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In cultured cells, co-expression of jet and cry is sufficient to recapitulate light-induced degradation of tim, suggesting that jet transduces cry-dependent light input to tim ( Beyond tim, jet has also been shown to mediate light-induced degradation of cry itself, indicating a broader role in light-responsive circadian protein turnover ( in vivo studies demonstrate that jet binds to cry in a light-induced manner, and that jet deficiency leads to cry accumulation in fly heads and cultured cells ( 4.1.12 MDM2 The E3 ligase MDM2 ubiquitinates PER2 at conserved lysine residues in mammalian cells, promoting its proteasomal degradation and regulating circadian period length ( 4.1.13 morgue morgue is a unique ubiquitin pathway protein in Drosophila notable for its dual-domain structure containing an F-box and a non-catalytic E2-conjugase domain ( 4.1.14 SIAH2 SIAH2 (Seven in Absentia 2) is a RING-type E3 ubiquitin ligase that promotes the ubiquitination and proteasomal degradation of REV-ERB and REB-ERB, two core repressors in the circadian clock ( SIAH2 deletion modestly affects expression of other clock genes such as BMAL1 and PER2 but does not significantly alter REV-ERB protein rhythms, likely due to compensatory E3 ligases ( SIAH2 deficiency in female mice leads to a phase-advanced circadian liver transcriptome and altered lipid rhythms, revealing an intriguing sex-specific role for UPS regulation in circadian rhythms, whose cause remains unknown ( 4.1.15 Supernumerary limbs (slmb) and -TrCP1 and -TrCP2 The Drosophila Cullin-RING E3 ligase component slmb, encoded by slmb , and its mammalian orthologs -TrCP1 and -TrCP2 (F-box proteins within the SCF complex) are critical regulators of circadian timing through their control of per and tim protein stability ( Slmb mutants fail to anticipate light-to-dark transitions under light/dark (LD) conditions and display completely arrhythmic behavior under constant darkness (DD), indicating disrupted circadian control ( slmb in Pdf-positive neurons, highlighting its essential role in the clock network ( In mammals, -TrCP1 and -TrCP2 similarly recognize, and target phosphorylated PER proteins, particularly following casein kinase 1 (CK1) phosphorylation, for degradation ( 4.1.16 STUB1 STIP1 homology U-box-containing protein 1 STUB1, also known as C terminus of HSP70-interacting protein (CHIP), is a multifunctional protein with both chaperone activity and U-box-dependent E3 ubiquitin ligase activity ( STUB1 , but not of a catalytically inactive mutant, leads to reduced BMAL1 protein levels, confirming its role in regulating BMAL1 stability through K48-linked polyubiquitination and proteasomal degradation ( 4.1.17 TRAF7 Tumor Necrosis Factor Receptor-Associated Factor 7 (TRAF7), a RING-type E3 ubiquitin ligase, has recently been identified as a key regulator of circadian timing through its modulation of DBP, a clock-controlled transcription factor that drives rhythmic gene expression via D-box elements ( TRAF7 promotes DBP degradation, while TRAF7 knockdown up-regulated DBP and disrupts its time-of-daydependent oscillation

For example, PER1 gene activity, which is often reduced in tumor progression, has been examined as a possible pathway of interest