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In per -null flies, ctrip knockdown still increases Clk protein levels but has no effect on tim, implying that ctrip may regulate Clk and per independently from tim ( 4.1.5 Cullin-3 (Cul3) In Drosophila , Cul3, a member of the Cullin E3 ligase family, plays a significant role in circadian regulation ( Cul3 in clock neurons disrupts morning anticipation and induces arrhythmic behavior under constant darkness (DD), while pan-neuronal knockdown causes complete lethality, highlighting its broader essential importance (Szabó et al., 2018)