The Roles Of Fbxl3in Regulating Circadian Clock

Circadian clock is an autonomous rhythm of the living creatures in order to anticipate daily environmental changes. In most species, circadian clock is generated by transcription-translation feedback loops, which are composed of different clock genes and proteins. In mammals, these feedback loops inter-couple with each other to form a network, which confers the robustness of the clock. Therefore, clock genes in mammals may perform multiple functions to link the different feedback loops. Here this thesis highlights the essential role of the clock protein FBXL3in coupling the circadian feedback loops.In2007, Fbxl3has been identified as a novel clock gene. Mutations of Fbxl3cause severe phenotypes in mice, implying its critical roles in regulating the circadian clock. In the mutant animals, the period of free wheel running extends extremely and the amplitude of circadian oscillatory transcriptions dampens dramatically. Fbxl3encodes an F-box containing protein which is proposed to be a component of E3ligase complex of the ubiquitin pathway. In vitro, FBXL3can strongly promote the ubiquitination of clock protein CRY. In Fbxl3mutant cells, CRY seems to be more stable. Thus it is assumed that FBXL3contributes to the turnover the repressors CRY in vivo. However, due to the network properties of mammalian circadian clock, manipulation of one component usually causes relatively mild phenotypes, suggesting additional functions of FBXL3in vivo.Through an unbiased screen, we find the genetic interaction between Fbxl3and Rev-erba. In addition, FBXL3can regulate the recruitment of Rev-Erba dependent HDAC3repressor complex. In this way, FBXL3influences both of the major feedback loops of the mammalian circadian clock. In the parallel study, our data show that FBXL3can promote not only the degradation of CRY but also the interaction between BMAL1and CRY. This interaction is critical for BMAL1to activate downstream transcription. Therefore this work provides more information about the functions of FBXL3as well as potential therapeutic target for treatment of clock related disorders.