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Repair of DNA Loops Involves DNA-Mismatch and Nucleotide letters to nature Acknowledgements. We thank T. Tanaka for IL-4 and CT4S cells; S. Nagata for pEF-BOS vector and Jak2 Msh3 or Msh6 and the MutL homologues Mlh1 and Pms1 (refs 6, cDNA; J. Krolewski for Tyk2 cDNA; K. Yasukawa for recombinant IL-6 and sIL-6R; Y. Shima, H. Danno, K. Kunisada and H. Tagoh for technical assistance; H. Saito for discussion; and A. Nobuhara for secretarial 7). Rad1 acts in conjunction with Rad10 to cleave 59 to the assistance. This work was supported by a Grant-in-Aid from the Ministry of Education, Science and pyrimidine dimer during nucleotide-excision repair1. We used Culture, Japan. two different types of mutant his4 alleles: his4-lopd (a 26-base- Correspondence and requests for materials should be addressed to T.K. (e-mail: [email protected]. pair (bp) non-palindromic insertion in HIS4; ref. 5) and his4-AAG osaka-u. ac.jp). The sequence of SSI-1 has been deposited with Genbank, under accession number AB000710. (a base-pair change within the initiating ATG codon of HIS4; ref. 8). Diploid strains heterozygous for one of these alleles and homozygous for rad1, msh2 or both mutations were sporulated and tetrads were dissected. Spore colonies grown on rich medium were replica-plated to medium lacking histidine and scored as Hisþ,His2 and sectored Repair of DNA loops involves Hisþ/His 2 (representing PMS events) (Tables 1 and 2). In DNY27, the wild-type strain heterozygous for his4-lopd, only DNA-mismatch and 12% of the aberrant segregation events represent PMS events, indicating that the 26-base loop expected within the heteroduplex nucleotide-excision is efficiently recognized and repaired. Homozygous rad1 or msh2 mutations increase the frequency of PMS about threefold, demon- repair proteins strating that Rad1 and Msh2 are involved in the repair of large DNA David T. Kirkpatrick & Thomas D. Petes loops. Moreover, they function in the same repair pathway, as the rad1 msh2 mutant has the same PMS frequency as the rad1 and Department of Biology, Curriculum in Genetics and Molecular Biology, msh2 strains. Surprisingly, the rad1 mutation also significantly University of North Carolina at Chapel Hill, Chapel Hill, increases the PMS frequency for his4-lopd when heterozygous, North Carolina 27599-3280, USA suggesting that the RAD1 gene product may be rate-limiting for ......................................................................................................................... repair in the RAD1 MSH2-dependent pathway. rad1 and msh2 A number of enzymes recognize and repair DNA lesions1. The mutations have no significant effect on the crossover frequency in DNA-mismatch repair system corrects base–base mismatches the HIS4 to LEU2 interval (Table 2). and small loops, whereas the nucleotide-excision repair In a wild-type strain heterozygous for the point mutation his4- system removes pyrimidine dimers and other helix-distorting AAG (PD83), we found that 14% of the aberrant segregants were lesions. DNA molecules with mismatches or loops can arise as PMS (Table 2). The rad1 mutation slightly (but significantly a consequence of heteroduplex formation during meiotic (P ¼ 0:03)) increased PMS frequency. In an msh2 derivative, PMS recombination2. In the yeast Saccharomyces cerevisiae, repair of constituted 87% of the total aberrant segregation events, as expected mismatches results in gene conversion or restoration, and failure from previous studies9. From these results, we suggest that Rad1 to repair the mismatch results in post-meiotic segregation (PMS) plays a smaller role in the meiotic repair of base–base mismatches (Fig. 1). The ratio of gene-conversion to PMS events reflects the than it does in the repair of loops. In previous studies10,11, no effects efficiency of DNA repair3,4. By examining the PMS patterns in of the rad1 mutation on PMS frequency of heterozygous mutations yeast strains heterozygous for a mutant allele with a 26-base-pair (presumably point mutations) were observed, although crossing- insertion, we find that the repair of 26-base loops involves Msh2 (a over was reduced in ultraviolet-irradiated rad1 diploids12. DNA-mismatch repair protein) and Rad1 (a protein required for The nucleotide-excision repair (NER) system in yeast requires the nucleotide-excision repair). concerted action of a large number of proteins. The NER endonu- We examined the effects of msh2 and rad1 mutations on the cleases, Rad1/Rad10 and Rad2, cleave 59 and 39 to the pyrimidine meiotic segregation patterns of heterozygous markers in the HIS4 dimer respectively, whereas Rad14 seems to be involved in the gene, a recombination hotspot5. Msh2 (a homologue of the MutS recognition of DNA damage1. To determine whether the effect on protein of Escherichia coli) is required for the