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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.

Pubmed ID: 17462724

Authors

  • Siepka SM
  • Yoo SH
  • Park J
  • Song W
  • Kumar V
  • Hu Y
  • Lee C
  • Takahashi JS

Journal

Cell

Publication Data

June 1, 2007

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:

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