title: Myc and Omomyc functionally associate with the Protein Arginine Methyltransferase 5 (PRMT5) in glioblastoma cells.
abstract: The c-Myc protein is dysregulated in many human cancers and its function has not been fully elucitated yet. The c-Myc inhibitor Omomyc displays potent anticancer properties in animal models. It perturbs the c-Myc protein network, impairs c-Myc binding to the E-boxes, retaining transrepressive properties and inducing histone deacetylation. Here we have employed Omomyc to further analyse c-Myc activity at the epigenetic level. We show that both Myc and Omomyc stimulate histone H4 symmetric dimethylation of arginine (R) 3 (H4R3me2s), in human glioblastoma and HEK293T cells. Consistently, both associated with protein Arginine Methyltransferase 5 (PRMT5)--the catalyst of the reaction--and its co-factor Methylosome Protein 50 (MEP50). Confocal experiments showed that Omomyc co-localized with c-Myc, PRMT5 and H4R3me2s-enriched chromatin domains. Finally, interfering with PRMT5 activity impaired target gene activation by Myc whereas it restrained Omomyc-dependent repression. The identification of a histone-modifying complex associated with Omomyc represents the first demonstration of an active role of this miniprotein in modifying chromatin structure and adds new information regarding its action on c-Myc targets. More importantly, the observation that c-Myc may recruit PRMT5-MEP50, inducing H4R3 symmetric di-methylation, suggests previously unpredictable roles for c-Myc in gene expression regulation and new potential targets for therapy.
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council (IBCN-CNR), Rome, Italy.
authors.forename: Maria Patrizia
authors.initials: MP
authors.lastname: Mongiardi
authors.affiliation: Nucleic Acids Laboratory, Institute of Molecular Biology and Pathology, National Research Council (IBPM-CNR) and Dept. of Biology and Biotechnologies, Sapienza University.
authors.forename: Mauro
authors.initials: M
authors.lastname: Savino
authors.affiliation: Nucleic Acids Laboratory, Institute of Molecular Biology and Pathology, National Research Council (IBPM-CNR) and Dept. of Biology and Biotechnologies, Sapienza University.
authors.forename: Laura
authors.initials: L
authors.lastname: Bartoli
authors.affiliation: Nucleic Acids Laboratory, Institute of Molecular Biology and Pathology, National Research Council (IBPM-CNR) and Dept. of Biology and Biotechnologies, Sapienza University.
authors.forename: Sara
authors.initials: S
authors.lastname: Beji
authors.affiliation: Istituto di Patologia Medica, Università Cattolica del Sacro Cuore, Rome, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Nanni
authors.affiliation: Nucleic Acids Laboratory, Institute of Molecular Biology and Pathology, National Research Council (IBPM-CNR) and Dept. of Biology and Biotechnologies, Sapienza University.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Scagnoli
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council (IBCN-CNR), Rome, Italy.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Falchetti
authors.affiliation: Nucleic Acids Laboratory, Institute of Molecular Biology and Pathology, National Research Council (IBPM-CNR) and Dept. of Biology and Biotechnologies, Sapienza University.
authors.forename: Annarita
authors.initials: A
authors.lastname: Favia
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council (IBCN-CNR), Rome, Italy.|Department of Experimental Oncology, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Farsetti
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council (IBCN-CNR), Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Levi
authors.affiliation: Nucleic Acids Laboratory, Institute of Molecular Biology and Pathology, National Research Council (IBPM-CNR) and Dept. of Biology and Biotechnologies, Sapienza University.
authors.forename: Sergio
authors.initials: S
authors.lastname: Nasi
authors.affiliation: Nucleic Acids Laboratory, Institute of Molecular Biology and Pathology, National Research Council (IBPM-CNR) and Dept. of Biology and Biotechnologies, Sapienza University.
authors.forename: Barbara
authors.initials: B
authors.lastname: Illi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D001120:Arginine / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008745:Methylation; D018613:Microscopy, Confocal; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D014157:Transcription Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001120:Arginine; D002843:Chromatin; D006657:Histones; D010446:Peptide Fragments; D011484:Protein-Arginine N-Methyltransferases; D016271:Proto-Oncogene Proteins c-myc; C568271:omomyc protein; C400529:PRMT5 protein, human; C478359:WDR77 protein, human; D014157:Transcription Factors