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Jan 16, 2014

Shifting the Molecular Gears Linking Circadian and Mitotic Clockwork

  • The circadian rhythm, an internal clock synchronized to light-dark cycles and other external cues, regulates various metabolic processes including the cell division cycle. Whereas a mechanical clock measures out time by means of springs, gears, and other mechanisms, the circadian clock schedules metabolic events through a network of molecular oscillators. That sounds complicated, and it is. Nonetheless, scientists at the University of Cincinnati (UC) have been able to identify the molecular components linking the circadian clock and the cell cycle.

    Alas, a cell’s molecular oscillators are less easily observed than a clock’s internal workings. To study these oscillators, the UC scientists resorted to computer models and a model organism, Neurospora crassa, a filamentous fungus. These investigative modes were more than convenient; they also proved to be fortuitous. They helped the UC scientists demonstrate a coupling mechanism that turns out to be conserved. This mechanism, which links the circadian clock and the cell cycle, exists via serine/threonine protein kinase-29 (STK-29), which happens to be the Neurospora homolog of mammalian WEE1 kinase. The coupling, the scientists determined, results in circadian clock-gated mitotic phases.

    These findings were detailed in an article published January 13 in the Proceedings of the National Academy of Sciences, in an article entitled “Circadian rhythms synchronize mitosis in Neurospora cassa.” In this article, the scientists write, “We experimentally demonstrate that G1 and G2 cyclins, CLN-1 and CLB-1, respectively, oscillate in a circadian manner with bioluminescence reporters. The oscillations of clb-1 and stk-29 gene expression are abolished in a circadian arrhythmic frqko mutant.”

    Additionally, the CU researchers conducted phase-shift experiments in which they transferred Neurospora to constant darkness, then administered a 90-minute pulse of white fluorescent light at indicated time points in order to induce phase-shift. Ordinarily, the organism’s cell divisions happened during a certain time of day and were molecularly regulated by the mechanism of circadian rhythms. Yet, by altering lighting conditions, the scientists showed that “when we phase-shift the circadian clock, we also observe phase-shifting of the cell cycle components,” said study leader Christian Hong, Ph.D.

    By building on experimentally validated mathematical models from Neurospora, the researchers hope to make predictions in other Neurospora strains and mammalian cells. As Hong puts it, “This discovery will serve as a stepping stone for further investigations to uncover conserved principles of coupled mechanisms between the cell cycle and circadian rhythms.”

    In the work ahead, the scientists will need to overcome a technical difficulty: it is hard to estimate the doubling time of mitotic cycles in Neurospora. This difficulty is significant because the doubling time is related to coupling strengths and oscillation frequencies, estimates of which help distinguish between different coupling mechanisms. Unlike a mechanical clock, the circadian pacemaker may have flexible couplings; that is, coupling may be strong or weak depending on factors such as aging or nutrient conditions. The coupling mechanisms, in fact, may be described as informational. From this perspective, the exploration of computer models seems especially apt.



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