Licensing Transcription Activator Activity with Ubiquitin Time Clocks

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Cells of complex higher organisms rely on information contained in their DNA genomes to provide instructions for development and how to respond to changes in their environment. The majority of information in the cell's genome is stored in genes that can be accessed by reading them, resulting in so-called gene expression. Gene expression is fine-tuned by the action of many different factors, amongst which activator proteins play a pivotal role. Activators exhibit potent activity that recruits all the other necessary factors for the expression of their target genes. They are therefore indispensable for accessing the information contained in genes but at the same time their strong activity poses a serious threat, as excessive gene expression can lead to genome instability and mutation. Accordingly, failure to correctly regulate the activity of activators often has catastrophic pathological consequences for an organism, including cancer cell formation, hormone imbalance, and either autoimmunity or low immune function. Despite the serious penalties associated with activator dysfunction, little is understood about how cells regulate their activity. Recently, data from our lab and others showed that many potent activators are unstable proteins because they are fused with chains of the small protein ubiquitin, a signal for activator degradation. From these data it has been hypothesized that cells provide activators with a limited license for activity and when this license expires the activator is degraded. While this is an attractive mechanism for keeping activators in check, the molecular identity of this license and the length of its validity remain elusive. Our latest genetic experiments suggest that we are now able to trap activators in their fully licensed states by mutating enzymes that potentially modify the length of ubiquitin chains fused to activators. Here we will investigate these enzymes in detail as they point to ubiquitin chain length being an adjustable time clock for activator activity. Using genetic, genomic, and biochemical tools we will identify all ubiquitin chain modifying enzymes involved in this process and assess their role in licensing activator activity. Unravelling the mechanisms by which activator activity is fine-tuned will provide deep insight into how higher organisms -from humans to plants- regulate access to information contained within their genomes. Such fundamental knowledge offers the foundation for designing new medicines or therapies to tackle a range of human diseases and for modernizing agriculture with novel crop protection strategies.