Ubiquitin-specific proteases 7 and 11 modulate Polycomb regulation of the INK4a tumour suppressor.
An important facet of transcriptional repression by Polycomb repressive complex 1 (PRC1) is the mono-ubiquitination of histone H2A by the combined action of the Posterior sex combs (Psc) and Sex combs extra (Sce) proteins. Here, we report that two ubiquitin-specific proteases, USP7 and USP11, co-purify with human PRC1-type complexes through ... direct interactions with the Psc orthologues MEL18 and BMI1, and with other PRC1 components. Ablation of either USP7 or USP11 in primary human fibroblasts results in de-repression of the INK4a tumour suppressor accompanied by loss of PRC1 binding at the locus and a senescence-like proliferative arrest. Mechanistically, USP7 and USP11 regulate the ubiquitination status of the Psc and Sce proteins themselves, thereby affecting their turnover and abundance. Our results point to a novel function for USPs in the regulation and function of Polycomb complexes.
Mesh Terms:
Cell Proliferation, Cells, Cultured, Cyclin-Dependent Kinase Inhibitor p16, Histones, Humans, Nuclear Proteins, Protein Binding, Proto-Oncogene Proteins, RNA Interference, Repressor Proteins, Thiolester Hydrolases, Ubiquitin Thiolesterase, Ubiquitination
Cell Proliferation, Cells, Cultured, Cyclin-Dependent Kinase Inhibitor p16, Histones, Humans, Nuclear Proteins, Protein Binding, Proto-Oncogene Proteins, RNA Interference, Repressor Proteins, Thiolester Hydrolases, Ubiquitin Thiolesterase, Ubiquitination
EMBO J.
Date: Aug. 04, 2010
PubMed ID: 20601937
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