title: Regulation of transcriptional activators by DNA-binding domain ubiquitination.
abstract: Ubiquitin is a key component of the regulatory network that maintains gene expression in eukaryotes, yet the molecular mechanism(s) by which non-degradative ubiquitination modulates transcriptional activator (TA) function is unknown. Here endogenous p53, a stress-activated transcription factor required to maintain health, is stably monoubiquitinated, following pathway activation by IR or Nutlin-3 and localized to the nucleus where it becomes tightly associated with chromatin. Comparative structure-function analysis and in silico modelling demonstrate a direct role for DNA-binding domain (DBD) monoubiquitination in TA activation. When attached to the DBD of either p53, or a second TA IRF-1, ubiquitin is orientated towards, and makes contact with, the DNA. The contact is made between a predominantly cationic surface on ubiquitin and the anionic DNA. Our data demonstrate an unexpected role for ubiquitin in the mechanism of TA-activity enhancement and provides insight into a new level of transcriptional regulation.
authors.affiliation: Cell Signalling Unit, ECRC, IGMM, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: Vivien
authors.initials: V
authors.lastname: Landré
authors.affiliation: Cell Signalling Unit, ECRC, IGMM, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: Bhindu
authors.initials: B
authors.lastname: Revi
authors.affiliation: Cell Signalling Unit, ECRC, IGMM, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: Maria Gil
authors.initials: MG
authors.lastname: Mir
authors.affiliation: Bioinformatics Institute (A*STAR), 30 Biopolis Street, 07-01 Matrix Singapore 138671, Singapore.|Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543, Singapore.|School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
authors.forename: Chandra
authors.initials: C
authors.lastname: Verma
authors.affiliation: Cell Signalling Unit, ECRC, IGMM, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: Ted R
authors.initials: TR
authors.lastname: Hupp
authors.affiliation: MRC Human Genetics Unit MRC, IGMM, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: Nick
authors.initials: N
authors.lastname: Gilbert
authors.affiliation: Cell Signalling Unit, ECRC, IGMM, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Ball
mesh_terms: D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D050856:Interferon Regulatory Factor-1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding; D000072417:Protein Domains; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013816:Thermodynamics; D015534:Trans-Activators / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D002843:Chromatin; D007093:Imidazoles; D050856:Interferon Regulatory Factor-1; D010879:Piperazines; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; C482205:nutlin 3; D004247:DNA; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C485369:RCHY1 protein, human; D044767:Ubiquitin-Protein Ligases