Hereditary nonpolyposis colorectal cancer (HNPCC) is a common inherited form of neoplasia caused by germline mutations in DNA mismatch ...SkiptomaincontentThankyouforvisitingnature.com.YouareusingabrowserversionwithlimitedsupportforCSS.Toobtainthebestexperience,werecommendyouuseamoreuptodatebrowser(orturnoffcompatibilitymodeinInternetExplorer).Inthemeantime,toensurecontinuedsupport,wearedisplayingthesitewithoutstylesandJavaScript.AdvertisementnatureoncogeneshortreportarticleHNPCCmutationsinthehumanDNAmismatchrepairgenehMLH1influenceassemblyofhMutLαandhMLH1–hEXO1complexesDownloadPDFAbstractHereditarynonpolyposiscolorectalcancer(HNPCC)isacommoninheritedformofneoplasiacausedbygermlinemutationsinDNAmismatchrepair(MMR)genes.MMRproteinshavebeenreportedtoassociatewithseveralproteins,includingthehumanexonuclease1(hEXO1).WereportherenovelHNPCC–hMLH1mutantproteins(T117M,Q426Xand1813insA)inDanishHNPCCpatients.WedemonstratethatthesemutantHNPCC–hMLH1proteinsareunabletoformcomplexeswithhEXO1andhPMS2invivo.TheresultsindicatethatmutationsfoundinHNPCCgenecarriersdisrupthMLH1–hEXO1complexformationandhMutLαheterodimerassemblyessentialforMMRactivity.DownloadPDFMainHereditarynonpolyposiscolorectalcancer(HNPCC)isageneticallyheterogeneousdisordercausedbygermlinemutationsinoneofseveralMMRgenes(Jiricny,1998a,b),althoughcurrentevidencesuggeststhatgerm-linemutationsinhMSH2andhMLH1accountforthemajorityofHNPCCcases(PeltomäkiandVasen,1997).HNPCCgenecarriersinheritamutationinoneoftheallelesencodingaMMRgene,andthesecondcopyismutatedorlostasanearlyeventinthedevelopmentofatumor.ThissecondeventrenderscellsDNAmismatchrepair(MMR)deficient,presumablyleadingtotherapidaccumulationofmutationsthatdrivestumordevelopment.WhatexactlycausestheunderlyingpredispositiontocolorectalcancerinHNPCCindividualsremainstobeelucidated.IthasbeenshownthatanaccurateassemblyofhumanMMRcomplexesisessentialforefficientMMRinordertomaintainthegenomicintegrity(Drummondetal.,1997).Thesedatasuggestthat,dependingonthenatureofthemutatio