Gene Symbol: Fbxl3
Description: F-box and leucine-rich repeat protein 3
Alias: AU041772, AW212966, FBK, Fbl3a, Fbxl3a, Ovtm, Play68, F-box/LRR-repeat protein 3, F-box and leucine-rich repeat protein 3a, F-box/LRR-repeat protein 3A, protein after-hours, protein overtime
Species: mouse
Products:     Fbxl3

Top Publications

  1. Siepka S, Yoo S, Park J, Song W, Kumar V, Hu Y, et al. Circadian mutant Overtime reveals F-box protein FBXL3 regulation of cryptochrome and period gene expression. Cell. 2007;129:1011-23 pubmed
    ..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...
  2. Bacon Y, Ooi A, Kerr S, Shaw Andrews L, Winchester L, Breeds S, et al. Screening for novel ENU-induced rhythm, entrainment and activity mutants. Genes Brain Behav. 2004;3:196-205 pubmed
    ..Mutant loci do not correspond with those previously associated with wheel-running behaviour. This result confirms that phenotype-driven approaches such as this should continue to provide material for mammalian gene function studies. ..
  3. Busino L, Bassermann F, Maiolica A, Lee C, Nolan P, Godinho S, et al. SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins. Science. 2007;316:900-4 pubmed
    ..We found that both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex...
  4. Godinho S, Maywood E, Shaw L, Tucci V, Barnard A, Busino L, et al. The after-hours mutant reveals a role for Fbxl3 in determining mammalian circadian period. Science. 2007;316:897-900 pubmed
    ..The mutation, a Cys(358)Ser substitution in Fbxl3, an F-box protein with leucine-rich repeats, results in long free-running rhythms of about 27 hours in homozygotes...
  5. Maywood E, Chesham J, Meng Q, Nolan P, Loudon A, Hastings M. Tuning the period of the mammalian circadian clock: additive and independent effects of CK1?Tau and Fbxl3Afh mutations on mouse circadian behavior and molecular pacemaking. J Neurosci. 2011;31:1539-44 pubmed publisher
    ..We therefore examined interactions between two mutations in male mice: Fbxl3(Afh), which lengthens period by stabilizing CRY, and Csnk1?(tm1Asil) (CK1?(Tau)), which destabilizes PER, thereby ..
  6. Yumimoto K, Muneoka T, Tsuboi T, Nakayama K. Substrate binding promotes formation of the Skp1-Cul1-Fbxl3 (SCF(Fbxl3)) protein complex. J Biol Chem. 2013;288:32766-76 pubmed publisher
    ..b>Fbxl3 is an F-box protein that is responsible for the ubiquitylation and consequent degradation of cryptochromes (Crys) ..
  7. Maywood E, Chesham J, O Brien J, Hastings M. A diversity of paracrine signals sustains molecular circadian cycling in suprachiasmatic nucleus circuits. Proc Natl Acad Sci U S A. 2011;108:14306-11 pubmed publisher
    ..Thus, a hierarchy of paracrine neuropeptidergic signals determines cell- and circuit-level circadian pacemaking in the SCN. ..
  8. Guilding C, Scott F, Bechtold D, Brown T, Wegner S, Piggins H. Suppressed cellular oscillations in after-hours mutant mice are associated with enhanced circadian phase-resetting. J Physiol. 2013;591:1063-80 pubmed publisher
    ..Together, these findings reveal unexpected consequences of the Afh mutation on the amplitude and synchrony of individual cellular oscillators in the SCN. ..
  9. Huber A, Papp S, Chan A, Henriksson E, Jordan S, Kriebs A, et al. CRY2 and FBXL3 Cooperatively Degrade c-MYC. Mol Cell. 2016;64:774-789 pubmed publisher
    ..Here we describe an unexpected function for the circadian repressor CRY2 as a component of an FBXL3-containing E3 ligase that recruits T58-phosphorylated c-MYC for ubiquitylation...

