Switches, Excitable Responses and Oscillations in the Ring1B/Bmi1 Ubiquitination System

In an active, self-ubiquitinated state, the Ring1B ligase monoubiquitinates histone H2A playing a critical role in Polycomb-mediated gene silencing. Following ubiquitination by external ligases, Ring1B is targeted for proteosomal degradation. Using biochemical data and computational modeling, we show that the Ring1B ligase can exhibit abrupt switches, overshoot transitions and self-perpetuating oscillations between its distinct ubiquitination and activity states. These different Ring1B states display canonical or multiply branched, atypical polyubiquitin chains and involve association with the Polycomb-group protein Bmi1. Bistable switches and oscillations may lead to all-or-none histone H2A monoubiquitination rates and result in discrete periods of gene (in)activity. Switches, overshoots and oscillations in Ring1B catalytic activity and proteosomal degradation are controlled by the abundances of Bmi1 and Ring1B, and the activities and abundances of external ligases and deubiquitinases, such as E6-AP and USP7.

[1]  D. Noble.  A modification of the Hodgkin—Huxley equations applicable to Purkinje fibre action and pacemaker potentials , 1962, The Journal of physiology.

[2]  Pier Paolo Di Fiore,et al.  Molecular mechanisms of coupled monoubiquitination , 2006, Nature Cell Biology.

[3]  M. Courtemanche,et al.  Ionic mechanisms underlying human atrial action potential properties: insights from a mathematical model. , 1998, The American journal of physiology.

[4]  Zhijian J. Chen,et al.  Nonproteolytic functions of ubiquitin in cell signaling. , 2009, Molecular cell.

[5]  A Ciechanover,et al.  Regulation of the Drosophila ubiquitin ligase DIAP1 is mediated via several distinct ubiquitin system pathways , 2007, Cell Death and Differentiation.

[6]  Yun-Fei Xia,et al.  Bmi-1 is a novel molecular marker of nasopharyngeal carcinoma progression and immortalizes primary human nasopharyngeal epithelial cells. , 2006, Cancer research.

[7]  T. Smithgall,et al.  Autophosphorylation of the Fes Tyrosine Kinase , 1996, The Journal of Biological Chemistry.

[8]  Aaron DiAntonio,et al.  Ubiquitin-dependent regulation of the synapse. , 2004, Annual review of neuroscience.

[9]  Yi Zhang,et al.  Role of Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene silencing. , 2005, Molecular cell.

[10]  A. Tzafriri,et al.  The total quasi-steady-state approximation is valid for reversible enzyme kinetics. , 2004, Journal of theoretical biology.

[11]  Johan Paulsson,et al.  Models of stochastic gene expression , 2005 .

[12]  C. Kostic,et al.  Bmi1 Loss Produces an Increase in Astroglial Cells and a Decrease in Neural Stem Cell Population and Proliferation , 2005, The Journal of Neuroscience.

[13]  J. Ferrell,et al.  A positive-feedback-based bistable ‘memory module’ that governs a cell fate decision , 2003, Nature.

[14]  Aaron Ciechanover,et al.  Regulation of the Polycomb protein RING1B ubiquitination by USP7. , 2010, Biochemical and biophysical research communications.

[15]  Wim Vermeulen,et al.  Regulation of UV-induced DNA damage response by ubiquitylation. , 2007, DNA repair.

[16]  Brian David Dynlacht,et al.  E2F mediates cell cycle-dependent transcriptional repression in vivo by recruitment of an HDAC1/mSin3B corepressor complex. , 2002, Genes & development.

[17]  Shengyun Fang,et al.  Mdm2 Is a RING Finger-dependent Ubiquitin Protein Ligase for Itself and p53* , 2000, The Journal of Biological Chemistry.

[18]  Oliver Weichenrieder,et al.  Structure and E3‐ligase activity of the Ring–Ring complex of Polycomb proteins Bmi1 and Ring1b , 2006, The EMBO journal.

[19]  J. Derisi,et al.  Single-cell proteomic analysis of S. cerevisiae reveals the architecture of biological noise , 2006, Nature.

[20]  A. Oudenaarden,et al.  Nature, Nurture, or Chance: Stochastic Gene Expression and Its Consequences , 2008, Cell.

[21]  Irving L Weissman,et al.  Bmi‐1‐Green Fluorescent Protein‐Knock‐In Mice Reveal the Dynamic Regulation of Bmi‐1 Expression in Normal and Leukemic Hematopoietic Cells , 2007, Stem cells.

[22]  Jens Timmer,et al.  Systems-level interactions between insulin–EGF networks amplify mitogenic signaling , 2009, Molecular systems biology.

[23]  J. Ferrell.  Self-perpetuating states in signal transduction: positive feedback, double-negative feedback and bistability. , 2002, Current opinion in cell biology.

[24]  Gerry Melino,et al.  Itch self-polyubiquitylation occurs through lysine-63 linkages. , 2008, Biochemical pharmacology.

[25]  Judith Campisi,et al.  The Bmi-1 oncogene induces telomerase activity and immortalizes human mammary epithelial cells. , 2002, Cancer research.

[26]  Huxley Af,et al.  A quantitative description of membrane current and its application to conduction and excitation in nerve. 1952. , 1990 .

[27]  L. Sui,et al.  Correlations of BMI-1 expression and telomerase activity in ovarian cancer tissues. , 2008, Experimental oncology.

[28]  A. Hodgkin,et al.  A quantitative description of membrane current and its application to conduction and excitation in nerve , 1952, The Journal of physiology.

[29]  J. Ferrell,et al.  Bistability in the JNK cascade , 2001, Current Biology.

[30]  Irving L. Weissman,et al.  Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells , 2003, Nature.

