Ubiquitin-specific proteases 7 and 11 modulate Polycomb regulation of the INK4a tumour suppressor

EMBO J. 2010 Aug 4;29(15):2553-65. doi: 10.1038/emboj.2010.129. Epub 2010 Jul 2.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Proliferation
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
  • Histones / metabolism
  • Humans
  • Nuclear Proteins / metabolism
  • Polycomb Repressive Complex 1
  • Polycomb-Group Proteins
  • Protein Binding
  • Proto-Oncogene Proteins / metabolism
  • RNA Interference
  • Repressor Proteins / metabolism*
  • Thiolester Hydrolases / genetics
  • Thiolester Hydrolases / metabolism*
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / metabolism*
  • Ubiquitin-Specific Peptidase 7
  • Ubiquitination

Substances

  • BMI1 protein, human
  • Cyclin-Dependent Kinase Inhibitor p16
  • Histones
  • Nuclear Proteins
  • Polycomb-Group Proteins
  • Proto-Oncogene Proteins
  • Repressor Proteins
  • USP11 protein, human
  • Polycomb Repressive Complex 1
  • Thiolester Hydrolases
  • USP7 protein, human
  • Ubiquitin Thiolesterase
  • Ubiquitin-Specific Peptidase 7