I x IOS. 0. 1 x 10". 1 x lox. 1 x IOX. CM-1027. CYCI -71 ICYCI -I 66. 3 x IO5. 0 ..... chrome c. combination observed for heteroallelic diploids bear- ing cycl-166 ...
Copyright 0 1988 by the Genetics Society of America
Differential Mismatch Repair Can Explain the Disproportionalities Between Physical Distances and Recombination Frequencies of cycl Mutations in Yeast Carol W. Moore,**'D. Michael Hampsey,"?' JoachimF. E r n ~ t * and ~ ~Fred *Department of Biophysics and ?Department of Biochemistry, University of Rochester School Rochester, New York 14642 Manuscript received February 2, 1987 Revised copy accepted January 30, 1988
of
Medicine and Dentistry,
ABSTRACT Recombination rates have been examined in two-point crosses of various defined cycl mutations that cause the loss ornonfunctionofiso-l-cytochrome c inthe yeast Saccharomyces cerevisiae. Recombinants arising by three different means were investigated, including X-ray induced mitotic recombination, spontaneous mitotic recombination, andmeiotic recombination. Heteroallelic diploid strains were derived by crossing cycl mutants containing a series of alterations at or near the same site to cycl mutants containing alterations atvariouis distances. Marked disproportionalities between physical distances andrecombinationfrequencieswereobserved with certain cycl mutations, indicating that certain mismatched bases can significantly affect recombination. The marker effects were more pronounced when the two mutational sites of the heteroalleles were within about 20 base pairs, but separated by at least 4 base pairs. Two alleles, cycl-163 and cycl-166, which arose by G-C+C-G transversions at nucleotide positions 3 and 194, respectively, gave rise to especially high rates of recombination.Othermutationshavingdifferentsubstitutionsatthesamenucleotide positionswere not associated with abnormally high recombination frequencies. Wesuggest that these marker effects are due to thelack of repair of eitherGIG or C/C mismatched base pairs, while the other mismatched base pair of the heteroallele undergoes substantial repair. Furthermore, we suggest thatdiminishedrecombinationfrequenciesare due totheconcomitantrepair of both mismatches within the same DNA tract.
D
EFINED cycl mutants of the yeast Saccharomyces cerevisiae have been used to investigate the relationships between the frequencies of recombination of heteroaileles and the nature of the mutational changes. Previous studies demonstratedthat various heteroallelic pairs of cycl mutations gave rise to a wide range of recombination frequencies that could not be simply related to the distances between the lesions; these studies included measurements of meiotic and mitotic recombinationoccurringspontaneously, aswell as mitotic recombination induced with X-rays, UV (ultravioletlight) andnear-UV (MOOREand SHERMAN 1975; 1977). We have chosento study mutations having variety a of different alterations within small regions,some affecting the same or adjacent base pairs. Our approach is to examine recombination in heteroallelic diploidswhere one cycl allele is one of a series containing alterations at or near the same site and I Present address: City University of New York Medical School, Department of Microbiology,ScienceiMarshakBuilding,138thStreet at Covent Avenue, New York, New York 10031. Present address: Department of Biochemistry and Molecular Biology, LSU Medical Center, 1501 Kings Highway, Shreveport, Lousianna 71130. Present address: Glaxo Institute for Molecular Biology S . A., Route des Acacias 46, 121 1 Geneva 24, Switzerland. To whom correspondence should be addressed.
'
Genetics 119: 21-34 fMav. 1988).
theother cycl allele carriesamutationat various distances from theother alteration. Systematic studies of this kind can elucidate the effects of specific types of mutationalchanges, andthe distances between them, on recombination frequencies. The sites of numerous c y 1 mutations were originally estimated by deletion mapping and two-point crosses (SHERMAN et al. 1975). In addition, the mutational changes for many of the cycl mutations were deduced from altered iso-l-cytochromes c in intragenic revertants (SHERMAN and STEWART 1978). Clusters of different types of mut'ations within small regions were uncovered from these studies, including numerous alterations at or near sites corresponding to the ATG initiator codon and the TGG tryptophan 64 codon. In a previous study of the effect of DNA sequences on genetic recombination (MOOREand SHERMAN 1977), heteroallelic diploid strains containing alterations at or near the ATG initiator codon wereinvestigated. In that study, however, thenucleotide sequences of some of the cycl mutations could not be completely defined from altered iso-lcytochromes c, especially if a cycl mutant completely lacked iso-l-cytochrome c and if intragenic revertants contained only normal iso-l-cytochrome c, or if the
C. W. Moore et al.
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AT188 (LG189
G194 G199 1193 G195 G194 -C -A
G214
-1
-G
-1
-1
FIGURE4.-The rates of X-ray-induced mitotic recombination for heteroallelic crosses involving mutations at nucleotideposition 15, and within positions 188-214. T h e black bars represent the crosses with an isogenic series of MATa haploid strains listed in Table 1; the white bars represent the mean frequencies of other diploid crosses involving the same allelic pairs hut not the isogenic 4 andaltered series. T h e recombinationdataarefromTable nucleotides are from Table 1.
cycl-71 cycl-84
cycl-166 cycl-189 csl-131 csl-72
AT188 G 1 9G 41 - A9G 41 - C9151*9TG 3 -1G9 9 - 1 &G189
FIGURE 6.-The frequencies of meiotic recombination of strains described in the legend of Figure 4 and in Table 1.
tribution of residual growth of missense mutants to recombinationalfrequencies. We can be confident, therefore, that the distinctly higher spontaneous and X-ray-induced mitotic and spontaneous meiotic re-
Mismatch Repair in Yeast
29
TABLE 7 Segregants from a cycl-84/cycl-166 cross and the spontaneous and X-ray-induced mitotic recombination frequenciesof the correspondingcycl-84icycl-71, cycl-166/cycl-71, cycl-84/cycl-76 and cycl -1 66Icycl-76heteroallelic diploids ~~
~
~~
Mitotic recombination Approximate total cytochrome c
Crosses Strain
(7c)
with q c I - 7 1 9Cl Spontaneous allele” X-rav
Crosses with q c l - 7 6
Spontaneous
X-ray
~~
CM163-1A CM163-1D CM163-1B CM163-1C
60 60
CM 163-2A CM 163-2C CM163-2B CM 163-2D
60 40
CM 163-4.4 CM 163-4B CM163-4C CM 163-4D
40 60
3 3
B-589 CM143-13C B-686 D533-2B
42 86 1.9 1 .a 44 174
~ J c-1l 66 cycl-166 cycl-84 CYCI-84
66
3 3
cycl -1 66 C ) C ~-1 cycl-84 Cycl-84
1.1
79 119 5.6
~ycl-166 CJC~-166 c y ~-84 l c y 1 -84
3 3
8.9 1 .5
c y 1 -84 c y 1 -84 ~ycl-166 c~cl-I66
3 3
60 60
T h e cycl-84 segregants were distinguished
1.2 187 194
314 385 58 82 425 308 39 40
103 74 87 52 -6 -
3640 3230 187 347 3200 2450 525 79
763 980 118 72
124 -
2150 4250 400 394
50 119 26 1 436
21 22 114 243
726 889 3220 2660
from cycl-166 segregants by the intensities of C,-band absorption at low temperature
( - 196°C); cycl-84 strains completely lack iso-l-cytochrome c and contain only the low-level of iso-2-cytochrome c (approximately 5%),
whereas cycl-166 strains contain approximately 50% of the normal amount of iso-l-cytochrome c. Dashes indicate not determined.
’
DISCUSSIOK TABLE 8 Segregants from a cycl-84/cycl-l32cross and the X-ray-induced recombination rates of the correspondingcycl-84icycl-71 and the cyel-l32/cycI-71 heteroallelic diploids ~~
X-ray-induced
Approximate total cytochrome c“
Strain no.
