Rhythms in red blood cells and the ever-present casein kinase

My latest research was published in Journal of Biological Rhythms this week. It is open access here: Casein Kinase 1 Underlies Temperature Compensation of Circadian Rhythms in Human Red Blood Cells.

How CK1 works in a RBC
Casein Kinase 1 modifies circadian rhythms in red blood cells

Red blood cells have a fun history in chronobiology. Eight years ago, my current boss, John O’Neill showed conclusively that there are circadian rhythms in human red blood cells using a technique that measured the state and abundance of a group of proteins called peroxiredoxins. This paper caused quite a stir because it showed that rhythms exist in a cell type that doesn’t have clock genes, contrary to perceived wisdom. We’re still not sure if these rhythms are unique to this cell type (though many other cases exist where rhythms can be seen without clock genes turning on or off), or if there is a fundamental underlying mechanism which might be applicable to all life.

This is where the results of my paper fit in. We show a key role for an enzyme called casein kinase 1. Casein kinase 1 has its own history, being the gene that was mutated in the first mammalian circadian mutant – a hamster discovered by Ralph and Menaker in 1988. It has subsequently adopted a key position in the clock gene model of transcription-translation feedback loop as an enzyme that modifies the status of core proteins such as the Period proteins of mammals and flies, but also plays roles in algae and fungi which have different ‘clock’ proteins. We reasoned if it has such a general role across many species, independent from the specific identity of a ‘clock’ protein, maybe it has a role when ‘clock’ proteins aren’t present?

It does – and disrupting it manipulates the period, length, of the circadian rhythm of red blood cells just as it does in every other case. We also showed that it plays a role in temperature compensation (a key feature of circadian rhythms), meaning that it has a very key role in the circadian clock of red cells. We still don’t know what that core mechanism is, but we’re working on it!

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