title: Competing E3 ubiquitin ligases govern circadian periodicity by degradation of CRY in nucleus and cytoplasm.
abstract: 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.
authors: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Seung-Hee
authors: SH
authors: Yoo
authors: Jennifer A
authors: JA
authors: Mohawk
authors: Sandra M
authors: SM
authors: Siepka
authors: Yongli
authors: Y
authors: Shan
authors: Seong Kwon
authors: SK
authors: Huh
authors: Hee-Kyung
authors: HK
authors: Hong
authors: Izabela
authors: I
authors: Kornblum
authors: Vivek
authors: V
authors: Kumar
authors: Nobuya
authors: N
authors: Koike
authors: Ming
authors: M
authors: Xu
authors: Justin
authors: J
authors: Nussbaum
authors: Xinran
authors: X
authors: Liu
authors: Zheng
authors: Z
authors: Chen
authors: Zhijian J
authors: ZJ
authors: Chen
authors: Carla B
authors: CB
authors: Green
authors: Joseph S
authors: JS
authors: Takahashi
mesh_terms: D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D003433:Crosses, Genetic; D056931:Cryptochromes / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D059748:Proteolysis
chemical_list: C538964:Cry1 protein, mouse; C538967:Cry2 protein, mouse; D056931:Cryptochromes; D044783:F-Box Proteins; C580664:Fbxl21 protein, mouse; C519794:Fbxl3 protein, mouse; D056926:CLOCK Proteins; C538944:Clock protein, mouse