title: OmoMYC blunts promoter invasion by oncogenic MYC to inhibit gene expression characteristic of MYC-dependent tumors.
abstract: MYC genes have both essential roles during normal development and exert oncogenic functions during tumorigenesis. Expression of a dominant-negative allele of MYC, termed OmoMYC, can induce rapid tumor regression in mouse models with little toxicity for normal tissues. How OmoMYC discriminates between physiological and oncogenic functions of MYC is unclear. We have solved the crystal structure of OmoMYC and show that it forms a stable homodimer and as such recognizes DNA in the same manner as the MYC/MAX heterodimer. OmoMYC attenuates both MYC-dependent activation and repression by competing with MYC/MAX for binding to chromatin, effectively lowering MYC/MAX occupancy at its cognate binding sites. OmoMYC causes the largest decreases in promoter occupancy and changes in expression on genes that are invaded by oncogenic MYC levels. A signature of OmoMYC-regulated genes defines subgroups with high MYC levels in multiple tumor entities and identifies novel targets for the eradication of MYC-driven tumors.
authors.affiliation: Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany.|Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany.
authors.forename: L A
authors.initials: LA
authors.lastname: Jung
authors.affiliation: Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Gebhardt
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Koelmel
authors.affiliation: Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany.
authors.forename: C P
authors.initials: CP
authors.lastname: Ade
authors.affiliation: Comprehensive Cancer Center, Core Unit Bioinformatics, Biocenter, Würzburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Walz
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Kuper
authors.affiliation: Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: von Eyss
authors.affiliation: Department of Biotechnology and Biophysics, Biocenter, University of Würzburg, Würzburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Letschert
authors.affiliation: Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Redel
authors.affiliation: Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, University of Tübingen, Tübingen, Germany.
authors.forename: L
authors.initials: L
authors.lastname: d'Artista
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow, UK.|West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK.|South Western Sydney Clinical School, Faculty of Medicine, University of NSW, Liverpool, New South Wales, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Biankin
authors.affiliation: Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, University of Tübingen, Tübingen, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Zender
authors.affiliation: Department of Biotechnology and Biophysics, Biocenter, University of Würzburg, Würzburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Sauer
authors.affiliation: Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Wolf
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, UK.
authors.forename: G
authors.initials: G
authors.lastname: Evan
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Kisker
authors.affiliation: Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany.
authors.forename: M
authors.identifier: 0000-0002-0376-6533
authors.initials: M
authors.lastname: Eilers
mesh_terms: D001665:Binding Sites; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D005799:Genes, Dominant; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011401:Promoter Regions, Genetic; D055503:Protein Multimerization; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D017385:Sequence Homology; D059467:Transcriptome; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D010446:Peptide Fragments; D016271:Proto-Oncogene Proteins c-myc; D025521:Tumor Suppressor Proteins; C568271:omomyc protein; D004247:DNA