(R)
CM239-1A CM239-1B CM239-IC CM239-1D
3
5 50 30
qcl allele
CYCI-84 cycl-84 cycl-132 cycl-132
40 32 2.7 4.4 36 45 0.70 1.4
CM239-2A CM239-2B CM239-2C CM239-2D
5 50 50
c y 1 -84 Cycl-84 qtl-I32 cycl-132
B-652 (MATa parent) CM143-13C ( M A T a parent) B-589 CM539-9C
50 5 5 40
C Y C-132 ~ c y 1 -84 CJCI-84 cycl-132
3
recombination of q c l - 7 1 crosses
3.9 119 50 2.8
Segregating alleles were identified by the intensities of C,band absorption at low temperature ( - 196°C); cycl-84 strains completely lack iso-l-cytochrome c and contain only the low-level of iso-2-cytochrome c (approximately 5%),whereas cycl-132 strains contain approximately 50% of the normal amount of iso-l-cytochrome c.
combination observed for heteroallelic diploids bearing c y c l - 1 6 6 , when compared to c y c l - 8 4 , reflect the contribution of the differentbase substitution in cycl166.
The studies of spontaneousand X-ray-induced mitotic and spontaneous meiotic interallelic recombination of cycl mutations reveal pronounced effects of DNA sequences on all three types of recombination. In previous papers (MOOREand SHERMAN 1975, 1977), we emphasized the lackof correspondence between physical distances and recombination rates derived from heteroallelic diploids by several mapping procedures. Mean rates of spontaneous mitotic recombination (prototrophs per 10’ cells per generation) for the heteroalleles ranged from 0.02 to 12 per base pair; mean frequencies of X-ray mapping milliunits (prototrophsper10” survivors perrad) ranged from 0.3 to 1.6 per base pair; meiotic recombination (prototrophs per 10’ asci) ranged from 0.18 to 9 per base pair. In theearly studies of the mutations in the initiator codon (MOOREand SHERMAN 1975, 1977), as illustrated in Figures 2 and 3, the cycl-131 mutant always yielded lower recombinationfrequencies thanthe cycl-51 mutant, even though both are altered at the same base pair. Moreover, the low and high recombination characteristics segregated with the c y c l - I 3 1 and cycl-51 allele, respectively, indicatingthat the different rates were attributable to the specific allele, and also indicatingthatthedifferencescanoccur with mutants having different alterationsof the same base pair. Similar studies demonstrated that crosses with the c y c l - 1 6 3 mutantexhibited unusually high
30
C. W. Moore et al.
frequencies of recombination; these studies included analogous crosses containing the c y c l - 1 3 and c y c l - 8 5 mutants, even though all three have different substitutions of the same base pair. A similar pattern of disproportionalities was observed with the tryptophan64 mutations. The highest frequencies of all three types of recombination per base pair involved cycl -I 66. The highest spontaneous mitotic and meiotic recombination per base pair were exhibited with the cycl-166lcycl-71 crosses (19.3 & 10.4 prototrophs/lO* cells/generation and 15.2 prototrophs/lO' asci, respectively; Figures 5 and 6, Tables 5 and 6); the mean value of mitotic recombination was 37 times higher, and the mean value of meiotic recombination was 36 times higher, than crosses of c y c l - 7 1 to the other mutant altered at the same base pair, c y c l - 8 4 . The highest frequencyof X-ray induced mitotic recombination per base pair was exhibited in cycl-166/cyc1-76 diploids (155 & 34 prototrophs11 0' survivors/rad;Figure 4, Table 4), where the mean value of recombination was 6.0 times higher than in c y 1 - 8 4 / c y c 1 - 7 6crosses. Crosses of c y c l - 1 6 6 with cycl7 1 and c y c l - 1 5 8 also exhibitedunusuallyhigh frequencies of X-ray-induced recombination per base pair(80.7 5 42.2 and 101.6 5 13 prototrophs/lO" survivors/rad, respectively; Figure 4, Table 4); these mean values were 7.9 and 2.4 times higher, respectively, than crossees of cycl-84 with these two tester mutants. T h e complexity of the data shown in Figures 2-6 reveal the difficulty in deducing simple generalizations concerning disproportionalities of recombination frequencies. Nevertheless, we wish to emphasize certain tendencies. Crosses of c y c l - 2 3 9 to the initiator mutants, whose mutations are separated by distances of not more than 14 base pairs, yielded variable and some unusually high ratesof recombination per base pair, whereascrosses of c y c l - 7 6 to these same initiator mutants, at distances of greater than 