title: Ubiquitin-Dependent Turnover of MYC Antagonizes MYC/PAF1C Complex Accumulation to Drive Transcriptional Elongation.
abstract: MYC is an unstable protein, and its turnover is controlled by the ubiquitin system. Ubiquitination enhances MYC-dependent transactivation, but the underlying mechanism remains unresolved. Here we show that MYC proteasomal turnover is dispensable for loading of RNA polymerase II (RNAPII). In contrast, MYC turnover is essential for recruitment of TRRAP, histone acetylation, and binding of BRD4 and P-TEFb to target promoters, leading to phosphorylation of RNAPII and transcriptional elongation. In the absence of histone acetylation and P-TEFb recruitment, MYC associates with the PAF1 complex (PAF1C) through a conserved domain in the MYC amino terminus ("MYC box I"). Depletion of the PAF1C subunit CDC73 enhances expression of MYC target genes, suggesting that the MYC/PAF1C complex can inhibit transcription. Because several ubiquitin ligases bind to MYC via the same domain ("MYC box II") that interacts with TRRAP, we propose that degradation of MYC limits the accumulation of MYC/PAF1C complexes during transcriptional activation.
authors.affiliation: Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Jaenicke
authors.affiliation: Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: von Eyss
authors.affiliation: Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Carstensen
authors.affiliation: Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Elmar
authors.initials: E
authors.lastname: Wolf
authors.affiliation: Comprehensive Cancer Center Mainfranken, Versbacher Straße 5, 97078 Würzburg, Germany.
authors.forename: Wenshan
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Structural Immunology, Institute of Innate Immunity, University Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany.
authors.forename: Ann Katrin
authors.initials: AK
authors.lastname: Greifenberg
authors.affiliation: Department of Structural Immunology, Institute of Innate Immunity, University Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Geyer
authors.affiliation: Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany; Comprehensive Cancer Center Mainfranken, Versbacher Straße 5, 97078 Würzburg, Germany. Electronic address: martin.eilers@biozentrum.uni-wuerzburg.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Eilers
authors.affiliation: Comprehensive Cancer Center Mainfranken, Versbacher Straße 5, 97078 Würzburg, Germany; Department of Radiation Oncology, University Hospital Würzburg, Josef-Schneider-Straße 11, 97080 Würzburg, Germany. Electronic address: nikita.popov@biozentrum.uni-wuerzburg.de.
authors.forename: Nikita
authors.initials: N
authors.lastname: Popov
mesh_terms: D000107:Acetylation; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D001665:Binding Sites; D018797:Cell Cycle Proteins; D049109:Cell Proliferation; D042002:Chromatin Assembly and Disassembly; D057809:HEK293 Cells; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D046912:Multiprotein Complexes; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D059748:Proteolysis; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012319:RNA Polymerase II / Q000378:metabolism; D013997:Time Factors; D061805:Transcription Elongation, Genetic; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D000092468:Bromodomain Containing Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D006657:Histones; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D010750:Phosphoproteins; D042925:Positive Transcriptional Elongation Factor B; D016271:Proto-Oncogene Proteins c-myc; D012319:RNA Polymerase II; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C454900:CDC73 protein, human; C484387:CTR9 protein, human; C489427:MYC protein, human; C501972:PAF1 protein, human; C113829:transformation-transcription domain-associated protein
keywords: MYC; PAF1C; RNA polymerase; proteasomal degradation; transcriptional elongation; ubiquitin