Table 1.
Ubiquitin-modifying enzymes involved in the regulation of mammalian clock proteins.
| Clock protein | Mammalian enzyme | Phenotype of mice, tissues, or cells upon loss-of-function mutation or knock-down of ubiquitin-modifying enzyme | Drosophila homolog | References |
|---|---|---|---|---|
| Ubiquitin ligases | ||||
| CRY1/2 | FBXL3 | Long free-running period of locomotor activity rhythms, cultured fibroblasts and SCN; stabilized CRYs; dampened and delayed rhythms of Per and Cry mRNAs; phenotype partly rescued by Fbxl21 loss-of-function. | Godinho et al. (2007), Siepka et al. (2007), Hirano et al. (2013), Yoo et al. (2013) | |
| FBXL21 | Normal or short free-running period of locomotor activity rhythms; short period of cultured fibroblasts, SCN and pituitary; destabilized CRYs (when subcellular fractions were studied, the mutation stabilized CRY1 in cytoplasm and destabilized it in the nucleus); mutation partly rescues Fbxl3 loss-of-function. | Dardente et al. (2008), Hirano et al. (2013), Yoo et al. (2013) | ||
| PER1/2 | β-TRCP1 (FBW1A), β-TRCP2 (FBW1B) | Dampened or long-period rhythms in fibroblasts; stabilized PERs; β-Trcp1 KO mice have no circadian-related phenotype. | SLIMB | Eide et al. (2005), Shirogane et al. (2005), Reischl et al. (2007), Ohsaki et al. (2008) |
| REV-ERBα | HUWE1 (ARF-BP1) | Stabilized REV-ERBα, decreased Bmal1/Cry1 expression (knock-down of both HUWE1 and PAM together). | CG8184 | Yin et al. (2010) |
| PAM (MYCBP2) | Stabilized REV-ERBα, decreased Bmal1/Cry1 expression (knock-down of both HUWE1 and PAM together). | Highwire | Yin et al. (2010) | |
| FBXL3? | Long-period phenotype of Fbxl3 mutants rescued by Rev-erbα KO; dampened but more sustained REV-ERBα levels in Fbxl3 mutants, and prolonged REV-ERBα transcriptional activity. | Shi et al. (2013) | ||
| BMAL1 | UBE3A | Dampening and longer period of circadian rhythms in cultured fibroblasts. | dUBE3A | Gossan et al. (2014) |
| Deubiquitinating enzymes | ||||
| CRY1 | USP2 | Decreased CRY1 protein levels in liver (with Usp2 knock-down). | Tong et al. (2012) | |
| PER1 | USP2 | Slightly elongated free-running period of locomotor activity rhythms; altered response to light; altered clock gene expression and increased levels of ubiquitinated PER1 in fibroblasts; no change in PER1 stability; alteration in the timing of PER1 intracellular localization. | Yang et al. (2012, 2014) | |
| BMAL1 | USP2 | Normal free-running period and slightly altered light response; reduced BMAL1 levels in the SCN. | Lee et al. (2008), Scoma et al. (2011) | |