200 base pairs, yielded lower and more uniform values (Figures 2 and 3). The same pattern is observed for similar crosses to the tryptophan 64 cluster of mutations. In this case crosses to c y c l - 7 6 , at distances of less than 20 base pairs, yielded variable recombination frequencies, whereas crosses to c y c l - 2 3 9 , at distances of greaterthan 180 base pairs, yield moreuniform values. These results indicate that crosses of mutations having lesions in close proximity are morelikely to reveal the markereffects that distort recombination frequencies. In order to define the lesions that distort recombination frequencies, we have analyzed different base substitutions at the same site. Although no quantitative results can bededuced, as will be discussed below, the lower values of crosses with c y c l - 1 3 1 , c y c l - 1 3 3 , and c y c l - 8 4 suggest that G/T or CfA and G/A or C / T mismatches are associated with lower recombination frequencies. On the other hand, thehigh values
of crosses with c y c l - 1 6 3 and c y c l - 1 6 6 suggest that G/ G o r C/C mismatches are associated with enhanced frequencies of all three types of recombination (Figures 2-6). Thus, it appearsthat certain base-pair mismatches, when separated from the accompanying mismatch by less than about 20 base pairs, account the for observed anomalous recombination frequencies. The only other pertinent information on the specificity of marker effects in bakers' yeast comes from the study of KURJANand HALL (1982), who determined meiotic recombination frequencies of defined mutations of the S U P 4 gene, which encodesa tRNATy'. Similar to our results, certain of the S U P 4 mutations showed aberrant recombination frequencies. The most abnormally high values were observed with crosses containing the M50 mutation, which was theresult of a G-C-+C.G transversion. However, other mutations with G-C+C*Gsubstitutionsdid not yield unusually high frequencies of recombination. It appears that certain GIG or C/C mismatches, when in combination with certain other mutations or in certaincontexts, cause higherfrequencies of recombination. We suggest the following mechanism to account for the observed disproportionalityof recombination frequencies and physical distances. First, we believe that recombination proceeds by way of an extensive heteroduplex region thatusually encompasses at least one-third of an averagegene. This assumption is based on the patterns of co-conversion during meiotic 1981; DICAPRIO and (FOGEL,MORTIMERand LUSNAK HASTINGS 1976) and mitotic (GOLINand ESPOSITO 1981,1984; AHNand LIVINGSTON 1986; GOLIN,FALCO 1986) recombination. If two mutaand MARGOLSKEE tional sites are far apart, one end-point of the heteroduplex region will likely fall between the two sites. If, however, the mutational sites are close together then both of them will be included within the same heteroduplex region.Second, we suggest thatthe base-pair mismatches within theheteroduplexare repaired by excision and resynthesis. Although there may be a wide range of frequencies associated with the same type of mismatch, and these frequencies would probably be influenced by theneighboring nucleotides, G/G or C/C mismatches generally would be associated with higher frequencies of recombination per physical distance, especially if the two mismatches of the heteroallelic pair are within about 20 base pairs of each other.These results are most simply explained by assuming that the G/G or C/C mismatch is not repaired because excision is inhibited at this mismatch, whereas the mismatch at the other site remains in the excision tract and is corrected. Recombination would then be higher as a result of the two mismatches being corrected with different efficiencies. This mechanism is schematically illustrated in Fig-
Mismatch Repair in Yeast I
I1 No repair, no recombination:
2 Y-S" vr a
a+@ a n d a b +
b+
u L
Repair of sites I and 11. no recombination:
7
or
a+ a-
b-
a+& a b+
or
+ c===w=======\c b+
a
b+
a+
b'
a+
b+
Repair of sites I, recombination:
a+b'
and
a+ b+
A v
and
a-
or
a-
a
b+
a+
8
or
a- b-
b+
Repair of sites 11, recombination:
d-fie aor
a+ b- and a- b-
bor b+
a+ b+ and a- b+
A vv a b+
FIGURE7.-A schematic diagram, illustrating the outcome of repair of two mismatched base-pairsat sites I and I1 of the heteroallelic cross a + b- x a- b+ .
