DNA Mismatch Repair.PDF

See online version for legend and references.SnapShot:DNA Mismatch RepairAndres A.Larrea,Scott A.Lujan,and Thomas A.KunkelNational Institutes of Environmental Health Sciences,NIH,DHHS,Research Triangle Park,NC 27709,USA730 Cell 141,May 14,2010 2010 Elsevier Inc.DOI 10.1016/j.cell.2010.05.002730.e1 Cell 141,May 14,2010 2010 Elsevier Inc.DOI 10.1016/j.cell.2010.05.002SnapShot:DNA Mismatch RepairAndres A.Larrea,Scott A.Lujan,and Thomas A.KunkelNational Institutes of Environmental Health Sciences,NIH,DHHS,Research Triangle Park,NC 27709,USAMismatch Repair in Bacteria and EukaryotesMismatch repair in the bacterium Escherichia coli is initiated when a homodimer of MutS binds as an asymmetric clamp to DNA containing a variety of base-base and insertion-deletion mismatches.The MutL homodimer then couples MutS recognition to the signal that distinguishes between the template and nascent DNA strands.In E.coli,the lack of adenine methylation,catalyzed by the DNA adenine methyltransferase(Dam)in newly synthesized GATC sequences,allows E.coli MutH to cleave the nascent strand.The resulting nick is used for mismatch removal involving the UvrD helicase,single-strand DNA-binding protein(SSB),and excision by single-stranded DNA exonucleases from either direction,depending upon the polarity of the nick relative to the mismatch.DNA polymerase III correctly resynthesizes DNA and ligase completes repair.In bacteria lacking Dam/MutH,as in eukaryotes,the signal for strand discrimination is uncertain but may be the DNA ends associated with replication forks.In these bacteria,MutL harbors a nick-dependent endonuclease that creates a nick that can be used for mismatch excision.Eukaryotic mismatch repair is similar,although it involves several dif-ferent MutS and MutL homologs:MutS(MSH2/MSH6)recognizes single base-base mismatches and 12 base insertion/deletions;MutS(MSH2/MSH3)recognizes insertion/deletion mismatches containing two or more extra bases.There are three eukaryotic MutL heterodimers:MutL(in humans MLH1/PMS2;in yeast MLH1/PMS1),MutL(MLH1/MLH3),and MutL(human MLH1/PMS1;yeast MLH1/MLH2).The eukaryotic MutS and MutL heterodimers have partial overlap in substrate specificity.MutL and MutL have endonuclease activity,with the active sites present in human PMS2(yeast PMS1)and human MLH3.The resulting nick can be used for excision by the double-strand DNA 5-exonuclease activity of Exo1.No helicase has yet been implicated in eukaryotic mismatch repair.Other exonucleases may perform excision,or the mismatch may be removed by strand displacement synthesis.DNA is resynthesized by DNA polymerase.Protein StructuresAlso depicted are structures of proteins involved in DNA mismatch repair(including Protein Data Bank ID,resolution,and species)among the many that are now available.Future studies will likely add to this list,possibly including proteins involved in excision,termination,and coordination of mismatch repair with nucleosome reloading and chromatin remodeling after replication.Evolutionary ConservationThe table provides information on the evolutionary conservation of mismatch repair proteins.Additional notes:grey icons indicate genes found only in subset of species;MSH1 in fungi is involved in mitochondrial DNA repair and is derived from-proteobacterial MutS via horizontal gene transfer from ancestral mitochondria;MutS in plants is derived from cyanobacterial MutS,is associated with chloroplasts,and is present in varying copy numbers;in archaea the general mismatch repair pathway is unknown,although MutS and MutL family members are found in limited species,likely due to horizontal gene transfer from bacteria.For archaeal MutS5,no mismatch repair-specific DNA binding has been reported.AcknowledgmentsWe would like to thank D.Erie and P.Hsieh for critical review and suggestions.A.A.L.and S.A.L.contributed equally to this work.RefeRencesAcharya,S.,Foster,P.,Brooks,P.,and Fishel,R.(2003).The coordinated functions of the E.coli MutS and MutL 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