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TECHNICAL ARTICLES
INTERCONNECTED NETWORK OF THE CELL CYCLE, CIRCADIAN RHYTHMS,
AND DNA DAMAGE RESPONSE
[Christian Hong]
Assistant Professor, Molecular and Cellular Physiology
University of Cincinnati College of Medicine
Fundamental cellular processes that maintain most organisms’ health and survival include cell cycle, DNA damage response, and
circadian rhythms. Cell cycle is equipped with multiple checkpoints for controlled growth, DNA replication, and divisions. DNA
damage response (DDR) mechanisms control cell fate by either repairing single or double strand breaks, or triggering apoptosis for
programmed cell death when the damage is fatal. Last, but not least, is circadian rhythm that keeps track of time of a day, and plays a
central role in most organisms for setting the sleep/wake cycle, feeding rhythms, and other daily activities. These distinct molecular
mechanisms communicate with each other and create a complex bio-molecular network to optimize conditions for cells to grow and
adapt to the surrounding environment. Perturbations and dysfunctional cellular responses in this network may lead to diseases such
as cancer, obesity, and sleep disorders among many others.
Figure 1. Simple schematic of
time-delayed negative feedback
loop of Neurospora circadian
rhythms
The mechanistic blueprints of circadian rhythms are similar from Neurospora crassa to Mus musculus
[1]. In Neurospora, the heterodimeric transcription factor, WCC that contains a conserved PAS
domain, activates a core clock component designated frq. The FRQ protein translocates into the
nucleus and inhibits its own transcription factor, WCC. In brief, this creates a time-delayed negative
feedback loop, which is at the heart of circadian rhythms [1] (Figure 1). While this circuit may be
at the core of the circadian clock system, its operation, however, is much more complex involving
interlocked feedback loops, transcriptional, post-transcriptional, and post-translational regulations
[2].
Cell cycle and circadian rhythms are coupled despite their discrete functions. The circadian gated
cell division cycles are observed in various organisms from cyanobacteria to mammals [3-6]. A
mammalian circadian transcription factor, BMAL1/CLOCK, directly binds the E-box in the Wee1
promoter and activates its transcription. WEE1 is one of the key cell cycle kinase that phosphorylates and inactivates the Mitosis
Promoting Factor (MPF) that facilitates the entry into the mitosis. The abundance and activity of WEE1 have been shown to oscillate
and be transiently elevated during the evening in mouse liver [5]. These, in turn, determine the duration of G2-phase. Cells divide
in late evening when the WEE1 level decreases in order to allow cells to enter into the M-phase. The component of the cell cycle
that is controlled by WEE1 operates in concert with another regulatory system that is
periodically imposed on WEE1 by the circadian clock.
The above seemingly unidirectional communication was recently shown to be conditionally
bidirectional. DNA damage induces responses that arrest the cell cycle, or
lead to programmed cell death, e.g. apoptosis. Ionizing radiation causes DNA doublestrand
breaks that trigger signaling cascades via ATM and CHK2 [7]. In Neurospora
crassa (filamentous fungi) and in mammals, the CHK2 checkpoint kinase physically
interacts with a core clock components, FRQ and PER1 [8, 9], respectively, and represents
an intersection point between cell cycle regulation and the circadian clock.
The CHK2 kinase phosphorylates and promotes premature degradations of FRQ/
PER1, which creates phase shifts in the circadian clock (Figure 2). The implications of
such a phenotype raise the hypothesis that the cell cycle machinery utilizes circadian
rhythms to activate WEE1/SWE1 by prematurely degrading FRQ [10]. This degradation
removes the negative feedback on its transcription factor, WCC, which will then
activate Swe1 and arrest cell cycle progression and provide time for DNA repair. There
are additional candidates that participate in the molecular coupling of the cell cycle
and the circadian clock. The transcript of c-Myc oscillates with a circadian period,
and its transcription is suppressed by a heterodimeric circadian transcription factor,
BMAL1/NAPS2 [11]. The molecular details of this coupling, however, remain unex-
Figure 2. DNA damage activates Chk2, which
phosphorylates one of the core circadian clock
component, PER1 in mammals and FRQ in
Neurospora, resulting in phase shifts of circadian
rhythms
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KSEA LETTERS Vol. 40 No. 3 April 2012