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This study investigates how circadian clocks maintain a stable roughly 24-hour period across varying temperatures, a property known as temperature compensation. The researchers demonstrate that two conserved protein kinases in Drosophila, DBT (CK1) and CK2, each contribute to temperature compensation through distinct molecular pathways: DBT acts via specific phosphorylation sites on the clock protein PER, while CK2 targets a phosphocluster on TIM and a separate PER residue. When both pathways are disrupted simultaneously, hyperphosphorylated PER accumulates and is inefficiently cleared from the nuclei of pacemaker neurons, pointing to nuclear PER phosphorylation dynamics as a central mechanism buffering circadian period against temperature fluctuations.
Why it matters
Understanding the molecular basis of temperature compensation in circadian clocks has broader implications for human health, as circadian disruption is linked to metabolic, neurological, and psychiatric disorders, and may inform therapeutic strategies targeting clock kinases.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Circadian (~24 h) rhythms are essential for the survival of most organisms, as they optimize physiology and behavior with the time of day. They are defined by three fundamental properties: they are driven by a self-sustained molecular oscillator, entrained by environmental cues such as light and temperature, and temperature-compensated, whereby circadian period remains close to 24 h over a physiological range of temperatures. The molecular basis of temperature compensation remains incompletely understood. Here, we build on previous studies supporting a conserved and important role for phosphorylation-dependent mechanisms in the control of temperature compensation. We found that reducing the activity of two highly conserved circadian kinases, DBT (casein kinase [CK] 1) and CK2, disrupts temperature compensation in Drosophila. Genetic analyses indicate that DBT and CK2 act through distinct pathways that have additive effects on temperature compensation. DBT acts through the perShort phosphorylation cluster and the S47 phosphodegron of the core clock protein PER, both of which are required for normal thermal compensation. In contrast, CK2 acts through a phosphocluster in TIM as well as PER S45 residue. Interestingly, simultaneous disruption of both pathways causes accumulation of hyperphosphorylated PER, which is inefficiently cleared from the nucleus of circadian pacemaker neurons. Combined with previous work, our findings support a central and unifying role for nuclear PER phosphorylation dynamics in buffering circadian period against environmental temperature fluctuations.