Circadian mutant Overtime reveals F-box protein FBXL3 regulation of cryptochrome and period gene expression.
Using a forward genetics ENU mutagenesis screen for recessive mutations that affect circadian rhythmicity in the mouse, we isolated a long period (approximately 26 hr) circadian mutant named Overtime (Ovtm). Positional cloning and genetic complementation reveal that Ovtm is encoded by the F-box protein FBXL3, a component of the SKP1-CUL1-F-box-protein ... (SCF) E3 ubiquitin ligase complex. The Ovtm mutation causes an isoleucine to threonine (I364T) substitution leading to a loss of function in FBXL3, which interacts specifically with the CRYPTOCHROME (CRY) proteins. In Ovtm mice, expression of the PERIOD proteins PER1 and PER2 is reduced; however, the CRY proteins CRY1 and CRY2 are unchanged. The loss of FBXL3 function leads to a stabilization of the CRY proteins, which in turn leads to a global transcriptional repression of the Per and Cry genes. Thus, Fbxl3(Ovtm) defines a molecular link between CRY turnover and CLOCK/BMAL1-dependent circadian transcription to modulate circadian period.
Mesh Terms:
Amino Acid Sequence, Amino Acid Substitution, Animals, Biological Clocks, Cell Cycle Proteins, Circadian Rhythm, Cryptochromes, F-Box Proteins, Female, Flavoproteins, Gene Expression Regulation, Humans, Male, Mice, Mice, Inbred Strains, Molecular Sequence Data, Mutagenesis, Nuclear Proteins, Period Circadian Proteins, Transcription Factors, Transcription, Genetic
Amino Acid Sequence, Amino Acid Substitution, Animals, Biological Clocks, Cell Cycle Proteins, Circadian Rhythm, Cryptochromes, F-Box Proteins, Female, Flavoproteins, Gene Expression Regulation, Humans, Male, Mice, Mice, Inbred Strains, Molecular Sequence Data, Mutagenesis, Nuclear Proteins, Period Circadian Proteins, Transcription Factors, Transcription, Genetic
Cell
Date: Jun. 01, 2007
PubMed ID: 17462724
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