ure 7 forthe heteroallelic cross a + b - X a - b + , containing mismatches at sites I and 11. If no mismatch repair took place at either site then recombination would not occur between them. If excision and repair of the mismatches at both sites on the same strandoccurred with high efficiency, or if excision and repair occurred at single tracts encompassing both sites, then recombination between them also would not occur. However, recombinationwould take place if corrections occurred at site I but not site 11, or at site I1 but not site I. Recombination also would occur if site I and site I1 were independently corrected such that the corrections occurred in separate strands of the heteroduplex. This model can befurther illustrated by examining the frequencies of X-ray-induced recombination of the selected examples presented in Figure 2. In these ideal cases, the absolute frequenciesof recombination are approximately the same for thecycl-163/cycl-239 and cycl-l63/cycl-76 crosses, where the mismatch at base-pair position 3 isG/G (or C/C). On the other hand, the absolute frequencies of recombination of the cycl-85lcycl-239 and cycl-85lcycI -76 crosses, where the base-pair position 3 mismatch isA/A (or TIT), are not independent of the distances between the mismatches. This observation indicates that the GIG (or C/C) mismatch has the effect of raising the absolute frequency of recombination to the level seen when the markersare far enough apart to be distanceindependent. However, if the mismatches are not
31
separated by at least 4 base pairs, noenhanced recombination is observed for crosses involving G/G o r C/C mismatches. This can be seen for the crosses of cycl-166 to cycl-84, cycl-189 and cycl-72 (Figure 4). Ifa G/G or C/C mismatch retardstherepair system, onecan envision that these GIG or C/C mismatches prevent the repair of the accompanied mismatch if it is in very close proximity such that the enzyme complex responsible for repair encompasses both sites. Information concerning the meiotic repair of specific mismatched lesions has come from the studies Of WHITE, LUSNAKFOGEL and (1985). The frequencies of postmeiotic segregation of heterozygous and heteroallelic crosses have been suggested to reflect the meiotic frequencies of repair of heteroduplex mismatches during genetic recombination. T h e heterozygous pair ARG4/arg4-16, which forms C/C or GIG mismatches, gave rise to a high frequency of postmeiotic segregation (33%), whereas the other pairs, ARG4/arg4-17" and arg4-17"/arg4-17", which can form A/A or T/T andA/C or G/T, respectively, gave rise to lower frequencies of postmeiotic segregation (4 to 5%). These results suggestthat G/G or C/C mismatches are less efficiently corrected than A/A or T/T and A/C or G R mismatches. FOGELet al. (1979) also observed that when single heterozygosity is introduced on either side of the arg4-16 mutation the basic conversion frequency remained the same, but the proportion of conversions increased at the expense of the class of postmeiotic segregation, which in turn reduced to approximately lo%, or one-third of the value, of the single arg4-16 heterozygous cross. Similar results were observed with his1 mutations by HASTINGS (1984). The simplest interpretation of these findings is that the arg4-16 and other mismatches are not efficiently repaired, but additional mismatches within the same heteroduplex tract enhance their repair. Further information pertaining to repair of mismatched bases comes from the studies of MUSTERNASAL and KOLODNER (1986) who examined a yeast cell-free system that catalyzes the repair of heteroduplex DNA. Their results suggest that repair tracts are shorter than one kilobase and are on the order of 10 to 20 nucleotides in length. Their data also indicatethat GIG mismatches are notrepaired in uitro, but C/C mismatches are, suggesting that G/G rather thanC/C is the mismatch responsible for repair inhibition. Their results resemble thepatterns of mismatch repair observed in vitro with various prokaryotes (Lv, CLARK and MODRICH1983; CLAVERYS et al. 1983; LACKS, DUNN and GREENBERG 1982; WAGNER et al. 1984; DOHET,WAGNER and RADMAN 1985; KRAMER,KRAMERand FRITZ1984). However, we do not believe thatthequantitativerelationshipsobserved in uitro should necessarily correspond exactly to quantitativerelationships of the frequencies of
32
C . W. Moore et al.
