TY - JOUR
T1 - Circadian Mutant Overtime Reveals F-box Protein FBXL3 Regulation of Cryptochrome and Period Gene Expression
AU - Siepka, Sandra M.
AU - Yoo, Seung Hee
AU - Park, Junghea
AU - Song, Weimin
AU - Kumar, Vivek
AU - Hu, Yinin
AU - Lee, Choogon
AU - Takahashi, Joseph S.
N1 - Funding Information:
We thank Michele Pagano and Pat Nolan for communicating unpublished results; Steven Reppert for clock gene expression plasmids; Lawrence H. Pinto for help with mutagenesis; Renee McGurk, Min Cheng, Dawn Olson, and Jennifer Wakowiak for mouse production, phenotyping, genotyping, and DNA sequencing; Ethan Buhr, Kazuhiro Shimomura, and Ming-Lee Chow for assistance with experiments; Andrew Schook for in situ hybridization experiments; and Kate Montgomery and Alex Tamburino at Harvard Partners Genome Center for DNA sequencing and analysis of candidate genes. Research supported by NIH grants U01 MH61915, P50 MH074924, and R01 MH078024 to J.S.T. and R01 NS053616 to C.L. J.S.T. is an Investigator in the Howard Hughes Medical Institute.
PY - 2007/6/1
Y1 - 2007/6/1
N2 - Using a forward genetics ENU mutagenesis screen for recessive mutations that affect circadian rhythmicity in the mouse, we isolated a long period (∼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, Fbxl3Ovtm defines a molecular link between CRY turnover and CLOCK/BMAL1-dependent circadian transcription to modulate circadian period.
AB - Using a forward genetics ENU mutagenesis screen for recessive mutations that affect circadian rhythmicity in the mouse, we isolated a long period (∼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, Fbxl3Ovtm defines a molecular link between CRY turnover and CLOCK/BMAL1-dependent circadian transcription to modulate circadian period.
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U2 - 10.1016/j.cell.2007.04.030
DO - 10.1016/j.cell.2007.04.030
M3 - Article
C2 - 17462724
AN - SCOPUS:34249097203
SN - 0092-8674
VL - 129
SP - 1011
EP - 1023
JO - Cell
JF - Cell
IS - 5
ER -