requires two other different MMR complexes, containing either Msh2 or Pms1.

	ACKNOWLEDGMENTS

We thank G. Baldacci for encouragement and support of this work. We thank M. Pierre and N. Thiercelin for efficient technical assistance. Strains were kindly provided by Alain Nicolas and Richard Kolodner. C.G.G. was supported by a fellowship from the Association pour la Recherche sur le Cancer. This work was supported by the Institut Curie (genotoxicology program) and the Centre National de Recherche Scientifique.

Manuscript received April 25, 2001; Accepted for publication September 27, 2001.

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