CK2 slows movement of TIMELESS out of the nucleus and changes CLOCK activity to regulate daily body rhythms

Identification of 12 phosphorylation sites on TIM reveals critical roles in circadian timekeeping.

• At least two TIM phosphorylation sites are essential for maintaining normal behavioral rhythms.
• Mutants with non-phosphorylatable TIM mutations display altered circadian rhythms.
• CK2-dependent phosphorylation of TIM(S1404) prevents its interaction with the nuclear export component Exportin 1 (XPO1), promoting nuclear accumulation of PER-TIM complexes.
• This nuclear accumulation is proposed to be necessary for the regulation of daily phosphorylation rhythms and phase-specific gene activity of CLOCK (CLK).
• Findings suggest a new mechanism where TIM phosphorylation influences the balance between negative (PER-TIM) and positive (CLK-CYC) elements of the circadian clock.
• The molecular characteristics of the tim(S1404A) mutant show similarities to a mutation in human timeless associated with familial advanced sleep phase syndrome (FASPS).

Simplified