More Information


  1. Shi G, Xie P, Qu Z, Zhang Z, Dong Z, An Y, et al. Distinct Roles of HDAC3 in the Core Circadian Negative Feedback Loop Are Critical for Clock Function. Cell Rep. 2016;14:823-834 pubmed publisher
    ..In subjective night, however, HDAC3 blocks FBXL3-mediated CRY1 degradation and strongly promotes BMAL1 and CRY1 association...
  2. St John P, Hirota T, Kay S, Doyle F. Spatiotemporal separation of PER and CRY posttranslational regulation in the mammalian circadian clock. Proc Natl Acad Sci U S A. 2014;111:2040-5 pubmed publisher
    ..Two such regulators, casein kinase 1 (CKI) and F-box and leucine-rich repeat protein 3 (FBXL3), modulate the stability of closely linked core clock proteins period (PER) and cryptochrome (CRY), respectively...
  3. Anand S, Maywood E, Chesham J, Joynson G, Banks G, Hastings M, et al. Distinct and separable roles for endogenous CRY1 and CRY2 within the circadian molecular clockwork of the suprachiasmatic nucleus, as revealed by the Fbxl3(Afh) mutation. J Neurosci. 2013;33:7145-53 pubmed publisher
    ..of CRY1 and CRY2 within circadian timing in vivo, we exploited the N-ethyl-N-nitrosourea-induced afterhours mutant Fbxl3(Afh) to stabilize endogenous CRY...
  4. Wegner S, Belle M, Hughes A, Diekman C, Piggins H. Delayed Cryptochrome Degradation Asymmetrically Alters the Daily Rhythm in Suprachiasmatic Clock Neuron Excitability. J Neurosci. 2017;37:7824-7836 pubmed publisher
    ..Loss-of-function point mutations in a component of this ligase complex, Fbxl3, delay CRY1/2 degradation, reduce circadian rhythm strength, and lengthen the circadian period by ?2.5 h...
  5. Peterson K, King B, Hagge Greenberg A, Roix J, Bult C, O Brien T. Functional and comparative genomic analysis of the piebald deletion region of mouse chromosome 14. Genomics. 2002;80:172-84 pubmed
    ..Our studies combining computational gene prediction with genetic and comparative genomic analyses provide insight regarding the functional composition and organization of this defined chromosomal region. ..
  6. Shi G, Xing L, Liu Z, Qu Z, Wu X, Dong Z, et al. Dual roles of FBXL3 in the mammalian circadian feedback loops are important for period determination and robustness of the clock. Proc Natl Acad Sci U S A. 2013;110:4750-5 pubmed publisher
    ..We found that the deletion of Rev-erb? in F-box/leucine rich-repeat protein (Fbxl3)-deficient mice rescued its long-circadian period phenotype, and our results further revealed that FBXL3 regulates ..
  7. Hirano A, Yumimoto K, Tsunematsu R, Matsumoto M, Oyama M, Kozuka Hata H, et al. FBXL21 regulates oscillation of the circadian clock through ubiquitination and stabilization of cryptochromes. Cell. 2013;152:1106-18 pubmed publisher
    ..Previous studies revealed that FBXL3, an F-box-type E3 ligase, ubiquitinates CRYs and mediates their degradation...
  8. Yoo S, Mohawk J, Siepka S, Shan Y, Huh S, Hong H, et al. Competing E3 ubiquitin ligases govern circadian periodicity by degradation of CRY in nucleus and cytoplasm. Cell. 2013;152:1091-105 pubmed publisher
    ..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...
  9. Xing W, Busino L, Hinds T, Marionni S, Saifee N, Bush M, et al. SCF(FBXL3) ubiquitin ligase targets cryptochromes at their cofactor pocket. Nature. 2013;496:64-8 pubmed publisher
    ..The SCF(FBXL3) ubiquitin ligase complex controls this negative feedback loop by promoting CRY ubiquitination and degradation...
  10. Keers R, Pedroso I, Breen G, Aitchison K, Nolan P, Cichon S, et al. Reduced anxiety and depression-like behaviours in the circadian period mutant mouse afterhours. PLoS ONE. 2012;7:e38263 pubmed publisher
    ..mutant, after hours (Afh), an ENU-derived mutant with a mutation in a recently identified circadian clock gene Fbxl3, results in a disturbed (long) circadian rhythm of approximately 27 hours...