Regulation of the polycomb protein Ring1B by self-ubiquitination or by E6-AP may have implications to the pathogenesis of Angelman syndrome

Daphna Zaaroor-Regev, Prim De Bie, Martin Scheffner, Tahel Noy, Ruth Shemer, Maya Heled, Ilan Stein, Eli Pikarsky, Aaron Ciechanover

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Abstract

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 H2Ain 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.

Original languageEnglish
Pages (from-to)6788-6793
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number15
DOIs
StatePublished - 13 Apr 2010

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Angelman Syndrome
Ubiquitination
Ligases
Histones
Proteins
Polycomb Repressive Complex 1
Polycomb-Group Proteins
Polyubiquitin
Purkinje Cells
Gene Expression Regulation
Ubiquitin
Knockout Mice
Lysine
Brain
Genes

Keywords

  • Polycomb complexes
  • Ubiquitin-proteasome system

Cite this

Zaaroor-Regev, Daphna ; De Bie, Prim ; Scheffner, Martin ; Noy, Tahel ; Shemer, Ruth ; Heled, Maya ; Stein, Ilan ; Pikarsky, Eli ; Ciechanover, Aaron. / Regulation of the polycomb protein Ring1B by self-ubiquitination or by E6-AP may have implications to the pathogenesis of Angelman syndrome. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 15. pp. 6788-6793.
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Regulation of the polycomb protein Ring1B by self-ubiquitination or by E6-AP may have implications to the pathogenesis of Angelman syndrome. / Zaaroor-Regev, Daphna; De Bie, Prim; Scheffner, Martin; Noy, Tahel; Shemer, Ruth; Heled, Maya; Stein, Ilan; Pikarsky, Eli; Ciechanover, Aaron.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 15, 13.04.2010, p. 6788-6793.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Regulation of the polycomb protein Ring1B by self-ubiquitination or by E6-AP may have implications to the pathogenesis of Angelman syndrome

AU - Zaaroor-Regev, Daphna

AU - De Bie, Prim

AU - Scheffner, Martin

AU - Noy, Tahel

AU - Shemer, Ruth

AU - Heled, Maya

AU - Stein, Ilan

AU - Pikarsky, Eli

AU - Ciechanover, Aaron

PY - 2010/4/13

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N2 - 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 H2Ain 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.

AB - 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 H2Ain 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.

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DO - 10.1073/pnas.1003108107

M3 - Article

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SP - 6788

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JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

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