Exploration of a melanoma antigen (MAGE)-E3 ubiquitin ligase circuit governing circadian rhythm

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All animals, including humans, undergo a 24-hour cycle of activities such as eating and sleeping. This circadian rhythm is primarily driven by external cues (sunlight) but is maintained by a highly regulated set of physiological and cellular processes. Inside the cell, selected proteins are produced, become active, or are inactivated at specific time points in the 24-hour cycle. These proteins are required for circadian rhythm: without them, the 24-hour oscillation of sleeping and other behaviours becomes abnormal or absent. This research program investigates the process by which key circadian rhythm proteins are regulated and inactivated, and how this form of regulation contributes to the maintenance of circadian rhythm. Many proteins are inactivated through the addition of a small molecule (ubiquitin), which serves as a flag that targets these proteins for inactivation and disposal. The proteins that add the ubiquitin molecule (called E3 ligases) cooperate with other proteins (called MAGE proteins) to complete the ubiquitylation process. There are 400 E3 ligases and 60 MAGE proteins, and combinations of these two types of proteins are used by the cell to accurately recognize which proteins to target for disposal and when to go about this process. Our previous NSERC-funded research demonstrated that when the MAGEL2 protein is absent (in a genetically engineered mouse), circadian rhythm is disrupted. We will now focus on discovering how MAGEL2 interacts with the many E3 ligase proteins that are important in circadian rhythm. We will test whether MAGEL2 affects the ability of the E3 ligases to add ubiquitin to key circadian rhythm proteins, and whether MAGEL2 regulates the stability and function of circadian rhythm proteins. This program will shed light on the molecular basis of the 24-hour circadian rhythm that is one of the most fundamental properties of animal behavior.