title: Switches, excitable responses and oscillations in the Ring1B/Bmi1 ubiquitination system.
abstract: 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.
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Lan K
authors.initials: LK
authors.lastname: Nguyen
authors.forename: Javier
authors.initials: J
authors.lastname: Muñoz-García
authors.forename: Helene
authors.initials: H
authors.lastname: Maccario
authors.forename: Aaron
authors.initials: A
authors.lastname: Ciechanover
authors.forename: Walter
authors.initials: W
authors.lastname: Kolch
authors.forename: Boris N
authors.initials: BN
authors.lastname: Kholodenko
mesh_terms: D003198:Computer Simulation; D020868:Gene Silencing; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D063146:Polycomb-Group Proteins; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D009687:Nuclear Proteins; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex