Circadian Regulation of Cell Division 5
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Circadian Gating of Cell Division
InChlamydomonas, the question whether or not the CDC is under circa-
dian control, has been a never-ending story. WhenChlamydomonascells
entrained by light/dark cycles are placed under constant light, cell divi-
sion persists with a period of 24 hours, suggesting that cell division is
under control of a circadian clock (Bruce 1972). Subsequent studies chal-
lenged the former studies suggesting that the CDC is directly regulated by
light, being dependent on energy available though photosynthesis (Spudich
and Sager 1980). The proposed model is that cell division is dependent on
a timer and a sizer (Donnan and John 1983). Cells divide only when they
have reached a critical size at a specific phase relative to the synchroniz-
ing light/dark cycle but the timer is not a circadian oscillator. Twenty five
years later Goto and Johnson clearly demonstrated that cell division is under
circadian control, fulfilling the three criteria of a circadian regulation: (1) en-
trainment by different photoperiods, (2) persistence under constant condi-
tions, (3) temperature compensation (Goto and Johnson 1995). The current
view is that the circadian clock gates cell division. Every day a circadian-
regulated gate is opened only during a limited time, allowing cell division.
Chlamydomonasdivides by multiple fission, i.e. a cell is able to divide sev-
eral times in a row, when it has reached a critical size. As a result, when
thegateisopenedinthemiddleofthenightcellscandivideseveraltimes
in a row, if they were large enough. Similar gating of cell division has been
described inEuglena,Synechococcus, or in animal cells suggesting that gat-
ing of cell division, which restricts cell division to specific phases of the
day, is widely distributed in living organisms (Cardone and Sassone-Corsi
2003). What is the meaning of the circadian gating of cell division? A se-
ducing hypothesis is that the circadian clock prevents cells from dividing
when DNA is the most exposed to mutations. In agreement with this hy-
pothesis,Chlamydomonascells exposed to UV exhibit a circadian-regulated
rhythm of survival, the most sensitive phases corresponding to the time of
nuclear division (Nikaido and Johnson 2000). The importance of circadian
gating of cell division in tumor suppression has been established in mouse
where the central clock genePeriod2 is required to arrest the CDC pro-
gression in animals exposed toγ-radiation (Fu et al. 2002). Finally, a tight
connection between the cell cycle control and the circadian clock was recently
reported in the fungusNeurospora(Pregueiro et al. 2006). In this organism,
the clock protein Period4 is a checkpoint kinase2 homolog, which is involved
in both the DNA damage checkpoint and cell cycle progression, suggesting
that the cell cycle can feedback to the clock though activation of a common
checkpoint.