Journal
SCIENCE
Volume 316, Issue 5826, Pages 900-904Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1141194
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Funding
- MRC [MC_U142684175, MC_U142684173, MC_U142684172, MC_UP_1502/1] Funding Source: UKRI
- Medical Research Council [MC_U142684173, MC_UP_1502/1, MC_U142684172, MC_U142684175] Funding Source: Medline
- NCI NIH HHS [R21-CA125173, R37-CA76584] Funding Source: Medline
- NIGMS NIH HHS [R01-GM57587] Funding Source: Medline
- Medical Research Council [MC_U142684175, MC_U142684172, MC_U142684173, MC_UP_1502/1] Funding Source: researchfish
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One component of the circadian clock in mammals is the Clock-Bmal1 heterodimeric transcription factor. Among its downstream targets, two genes, Cry1 and Cry2, encode inhibitors of the Clock-Bmal1 complex that establish a negative-feedback loop. We found that both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCFFbxl3 ubiquitin ligase complex. This regulation by SCFFbxl3 is a prerequisite for the efficient and timely reactivation of Clock-Bmal1 and the consequent expression of Per1 and Per2, two regulators of the circadian clock that display tumor suppressor activity. Silencing of Fbxl3 produced no effect in Cry1(-/-); Cry2(-/-) cells, which shows that Fbxl3 controls clock oscillations by mediating the degradation of CRY proteins.
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