biostudies-literatureReijns MAMCancer Research UKMedical Research CouncilBlood Cancer UKEuropean Hematology AssociationNational Institute for Health Research (NIHR)Wellcome TrustBiotechnology and Biological Sciences Research CouncilAcademy of Medical Sciences623-631https://www.ebi.ac.uk/biostudies/studies/S-EPMC8866115biostudies-literatureUnknown602(7898)The mutational landscape is shaped by many processes. Genic regions are vulnerable to mutation but are preferentially protected by transcription-coupled repair¹. In microorganisms, transcription has been demonstrated to be mutagenic^2,3; however, the impact of transcription-associated mutagenesis remains to be established in higher eukaryotes⁴. Here we show that ID4-a cancer insertion-deletion (indel) mutation signature of unknown aetiology⁵ characterized by short (2 to 5 base pair) deletions -is due to a transcription-associated mutagenesis process. We demonstrate that defective ribonucleotide excision repair in mammals is associated with the ID4 signature, with mutations occurring at a TNT sequence motif, implicating topoisomerase 1 (TOP1) activNatureSignatures of TOP1 transcription-associated mutagenesis in cancer and germline.PMC8866115MC_UU_00007/11MR/X013677/11504719771BB/J004243/1MC_PC_14089NF-SI-0617-10154275892796325514AMS-CSF4-ChurchMR/K001744/1204802/Z/16/ZMC_EX_MR/M009203/128640NF-SI-0512-10113MC_UU_00007/5MC_UU_00009/2RG69CL-2010-13-007Williams TCChan GCWilliams ELopez-Bigas NCulliford RSottoriva AMaleady-Crowe FCornish AJNadeu FLahnstein LHubbard TJPThorn SWelland MJPalles CStuckey ACaulfield MJHamblin AMueller MO'Donovan PFrangou AAmbrose JCScott RHTucci AJackson APBleda MLeigh SEAPatch CThomas ERAStankovic TJones LJArumugam PHenderson SCross WGruber AMurugaesu NReijns MAMLeong IUSKousathanas AWitkowska KTanguy MSmith SCGiess ASchuh ARendon APerez-Gil DCampo EWood HBoustred CRSiddiq AOdhams CAWood SMHoulston RSavage KTaylor Tavares ALBevers RFowler TPullinger JCornish ATaylor MSCaravagna GGenomics England Research ConsortiumMinneci FNoyvert BRidout KElgar GSieghart AChubb DArnedo-Pac CParry DAGraham TBoyle SCarroll PChurch DMoutsianas LBrittain HKasperaviciute DXiang HPereira MBAden KRogers TTomlinson IBoardman-Pretty FKinnersley BMcEntagart MKayikci MThompson SRRoyo RJackson RLopez JFQuirke PSosinsky ARios Szwed DONeed ACSawant KWedge DNicholson MDColorectal Cancer Domain UK 100,000 Genomes ProjectHindshaw RLRahim TfalseSignatures of TOP1 transcription-associated mutagenesis in cancer and germline.The mutational landscape is shaped by many processes. Genic regions are vulnerable to mutation but are preferentially protected by transcription-coupled repair¹. In microorganisms, transcription has been demonstrated to be mutagenic^2,3; however, the impact of transcription-associated mutagenesis remains to be established in higher eukaryotes⁴. Here we show that ID4-a cancer insertion-deletion (indel) mutation signature of unknown aetiology⁵ characterized by short (2 to 5 base pair) deletions -is due to a transcription-associated mutagenesis process. We demonstrate that defective ribonucleotide excision repair in mammals is associated with the ID4 signature, with mutations occurring at a TNT sequence motif, implicating topoisomerase 1 (TOP1) activ2022-01-01T00:00:00Z2022 Feb2026-04-08T17:58:18.65Z2026-04-08T08:10:41.457ZS-EPMC88661153514039610.1038/s41586-022-04403-y