postmeiotic segregation and recombination observed in vivo, since these in vivo data represent deduced frequencies of mismatch repair. Moreover, the frequency of mismatch repair is likely to be affected by the sequences in the immediate vicinity of the mismatch, ashas been observed for repair in Streptococcus LACKS 1986; LACKS, DUNN pneumoniae (CLAVERYS and and GREENBERG 1982). The model presented in Figure 7 is based on the premisethattracts of mismatch repairareshort. Although this is consistent with the in vitro results of BISHOP and KOLODNER (1986) and MUSTER-NASSAL and KOLODNER(1986), meiotic studies of heteroallelic crosses involving co-conversion of markers with high and low frequencies of postmeiotic segregation suggest that mismatched repair tracts may be long and may cover distant sites (FOGEL,MORTIMERand LUSNAK 1983). This is analogous to mismatch repair in E . coli, in which the excision and resynthesis tracts are several kilobases long (Lu et al. 1984). In order to consolidate these findingsof the effect of adjacent heterozygosity on the frequencies of postmeiotic segregation with the findings reported in this paper and those of MUSTER-NASSAL and KOLODNER(1986), we propose that yeast has two excision-repair pathways that process heteroduplex DNA intohomoduplex structures. These are a long tract and a short tract system that are similar to the two systems found in S . pneumoniae and possibly in E . coli. By using the pneumococcal transformation system, SICARD et al. (1985a,b)observed an aberrant marker that appeared to enhance recombination frequencies when crossed to other heteroalleles of the same locus, a finding that is formally similar to the findings reported here. Furtherexperimentssuggestedthattheenhanced recombination was due to mismatch repair of a short tract of 3 to 27 base-pairs and that this short-tract repair system differedfromthemismatch-repair system that involves 2000-3000 base pairs and is controlled by the hex genes of S. pneumoniae. Shorttractrepair also has been observed with bacteriophage, but only with specific structures (LIEB1983; LIEB, ALLEN and READ 1986). In summary, we propose that disproportionalities between physical distances and recombinationfrequencies can be explained by differential mismatch repair. Enhanced recombination results from diminished G/G (or C/C) mismatch repair within an excision tract that includes the adjacent mismatch. Furthermore, we suggest that this specificity takes place because the excision tract is blocked at the site of the G/G or C/C mismatch. Conversely, we suggest that diminished recombination generally is caused by the concomitant excision and repair of both mismatches within the same tract. Although other mechanisms can be proposed to explain the data presented here, our model allows specific predictions. Recombination
would be greatly diminished if both mismatches were either particularly prone to repair or resistant to repair. For example, heteroallelic pairshaving two G.C+C*Gchangesshould have especially low frequencies of recombination because neither is repaired, and heteroallelic pairs having two small insertions or deletions(such as cycl-239 or cycl-71) should have low frequencies of recombination because both are concomitantly repaired. Furthermore, our model predicts that aG.C mismatch would inhibit excision alongthetract,apredictionthat is now feasible to test i n vitro. This model also predicts that recombinationfrequency involving one G.C+C-G mutation would tend to be independent of the distances separating the two sites within the heteroduplex region. We wish tothank P. J. HASTISGS(DepartmentofGenetics, University of Alberta, Edmonton, Canada) and A. T. C. CARPESTER (Department of Biology, University of California, San Diego) for useful discussions and suggestions, and for critically reading the manuscript. The technical assistance of L. POLOGE,M. JOSES and H. DA CRUZis gratefullyacknowledged. This investigation was supported by National Science Foundation grant BMS 7513172, AmericanCancer Society grant VC-190, United States Public Health Service Research grants R01 GM12702 and CA25609 and TraininggrantT32 GM07089 fromthe National Institues of Health. D.M.H. was the recipient of an American Cancer Society Postdoctoral Fellowship, PF-2347.
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