The Cell Cycle & Circadian Clock: a tale of two cycles

Most organisms have evolved an internal timekeeper to anticipate and coordinate internal processes with the external 24-h environment imposed upon all living creatures due to rotation of the Earth around its axis. At the cellular level, the circadian clock is generated by a genetic program in which genes and their protein products generate a molecular oscillator. In mammal cells, this oscillator consists of one essential negative transcription/translation feedback loop and several other positive and negative feedback loops that function mainly to confer robustness and precision to the core negative feedback loop. The work described in Chapter 2 shows that exposure of mice to a mutagenic compound at different times-of-day did not result in differences in mutation frequency. Chapter 3 shows that mice lacking the Cry1 gene or the Cry2 gene have circadian gene expression programs in peripheral tissues like liver and kidney that are out of phase with their behavior. Despite this internal dissonance, the mice did not have decreased survival curves. Chapter 4 shows that even though the Cry genes control cell cycle progression, they do so regardless of an intact circadian clock. Furthermore, this chapter provides evidence that the circadian clock does not control cell cycle progression under normal conditions and after exposure to genotoxic stress in a cell-autonomous manner. Conversely, Chpater 5 shows that genotoxic stress exposure does affect the circadian clock in cells and in mice in an ATM-dependent manner. Chapter 6 shows that microRNAs control the circadian clock by posttranscriptionally controlling expression of clock genes.