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Mismatch Repair Mutants in Yeast Are Not Defective in Transcription-Coupled DNA Repair of UV-Induced DNA Damage

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Mismatch Repair Mutants in Yeast Are Not Defective in Transcription-Coupled DNA Repair of UV-Induced DNA Damage Copyright 0 1996 by the Genetics Society of America Mismatch Repair Mutants in Yeast Are Not Defective in Transcription-Coupled DNA Repair of UV-Induced DNA Damage Kevin S. Sweder,* Richard A. Verhage,t David J. Crowley," Gray F. Grouse,* Jaap Brouwert and Philip C. Hanawalt" *Department of Biological Sciences, Stanford University, Stanford, California 94305-5020, fLaboratory of Molecular Genetics, Leiden Znstitute of Chemistry, Gorlaeus Laboratories, University of Leiden, 2300 RA Leiden, The Netherlands and $Department of Biology, Emory University, Atlanta, Georgia 30322 Manuscript received December 4, 1995 Accepted for publication April 8, 1996 ABSTRACT Transcription-coupled repair, the targeted repairof the transcribed strandsof active genes, is defective in bacteria, yeast, and human cells carrying mutations in mfd, RAD26 and ERCC6, respectively. Other factors probably are also uniquely involved in transcription-repair coupling. Recently, a defect was described in transcription-coupled repair forEscherichia coli mismatch repair mutants andhuman tumor cell lines with mutations in mismatch repair genes. We examined removal of UV-induced DNA damage in yeast strains mutated in mismatch repair genes in an effort to confirm a defect in transcription- coupled repair in this system. In addition, we determined the contributionof the mismatch repair gene MSHZ to transcription-coupled repair in the absence of global genomic repair using rad7A mutants. We also determined whether the RadZGindependent transcription-coupled repair observedin rad26A and rad7A rad26A mutants depends on MSH2 by examining repair deficienciesof rad26A mh2Aand rad7A rad26A mh2Amutants. We found no defectsin transcriptioncoupled repaircaused by mutations in the mismatch repair genesMSH2, MLHI, PMSI, and MSH3. Yeast appears to differ from bacteria and human cells in the capacity for transcription-coupled repair in a mismatch repair mutant background. ULTIPLE mechanisms for processing damaged and RAD16 genes are essential for this mode of repair M DNA haveevolved in essentiallyall organisms. of chromatin in vivo (VERHAGEet al. 1994) and in vitro In the yeast Saccharomyces cermisiae, for example, these (see ref. 39 of VERHACE et al. 1996). A second class include the nucleotide and base excision repair path- of nucleotide excision repair acts specifically for the ways, the mismatch repair pathway, and photoreactiva- removal of DNA damage from the transcribed strand tion, as well as lesion tolerance modes such as recombi- of activegenes. This specialized form of nucleotide exci- nation. On the basis of epistasis analyses, it is believed sion repair, called transcription-coupled repair, re- that these pathways operate largely independently from quires most of the same proteins required for genomic one another. However, recent reports indicate that a nucleotide excision repair (SWEDER1994). The pres- number of repair proteins function in more than one ence of W-induced DNA damage in the transcribed of these pathways. For example, Rad1 and Rad10 operate strand of an expressed gene blocks the progression of in both nucleotide excision repair and recombination transcribing RNA polymerase complexes in vivo (SAUER- BIER and HERCULES1978) and vitro (SELBYand (FISHMAN-LOBELLand HABER 1992; IVANOVand HABER in 1995). Thus,it is possible that nucleotide excision repair SANCAR1990; DONAHUEet al. 1994). Such impeded proteins can interact with proteins from other repair RNA polymerase complexes may be perceived as sub strates for the nucleotide excision repair pathway. The pathways and influence those other processes. result of recognition of stalled RNA polymerase com- Nucleotide excision repair is an ubiquitous process plexes may be the preferential repairof the transcribed wherein repair proteins recognize DNA lesions and ef- strands of active genes over that of the nontranscribed fect dual DNA incisions resulting in removal of damage strands of active genes and nontranscribed regions of as part of an oligonucleotide. Subsequently, DNA poly- the genome (i.e., transcription-coupled repair). Defi- merases, ligases, and accessory factors fill in the re- ciencies in transcription-coupled repair result in repair sulting gapped duplex DNA to regenerate the intact of the transcribed strands of active genes that is no duplex. There are at least two subpathways of nucleo- greater than that of the nontranscribed strands or the tide excision repair in vivo. One operates globally genome overall. Mutations in the mfd gene of Eschm'cl~ia throughout an organism's genome. In yeast the RAD7 coli, the RAD26 gene of S. cermisiae, and the ERCCG (CSB) and CSA genes of humans result in deficiencies Corresponding author: Kevin S. Sweder, Laboratory €or Cancer Re- search, Department of Chemical Biology, College of Pharmacy, Rut- in transcription-coupled repair (VENEMAet al. 1990; gers, The State University of New Jersey, Frelinghuysen Rd., Piscata- SELBYet nl. 1991; VAN HOFFENet al. 1993; VAN GOOLet way, NJ 088554789, E-mail: [email protected] nl. 1994; HENNINGet al. 1995). Genetics 143 3127-1135 (July, 1996) 1128 K. S. Sweder et al. Recently another repair pathway, mismatch repair, dependent upon MSH2, by examining the repair defi- was found to influence the process of transcription- ciencies of rad26A msh2A and rad7A rad26A msh2A coupled repair in E. coli (MELLONand CHAMPE1996). mutants. Unlike the results reported for theE. coli mis- As its name implies, mismatch repair is a pathway for match repair mutants,we found that mutationsin yeast the removal of mismatched base pairs in duplex DNA. mismatch repair genes had no discernable effect upon In E. coli the recognition and removal of mismatches is either transcription-coupled repair or global nucleotide accomplished by the MutS, MutL, and MutH proteins excision repair of UV-induced DNA damage. (MODRICH 1991). MutS binds to the mismatched bases, while MutH binds to a nearby hemimethylated GATC MATERIALSAND METHODS site. The MutS, MutL, and MutH proteins then form Media, plasmids, and strains: All media were prepared as a multiprotein complex that leads to a single-strand described by SHERMANet al. (1986). WD medium is 1% yeast cleavage atthe hemimethylated site. Excision of a extract/2% Bacto-peptone (Difco)/2% glucose. Synthetic stretch of nucleotides either 3’ or 5’ from the nick is glucose medium (SD) is 2% glucose/0.67% Bacto-yeast nitro- followed by resynthesis employing DNA polymerase 111 gen base without vitamins (Difco) supplemented with the ap and associated factors. When MELLONand CHAMPE propriate amino acids and bases. Agar (1.5%) was added to media for plates. Yeast strains used in this study are listed in (1996) examined transcription-coupled repair in E. coli Table 1. Plasmid pKS212 is a Bluescript vector (Stratagene) mismatch repair mutants mutS and mutL, they observed containing the internal1.0-kb EcoRI-XhoI from RPB2 (SWEDEK a lack of transcription-coupled repair similar to the re- and HANAWALT1992). RPB2 encodes the second largest sub- pair deficiency observed for mfd mutants. A deficiency unit of RNA polymerase 11. Plasmid pKS212 was linearized by in transcription-coupled repair was not observed in cleaving with XhoI or EcoRI and was incubated with rNTPs and T7RNA polymerase or T3RNA polymerase, respectively, mutH mutants. Thus, mutations in mutS and mutL ap- under conditions recommended by the manufacturer to gen- pear to influence transcription-coupled repair in vivo. erate strand-specific RNA probes for RPB2. Alternatively, However, SELsYandSmcm (1995) reported that MutS strand-specific single-stranded DNA probes were used as de- and MutL proteins had no effect on transcription-cou- scribed previously (VERHAGEet al. 1994). Haploid strains YSH1475(msh2A) and YSH1476(MSH2) pled repair in vitro. were isolated by sporulation of RKYl476 (REENAN and KO- Eukaryotes alsopossess a general mismatch repair 1,ODNER 1992) under selection for uracil and histidine auxo- pathway that is performed by proteins that arehomolo- trophy and lysine and leucine prototrophy as described gous to the E. coli MutS and MutL proteins. Mutations (SHERMANet al. 1986). The mutator phenotype of the mis- in the genes encoding human homologuesof MutS and match repair strains, except for the W303-1Bderived ones, used in this study was confirmed by determining themutation MutL, hMSH2, hPMS2 and hMLH1, result in genomic frequency on complete synthetic medium lacking arginine instability of nucleotide repeats and are associated with and containing 60 bg/ml of L-canavanine. severaltypes of cancer (FISHEL et al. 1993; LEACH et Disruption of mismatch repair genes in yeast: All strains al. 1993; BRONNERet al. 1994; NICOWDESet al. 1994; designated with a GCY were derived from SJR231 (DATTAet PAPADOPOULOSet al. 1994; BOER et al. 1995). Mutations al. 1996) by lithiumacetate mediated transformation. GCYl27(msh2A) was constructed by two-step gene replace- in the yeast MSH2, MSH3, PMSl, and MLHl genes re- ment (ROTHSTEIN 1991). Strains were transformed with lin- sult ingenomic instabilityof dinucleotiderepeats earized URAkontaining plasmid p306m2RID (mh2A), and (STRAND et al. 1993, 1995). Ura+transformants were selected (DATTA et al. 1996). To determine whether mismatch repair influences p306m2RID contains MSH2 with an internal PuuII-XbaI frag- transcription-coupled repair in yeast as it appears to ment (2.4 kb) deleted. Excision of the integrated plasmids was selected for by resistance to 5-fluoroorotic acid (5-FOA) . do in E. coli, we examined the ability of several
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