CK2 Inhibits TIMELESS Nuclear Export and Modulates CLOCK Transcriptional Activity to Regulate Circadian Rhythms

Nov 20, 2020Current biology : CB

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

AI simplified

Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

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).

AI simplified

Circadian clocks orchestrate daily rhythms in organismal physiology and behavior to promote optimal performance and fitness. In Drosophila, key pacemaker proteins PERIOD (PER) and TIMELESS (TIM) are progressively phosphorylated to perform phase-specific functions. Whereas PER phosphorylation has been extensively studied, systematic analysis of site-specific TIM phosphorylation is lacking. Here, we identified phosphorylation sites of PER-bound TIM by mass spectrometry, given the importance of TIM as a modulator of PER function in the pacemaker. Among the 12 TIM phosphorylation sites we identified, at least two of them are critical for circadian timekeeping as mutants expressing non-phosphorylatable mutations exhibit altered behavioral rhythms. In particular, we observed that CK2-dependent phosphorylation of TIM(S1404) promotes nuclear accumulation of PER-TIM heterodimers by inhibiting the interaction of TIM and nuclear export component, Exportin 1 (XPO1). We propose that proper level of nuclear PER-TIM accumulation is necessary to facilitate kinase recruitment for the regulation of daily phosphorylation rhythm and phase-specific transcriptional activity of CLOCK (CLK). Our results highlight the contribution of phosphorylation-dependent nuclear export of PER-TIM heterodimers to the maintenance of circadian periodicity and identify a new mechanism by which the negative elements of the circadian clock (PER-TIM) regulate the positive elements (CLK-CYC). Finally, because the molecular phenotype of tim(S1404A) non-phosphorylatable mutant exhibits remarkable similarity to that of a mutation in human timeless that underlies familial advanced sleep phase syndrome (FASPS), our results revealed an unexpected parallel between the functions of Drosophila and human TIM and may provide new insights into the molecular mechanisms underlying human FASPS.

Full Text

We can’t show the full text here under this license. Use the link below to read it at the source.

View full text (XML) ↗View full text ↗

CK2 Inhibits TIMELESS Nuclear Export and Modulates CLOCK Transcriptional Activity to Regulate Circadian Rhythms

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief