Minimum Criteria for DNA Damage-Induced Phase Advances in Circadian Rhythms

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Abstract
Robust oscillatory behaviors are common features of circadian and cell cycle rhythms. These cyclic processes, however, behave distinctively in terms of their periods and phases in response to external influences such as light, temperature, nutrients, etc. Nevertheless, several links have been found between these two oscillators. Cell division cycles gated by the circadian clock have been observed since the late 1950s. On the other hand, ionizing radiation (IR) treatments cause cells to undergo a DNA damage response, which leads to phase shifts (mostly advances) in circadian rhythms. Circadian gating of the cell cycle can be attributed to the cell cycle inhibitor kinase Wee1 (which is regulated by the heterodimeric circadian clock transcription factor, BMAL1/CLK), and possibly in conjunction with other cell cycle components that are known to be regulated by the circadian clock (i.e., c-Myc and cyclin D1). It has also been shown that DNA damage-induced activation of the cell cycle regulator, Chk2, leads to phosphorylation and destruction of a circadian clock component (i.e., PER1 in Mus or FRQ in Neurospora crassa). However, the molecular mechanism underlying how DNA damage causes predominantly phase advances in the circadian clock remains unknown. In order to address this question, we employ mathematical modeling to simulate different phase response curves (PRCs) from either dexamethasone (Dex) or IR treatment experiments. Dex is known to synchronize circadian rhythms in cell culture and may generate both phase advances and delays. We observe unique phase responses with minimum delays of the circadian clock upon DNA damage when two criteria are met: (1) existence of an autocatalytic positive feedback mechanism in addition to the time-delayed negative feedback loop in the clock system and (2) Chk2-dependent phosphorylation and degradation of PERs that are not bound to BMAL1/CLK. Molecular components and mechanisms that connect cell cycle and circadian rhythms are important for the well-being of an organism. Cell cycle machinery regulates the progress of cell growth and division while the circadian rhythm network generates an ∼24 h time-keeping mechanism that regulates the daily processes of an organism (i.e. metabolism, bowel movements, body temperature, etc.). It is observed that cell divisions usually occur during a certain time window of a day, which indicated that there are circadian-gated cell divisions. Moreover, it's been shown that mice are more prone to develop cancer when certain clock genes are mutated resulting in an arrhythmic clock. Recently, a cell cycle checkpoint regulator, Chk2, was identified as a component that influences a core clock component and creates mostly phase advances (i.e., jet lags due to traveling east) in circadian rhythms upon DNA damage. This phase response with minimum delays is an unexpected result, and the molecular mechanism behind this phenomenon remains unknown. Our computational analyses of a mathematical model reveal two molecular criteria that account for the experimentally observed phase responses of the circadian clock upon DNA damage. These results demonstrate how circadian clock regulation by cell cycle checkpoint controllers provides another layer of complexity for efficient DNA damage responses.