Journal
CELL
Volume 152, Issue 5, Pages 1091-1105Publisher
CELL PRESS
DOI: 10.1016/j.cell.2013.01.055
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Funding
- NIH [U01 MH61915, R01 MH078024, P50 MH074924, R01 GM090247, R01 GM63692, F32 DA024556]
- Howard Hughes Medical Institute
- Welch Foundation [I-1389]
- American Heart Association [11SDG7600045]
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Period determination in the mammalian circadian clock involves the turnover rate of the repressors CRY and PER. We show that CRY ubiquitination engages two competing E3 ligase complexes that either lengthen or shorten circadian period in mice. Cloning of a short-period circadian mutant, Past-time, revealed a glycine to glutamate missense mutation in Fbxl21, an F-box protein gene that is a paralog of Fbxl3 that targets the CRY proteins for degradation. While loss of function of FBXL3 leads to period lengthening, mutation of Fbxl21 causes period shortening. FBXL21 forms an SCF E3 ligase complex that slowly degrades CRY in the cytoplasm but antagonizes the stronger E3 ligase activity of FBXL3 in the nucleus. FBXL21 plays a dual role: protecting CRY from FBXL3 degradation in the nucleus and promoting CRY degradation within the cytoplasm. Thus, the balance and cellular compartmentalization of competing E3 ligases for CRY determine circadian period of the clock in mammals.
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