@article { , title = {GSK3β-SCFFBXW7α mediated phosphorylation and ubiquitination of IRF1 are required for its transcription-dependent turnover}, abstract = {IRF1 (Interferon Regulatory Factor-1) is the prototype of the IRF family of DNA binding transcription factors. IRF1 protein expression is regulated by transient up-regulation in response to external stimuli followed by rapid degradation via the ubiquitin-proteasome system. Here we report that DNA bound IRF1 turnover is promoted by GSK3β (Glycogen Synthase Kinase 3β) via phosphorylation of the T181 residue which generates a phosphodegron for the SCF (Skp-Cul-Fbox) ubiquitin E3-ligase receptor protein Fbxw7α (F-box/WD40 7). This regulated turnover is essential for IRF1 activity, as mutation of T181 results in an improperly stabilised protein that accumulates at target promoters but fails to induce RNA-Pol-II elongation and subsequent transcription of target genes. Consequently, the anti-proliferative activity of IRF1 is lost in cell lines expressing T181A mutant. Further, cell lines with dysfunctional Fbxw7 are less sensitive to IRF1 overexpression, suggesting an important co-activator function for this ligase complex. As T181 phosphorylation requires both DNA binding and RNA-Pol-II elongation, we propose that this event acts to clear " spent " molecules of IRF1 from transcriptionally engaged target promoters.}, doi = {10.1093/nar/gkz163}, eissn = {1362-4962}, issn = {0305-1048}, issue = {9}, journal = {Nucleic Acids Research}, pages = {4476-4494}, publicationstatus = {Published}, publisher = {Oxford University Press}, url = {https://nottingham-repository.worktribe.com/output/1612445}, volume = {47}, keyword = {Interferon Regulatory Factor-1, phosphodegron, GSK3, FBXW7}, year = {2019}, author = {Garvin, Alexander J. and Khalaf, Ahmed H.A. and Rettino, Alessandro and Xicluna, Jerome and Butler, Laura and Morris, Joanna R. and Heery, David M. and Clarke, Nicole M.} }