Regulation of the polycomb protein Ring1B by self-ubiquitination or by E6-AP may have implications to the pathogenesis of Angelman syndrome
| Autor: | Eli Pikarsky, Aaron Ciechanover, Martin Scheffner, Maya Heled, Ruth Shemer, Prim de Bie, Daphna Zaaroor-Regev, Tahel Noy, Ilan Stein |
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| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Proteasome Endopeptidase Complex
Ubiquitin-Protein Ligases Biology Models Biological Catalysis Mice Ubiquitin Cell Line Tumor Angelman syndrome ddc:570 Histone H2A ubiquitin medicine Animals Humans Angelman-Syndrom [gnd] Mice Knockout Neurons Polycomb Repressive Complex 1 Regulation of gene expression chemistry.chemical_classification DNA ligase Multidisciplinary Lysine Biological Sciences medicine.disease Molecular biology Ubiquitin ligase DNA-Binding Proteins Gene Expression Regulation chemistry Knockout mouse biology.protein Angelman Syndrome PRC1 E6AP |
| Popis: | The polycomb repressive complex (PRC) 1 protein Ring1B is an ubiquitin ligase that modifies nucleosomal histone H2A, a modification which plays a critical role in regulation of gene expression. We have shown that self-ubiquitination of Ring1B generates multiply branched, “noncanonical” polyubiquitin chains that do not target the ligase for degradation, but rather stimulate its activity toward histone H2A. This finding implies that Ring1B is targeted by a heterologous E3. In this study, we identified E6-AP (E6-associated protein) as a ligase that targets Ring1B for “canonical” ubiquitination and subsequent degradation. We further demonstrated that both the self-ubiquitination of Ring1B and its modification by E6-AP target the same lysines, suggesting that the fate of Ring1B is tightly regulated (e.g., activation vs. degradation) by the type of chains and the ligase that catalyzes their formation. As expected, inactivation of E6-AP affects downstream effectors: Ring1B and ubiquitinated H2A levels are increased accompanied by repressed expression of HoxB9, a PRC1 target gene. Consistent with these findings, E6-AP knockout mice display an elevated level of Ring1B and ubiquitinated histone H2A in various tissues, including cerebellar Purkinje neurons, which may have implications to the pathogenesis of Angelman syndrome, a neurodevelopmental disorder caused by deficiency of E6-AP in the brain. |
| Databáze: | OpenAIRE |
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