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PhD Transfer Exam – Sara Hegazi (Cheng/Levine labs)
December 17, 2015 @ 11:10 am - 12:10 pm
PhD Transfer Examination
Thursday December 17th, 11:10 am – DV 3129, University of Toronto at Mississauga
Sara Hegazi (Cheng/Levine labs)
“Elucidating the role of UBR4/POE in the regulation of circadian rhythms in Mus musculus and Drosophila melanogaster“
Abstract
Most organisms possess a widely conserved timekeeping mechanism that is synchronized by daily light:dark cycles to generate 24-hour oscillations in physiology and behaviour. This regulatory mechanism is controlled by a central pacemaker located within the 20,000 neurons of the suprachiasmatic nucleus (SCN) in mammals and within a network of 150 neurons in D. melanogaster.
The central pacemaker achieves circadian regulation through the generation of rhythmic gene expression, where post-translational modifications play a critical role. Post-translational ubiquitination of clock proteins via interactions with ubiquitin ligases marks them for degradation, resetting the clock’s machinery. In a recent mass spectrometry screen, a novel ubiquitin ligase, UBR4, was identified in the murine SCN following light stimulation. Mutant mice for the ubr4 gene exhibit abnormal behavioural rhythms. This suggests that UBR4 is critical for circadian regulation. However, the molecular mechanisms underlying its function remain unknown.
The novelty of UBR4 in circadian timekeeping and its sequence homology across species have prompted the outstanding investigation of its function. I will be carrying out this investigation in two model organisms, M. musculus and D. melanogaster, utilizing the unique advantages offered by each organism for studying circadian timing. I have successfully shown that POE, the fly homolog of UBR4, plays a pivotal role in the generation of behavioural and molecular rhythms. However, the underlying mechanisms are unknown.
My project aims to elucidate the biochemical mechanisms underlying the UBR4/POE-mediated circadian regulation, and to determine whether UBR4/POE is functionally conserved between insects and mammals. Ultimately, my work will establish UBR4/POE as a key regulator in circadian timekeeping, and will potentially permit the extrapolation of our findings to higher organisms such as humans.