repair of both base– the repair of large loops observed with Rad1 required other NER base subsitutions and small DNA loops, acting together with either proteins, we examined the effects of rad2 and rad14 mutations on Table 1 Effects of rad1 and msh2 mutations on the meiotic segregation patterns of heterozygous markers at the HIS4 locus Number of tetrads with various meiotic segregation patterns* Diploid Mutant RAD1† MSH2† Other Ab Other Total his4 allele alleles 4 : 4 6 : 2 2 : 6 5 : 3 3 : 5 4:4 7:1 1:7 8:0 0:8 PMS tetrads DNY27 his4-lopd þ=þþ=þ – 252 54 38 11 1 0 0 1 1 1 0 359 TP1012 his4-lopd þ= 2 þ=þ – 201 37 25 10 9 1 0 0 1 0 0 284 TP1013 his4-lopd 2 = 2 þ=þ – 294 86 28 37 24 3 4 2 3 0 0 481 DTK223 his4-lopd þ=þ 2 = 2 – 832112174 3002 0 0 142 DTK230 his4-lopd 2 = 22=2 –611210131202020 0112 DTK241 his4-lopd þ=þþ=þrad2 16422141 4 0000 0 0 205 DTK242 his4-lopd þ=þþ=þrad14 16239185 1 0002 1 0 228 ................................................................................................................................................................................................................................................................................................................................................................... MW103‡ his4-Sal þ=þþ=þ – 202 31 50 0 0 0 0 0 2 6 0 291 DTK257 his4-Sal 2 = 2 þ=þ – 249 66 70 0 0 0 0 0 4 3 0 392 ................................................................................................................................................................................................................................................................................................................................................................... PD83§ his4-AAG þ=þþ=þ – 142 54 58 11 10 0 1 2 13 23 1 315 DTK224 his4-AAG 2 = 2 þ=þ – 80 41 48 13 11 4 2 1 10 10 0 220 No. 5k his4-AAG þ=þ 2 = 2 –4063162580100 12111 DTK232 his4-AAG 2 = 22=2 – 4066221810110 1 11116 ................................................................................................................................................................................................................................................................................................................................................................... * For all segregation patterns, the first number represents the wild-type allele and the second represents the mutant allele. The segregation patterns include: 4 : 4 (normal mendelian segregation), 6 : 2 and 2 : 6 (gene conversion), 5 : 3 and 3 : 5 (tetrads with a single PMS event), Ab 4 : 4 (aberrant 4 : 4; one wild-type, one mutant, and two sectored colonies), 7: 1 and 1 : 7 (tetrads yielding three spore colonies of one genotype and one sectored colony), 8 : 0 and 0 : 8 (tetrads yielding four spores of a single genotype). The ‘other PMS’ class includes aberrant 6 : 2 and 2 : 6 tetrads as well as tetrads with three PMS events. † Notation: þ=þ, homozygous wild-type at the designated locus; þ= 2 , heterozygosity for the mutant allele; 2 = 2 , homozygosity for the mutant allele. ‡ Ref. 5. § Ref. 8. k Aberrant segregation patterns from this strain sporulated at 30 8C were examined previously9. As here all strains were sporulated at 18 8C, the earlier results are not included. Nature © Macmillan Publishers Ltd 1997 NATURE | VOL 387 | 26 JUNE 1997 929 letters to nature the segregation of his4-lopd (DTK241 and DTK242; Table 1). of restoration repair would lead to an increase in 5 : 3 events without Neither mutation increased the PMS frequency, indicating that a change in 6 : 2 events. Rad1 may be used for conversion repair in the complete NER complex is not required for the repair of large heteroduplexes in which the mutant strand is donated (Fig. 1b), DNA loops. because loss of conversion repair would lead to both a gain of 3 : 5 As the his4-AAG and his4-lopd mutations are located about events and a loss of 2 : 6 events. Thus, Rad1 may be involved in repair 470 bp apart in HIS4, an alternative explanation of our results is in which the wild-type strand is excised from the heteroduplex, that Rad1 affects DNA-mismatch repair as a function of the position because such events are restorations when the wild-type strand is of the mutation within the gene. Consequently, we examined the donated and conversions when the mutant strand is donated (Fig. effects of the rad1 mutation on the aberrant segregation pattern of 1). Alternatively, as the sequences at the mismatch depend on which his4-Sal, a 4-bp insertion located at the same position as his4-lopd. strand is donated, Rad1 may have a sequence-specific role in repair. We found that none of the aberrant segregants was a PMS tetrad Note that there is an increase in PMS without a compensating (Table 1). As we previously found similar segregation
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