Abstract
Circadian rhythms provide temporal information to other cellular processes, such as metabolism. We investigate the coupling between the cell cycle and the circadian clock using mathematical modeling and experimentally validate model-driven predictions with a model filamentous fungus,
Neurospora crassa
. We demonstrate a conserved coupling mechanism between the cell cycle and the circadian clock in Neurospora as in mammals, which results in circadian clock-gated mitotic cycles. Furthermore, we observe circadian clock-dependent phase shifts of G1 and G2 cyclins, which may alter the timing of divisions. Our work has large implications for the general understanding of the connection between the cell cycle and the circadian clock.
The cell cycle and the circadian clock communicate with each other, resulting in circadian-gated cell division cycles. Alterations in this network may lead to diseases such as cancer. Therefore, it is critical to identify molecular components that connect these two oscillators. However, molecular mechanisms between the clock and the cell cycle remain largely unknown. A model filamentous fungus,
Neurospora crassa
, is a multinucleate system used to elucidate molecular mechanisms of circadian rhythms, but not used to investigate the molecular coupling between these two oscillators. In this report, we show that a conserved coupling between the circadian clock and the cell cycle exists via serine/threonine protein kinase-29 (STK-29), the Neurospora homolog of mammalian WEE1 kinase. Based on this finding, we established a mathematical model that predicts circadian oscillations of cell cycle components and circadian clock-dependent synchronized nuclear divisions. 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
frq
ko
mutant. Additionally, we show the light-induced phase shifts of a core circadian component,
frq
, as well as the gene expression of the cell cycle components
clb-1
and
stk-29
, which may alter the timing of divisions. We then used a histone hH1-GFP reporter to observe nuclear divisions over time, and show that a large number of nuclear divisions occur in the evening. Our findings demonstrate the circadian clock-dependent molecular dynamics of cell cycle components that result in synchronized nuclear divisions in Neurospora.