Regulation of transcriptional activators by DNA-binding domain ubiquitination.

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.
Mesh Terms:
Cell Line, Tumor, Chromatin, Crystallography, X-Ray, DNA, Humans, Imidazoles, Interferon Regulatory Factor-1, Lymphocytes, Melanocytes, Models, Molecular, Piperazines, Protein Binding, Protein Domains, Proto-Oncogene Proteins c-mdm2, Thermodynamics, Trans-Activators, Transcriptional Activation, Tumor Suppressor Protein p53, Ubiquitin, Ubiquitin-Protein Ligases, Ubiquitination
Cell Death Differ.
Date: Dec. 01, 2016
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