TY - JOUR T1 - Switches, Excitable Responses and Oscillations in the Ring1B/Bmi1 Ubiquitination System A1 - Nguyen, Lan K. A1 - Muñoz-García, Javier A1 - Maccario, Helene A1 - Ciechanover, Aaron A1 - Kolch, Walter A1 - Kholodenko, Boris N. Y1 - 2011/12/15 N2 - Author Summary The generation of polyubiquitin chains on target proteins as a degradation signal was a landmark discovery rewarded by the 2004 Nobel Prize in Chemistry. However, emerging evidence suggests that protein ubiquitination is more versatile. Different types of ubiquitin chains serve numerous non-proteolytic functions, among them regulation of the biological activities of target proteins. Here we demonstrate a flexible role of ubiquitination in the dynamic control of Ring1B, a ubiquitin ligase that monoubiquitinates histone H2A, which in turn silences gene expression. Remarkably, Ring1B increases its own activity by self-ubiquitination. A binding partner of Ring1B, Bmi1, facilitates Ring1B self-ubiquitination and protects both proteins from rapid degradation. We use computational modeling to show that the Ring1B/Bmi1 system can act as analog-digital converter, generating abrupt switches, multistable dynamics, oscillations and excitable overshoots. For instance, an increase in Bmi1 abundance brings about an abrupt “On” switch of Ring1B monoubiquitinating activity and downregulation of H2A-controlled genes, while a decrease in Bmi1 leads to an “Off” switch. These digital responses can display hysteresis, creating the biological memory. Distinct types of Ring1B activity responses (oscillatory, bistable and excitable) facilitate signal discrimination and allow the Ring1B/Bmi1/H2A system to distinctly affect gene silencing and potentially trigger different cell fates. JF - PLOS Computational Biology JA - PLOS Computational Biology VL - 7 IS - 12 UR - https://doi.org/10.1371/journal.pcbi.1002317 SP - e1002317 EP - PB - Public Library of Science M3 - doi:10.1371/journal.pcbi.1002317 ER -