[31]  Boris N Kholodenko,et al.  Toggle switches, pulses and oscillations are intrinsic properties of the Src activation/deactivation cycle , 2009, The FEBS journal.

[32]  Ping Zhu,et al.  Histone H2A monoubiquitination represses transcription by inhibiting RNA polymerase II transcriptional elongation. , 2008, Molecular cell.

[33]  M. Sofroniew,et al.  Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene. , 1994, Genes & development.

[34]  K. Brown,et al.  Regulation of TRAF2 Signaling by Self-induced Degradation* , 2002, The Journal of Biological Chemistry.

[35]  Yoosik Kim,et al.  Substrate-dependent control of MAPK phosphorylation in vivo , 2011, Molecular systems biology.

[36]  Anke Sparmann,et al.  Polycomb silencers control cell fate, development and cancer , 2006, Nature Reviews Cancer.

[37]  Aaron Ciechanover,et al.  The polycomb protein Ring1B generates self atypical mixed ubiquitin chains required for its in vitro histone H2A ligase activity. , 2006, Molecular cell.

[38]  Claude Desplan,et al.  Stochasticity and Cell Fate , 2008, Science.

[39]  J. Neefjes,et al.  DNA damage triggers nucleotide excision repair-dependent monoubiquitylation of histone H2A. , 2006, Genes & development.

[40]  Haruhiko Koseki,et al.  Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation. , 2004, Developmental cell.

[41]  A. Brunati,et al.  Autocatalytic tyrosine-phosphorylation of protein kinase CK2 alpha and alpha' subunits: implication of Tyr182. , 2001, The Biochemical journal.

[42]  B. Kholodenko,et al.  Signaling switches and bistability arising from multisite phosphorylation in protein kinase cascades , 2004, The Journal of cell biology.

[43]  B. Kholodenko.  Cell-signalling dynamics in time and space , 2006, Nature Reviews Molecular Cell Biology.

[44]  R. V. van Etten,et al.  c-Abl Has High Intrinsic Tyrosine Kinase Activity That Is Stimulated by Mutation of the Src Homology 3 Domain and by Autophosphorylation at Two Distinct Regulatory Tyrosines* , 2000, The Journal of Biological Chemistry.

[45]  D. Dubnau,et al.  Noise in Gene Expression Determines Cell Fate in Bacillus subtilis , 2007, Science.

[46]  Anna Czypionka,et al.  The isolated C-terminal domain of Ring1B is a dimer made of stable, well-structured monomers. , 2007, Biochemistry.

[47]  M. Lohuizen,et al.  The bmi-1 oncoprotein is differentially expressed in non-small cell lung cancer and correlates with INK4A-ARF locus expression , 2001, British Journal of Cancer.

[48]  Dmitri A. Nusinow,et al.  Stable X chromosome inactivation involves the PRC1 Polycomb complex and requires histone MACROH2A1 and the CULLIN3/SPOP ubiquitin E3 ligase. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[49]  Robert E. Kingston,et al.  Mechanisms of Polycomb gene silencing: knowns and unknowns , 2009, Nature Reviews Molecular Cell Biology.

[50]  Hideki Ohdan,et al.  Deubiquitylation of histone H2A activates transcriptional initiation via trans-histone cross-talk with H3K4 di- and trimethylation. , 2008, Genes & development.

[51]  S. Kimura,et al.  A computational model on the modulation of mitogen-activated protein kinase (MAPK) and Akt pathways in heregulin-induced ErbB signalling. , 2003, The Biochemical journal.

[52]  D. Tranchina,et al.  Stochastic mRNA Synthesis in Mammalian Cells , 2006, PLoS biology.

[53]  Yi Zhang,et al.  Structure of a Bmi-1-Ring1B Polycomb Group Ubiquitin Ligase Complex* , 2006, Journal of Biological Chemistry.

[54]  L. Segel,et al.  Extending the quasi-steady state approximation by changing variables. , 1996, Bulletin of mathematical biology.

[55]  B N Kholodenko,et al.  Signal processing at the Ras circuit: what shapes Ras activation patterns? , 2004, Systems biology.

[56]  Nils Blüthgen,et al.  Effects of sequestration on signal transduction cascades , 2006, The FEBS journal.

[57]  Tao Huang,et al.  Prediction of lysine ubiquitination with mRMR feature selection and analysis , 2011, Amino Acids.

[58]  Haruhiko Koseki,et al.  Ring1-mediated ubiquitination of H2A restrains poised RNA polymerase II at bivalent genes in mouse ES cells , 2007, Nature Cell Biology.

[59]  Aaron Ciechanover,et al.  Regulation of the polycomb protein Ring1B by self-ubiquitination or by E6-AP may have implications to the pathogenesis of Angelman syndrome , 2010, Proceedings of the National Academy of Sciences.

[60]  D. Housman,et al.  A transient increase in histone H2A ubiquitination is coincident with the onset of erythroleukemic cell differentiation. , 1988, Blood.

[61]  Lei Wang,et al.  Bistable switches control memory and plasticity in cellular differentiation , 2009, Proceedings of the National Academy of Sciences.

[62]  Hongjuan Cui,et al.  Bmi-1 is essential for the tumorigenicity of neuroblastoma cells. , 2007, The American journal of pathology.

[63]  Boris N Kholodenko,et al.  Long-range signaling by phosphoprotein waves arising from bistability in protein kinase cascades , 2006, Molecular systems biology.

[64]  R Thomas,et al.  A complex control circuit. Regulation of immunity in temperate bacteriophages. , 1976, European journal of biochemistry.

[65]  D. Koshland,et al.  An amplified sensitivity arising from covalent modification in biological systems. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[66]  David M. Livingston,et al.  A Complex with Chromatin Modifiers That Occupies E2F- and Myc-Responsive Genes in G0 Cells , 2002, Science.