title: An interaction proteomics survey of transcription factor binding at recurrent TERT promoter mutations.
abstract: Aberrant telomerase reactivation in differentiated cells represents a major event in oncogenic transformation. Recurrent somatic mutations in the human telomerase reverse transcriptase (TERT) promoter region, predominantly localized to two nucleotide positions, are highly prevalent in many cancer types. Both mutations create novel consensus E26 transformation-specific (ETS) motifs and are associated with increased TERT expression. Here, we perform an unbiased proteome-wide survey of transcription factor binding at TERT promoter mutations in melanoma. We observe ELF1 binding at both mutations in vitro and we show that increased recruitment of GABP is enabled by the spatial architecture of native and novel ETS motifs in the TERT promoter region. We characterize the dynamics of competitive binding between ELF1 and GABP and provide evidence for ELF1 exclusion by transcriptionally active GABP. This study thus provides an important description of proteome-wide, mutation-specific binding at the recurrent, oncogenic TERT promoter mutations.
authors.affiliation: Radboud Institute of Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Makowski
authors.affiliation: Radboud Institute of Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Willems
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Fang
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Choi
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Tongwu
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Radboud Institute of Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands.
authors.forename: Pascal W T C
authors.initials: PW
authors.lastname: Jansen
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Brown
authors.affiliation: Radboud Institute of Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands.|Cancer GenomiCs Netherlands, Utrecht, The Netherlands.
authors.forename: Michiel
authors.initials: M
authors.lastname: Vermeulen
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051268:GA-Binding Protein Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D059372:Nucleotide Motifs; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D025941:Protein Interaction Mapping; D040901:Proteomics / Q000379:methods; D015398:Signal Transduction; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C512897:ELF1 protein, human; D051268:GA-Binding Protein Transcription Factor; D009687:Nuclear Proteins; D014157:Transcription Factors; C509186:TERT protein, human; D019098:Telomerase
keywords: Biomedicine; Melanoma; Telomerase; Transcription