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Circadian mutant Overtime reveals F-box protein FBXL3 regulation of cryptochrome and period gene expression.

Cell | Jun 1, 2007

http://www.ncbi.nlm.nih.gov/pubmed/17462724

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.

Pubmed ID: 17462724 RIS Download

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

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Associated grants

  • Agency: NIMH NIH HHS, Id: P50 MH074924
  • Agency: NIMH NIH HHS, Id: P50 MH074924
  • Agency: NIMH NIH HHS, Id: R01 MH078024
  • Agency: NIMH NIH HHS, Id: R01 MH078024
  • Agency: NINDS NIH HHS, Id: R01 NS053616
  • Agency: NINDS NIH HHS, Id: R01 NS053616
  • Agency: NIMH NIH HHS, Id: U01 MH061915
  • Agency: NIMH NIH HHS, Id: U01 MH61915
  • Agency: Howard Hughes Medical Institute, Id:

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