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Abstract
Studies from a number of model systems have shown that the circadian clock controls expression of key cell cycle checkpoints, thus providing permissive or inhibitory windows in which specific cell cycle events can occur. However, a major question remains: Is the clock actually regulating the cell cycle through such a gating mechanism or, alternatively, is there a coupling process that controls the speed of cell cycle progression? Using our light-responsive zebrafish cell lines, we address this issue directly by synchronizing the cell cycle in culture simply by changing the entraining light-dark (LD) cycle in the incubator without the need for pharmacological intervention. Our results show that the cell cycle rapidly reentrains to a shifted LD cycle within 36 h, with changes in p21 expression and subsequent S phase timing occurring within the first few hours of resetting. Reentrainment of mitosis appears to lag S phase resetting by 1 circadian cycle. The range of entrainment of the zebrafish clock to differing LD cycles is large, from 16 to 32 hour periods. We exploited this feature to explore cell cycle entrainment at both the population and single cell levels. At the population level, cell cycle length is shortened or lengthened under corresponding T-cycles, suggesting that a 1:1 coupling mechanism is capable of either speeding up or slowing down the cell cycle. However, analysis at the single cell level reveals that this, in fact, is not true and that a gating mechanism is the fundamental method of timed cell cycle regulation in zebrafish. Cell cycle length at the single cell level is virtually unaltered with varying T-cycles.
Highlights
Studies from a number of model systems have shown that the circadian clock controls expression of key cell cycle checkpoints, providing permissive or inhibitory windows in which specific cell cycle events can occur
Zebrafish Cell Cycle Rhythms Are Rapidly Reentrained to a Reverse LD Cycle
We know a considerable amount about circadian clock entrainment in zebrafish, very little is known about how the cell cycle becomes entrained to an environmental LD cycle
Summary
Studies from a number of model systems have shown that the circadian clock controls expression of key cell cycle checkpoints, providing permissive or inhibitory windows in which specific cell cycle events can occur. Cyclin B1 expression rhythms have been implicated in regulating mitotic timing, whereas p21 and the related p20 gene appear to be essential for the clock regulation of DNA replication, or S phase timing (Tamai et al, 2012; Laranjeiro et al, 2013) All of these results point to the idea that the clock directly regulates well-established cell cycle checkpoint pathways and, in this way, establishes a “circadian checkpoint” mechanism for temporal cell cycle control. Such results imply that the clock uses these circadian checkpoints to create a window or gate that is either permissive or repressive for cell cycle progression. Is the clock coupling to the cell cycle through such a gating mechanism?
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