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Initially identified as a CRY1-interacting protein in a high-throughput yeast two-hybrid screen ( TRAF2 overexpression enhances BMAL1 ubiquitination and proteasomal degradation, thereby attenuating E-box-mediated transcription and dampening PER1 oscillations ( 4.1.18 UBE3A UBE3A, an E3 ubiquitin ligase previously implicated in Angelman syndrome and HPV-related tumorigenesis, has recently emerged as a conserved regulator of the circadian clock through its post-translational control of BMAL1 stability ( UBE3A achieved via expression of the HPV E6/E7 oncogenesin murine fibroblasts significantly disrupted circadian oscillations, reduced BMAL1 protein levels, and increased BMAL1 ubiquitination ( In Drosophila , both overexpression and knockdown of Ube3a in central clock neurons resulted in pronounced alterations in circadian locomotor rhythms, indicating that tight regulation of Ube3a levels is essential for proper pacemaker function across species ( Ube3a exhibited significant circadian deficits, supporting the notion that Ube3a is an integral component of the Drosophila circadian clock ( 4.1.19 UBE2O UBE2O, a unique ubiquitin-conjugating enzyme with hybrid E2/E3 ligase activity ( UBE2O overexpression leads to a dose-dependent reduction of endogenous BMAL1, while its knockdown increases BMAL1 protein levels ( UBE2O overexpression attenuates BMAL1-driven transcription and dampens downstream circadian outputs, while its silencing increases PER2 rhythm amplitude, confirming its role in maintaining clock dynamics ( 4.2 Deubiquitinating enzymes and their role in circadian regulation 4.2.1 Deubiquitinating enzymes Deubiquitinases (DUBs) are enzymes that remove ubiquitin moieties from target proteins, reversing the action of E3 ubiquitin ligases and thereby shaping ubiquitin signaling with high accuracy (Table 2)