June 30, 2006 — Dartmouth Medical School
geneticists have discovered that DNA damage resets the cellular
circadian clock, suggesting links among circadian timing, the cycle of
cell division, and the propensity for cancer.
Their work, reported June 29 in Science Express, the advance
electronic publication of Science, implies a protective dimension for
the biological clock in addition to its pacemaker functions that play
such a sweeping role in the rhythms and activities of life.
"The notion that the clock regulates DNA-damage input and that
mutation can affect the clock as well as the cell cycle is novel," says
Jay Dunlap, professor and chair of genetics at DMS. "It suggests a
fundamental connection among circadian timing, cell cycle progress, and
potentially the origins of some cancers."
Dunlap is a co-author of the paper with DMS colleagues, Jennifer
Loros, professor of biochemistry, graduate student Christopher L.
Baker, and former students António M. Pregueiro and Qiuyun Liu.
The team of Loros and Dunlap were among to first to delineate the
intricate web of clockwork genes, proteins and feedback loops that
drive circadian rhythms, working chiefly in the classic genetic model
organism Neurospora, the common bread mold.
One gene (period-4) was identified over 25 years ago by a mutation
that affects two clock properties, shortening the circadian period and
altering temperature compensation. For this study, the researchers
cloned the gene based on its position in the genome, and found it was
an important cell cycle regulator. When they eliminated the gene from
the genome, the clock was normal, indicating that the mutation
interfered in some way with the clock, rather than supplying something
that the clock normally needs to run.
Biochemically, the mutation results in a premature modification of
the well understood clock protein, frequency (FRQ). The investigators
demonstrated that this was a direct result of action by an enzyme,
called in mammals checkpoint kinase-2 (CHK2), whose normal role is
exclusively in regulating the cell division cycle. CHK2 physically
interacts with FRQ; the mutation makes this interaction much stronger.
However, a mutant enzyme that has lost its activity has no effect on
Normally CHK2 is involved in the signal response pathway that begins
when DNA is damaged and results in a temporary stoppage of cell
division until the damage is fixed. The researchers found that the
resetting effect of DNA damage requires the period-4 clock protein, and
that period-4 is the homolog, the Neurospora version, of the mammalian
Moreover, the clock regulates expression of the period-4 gene. This
closes a loop connecting the clock to period-4 and period-4 to the
clock and the cell cycle. The clock normally modulates expression of
this gene that encodes an important cell cycle regulator, and that cell
cycle regulator in turn affects not only the cell cycle but also the
Recent evidence in mammalian cells shows that other cell cycle
regulators physically interact with clock proteins. Loss of at least
one clock protein (mammalian period-2) is known to increase cancer
susceptibility. The coordination of the clock and cell division through
cell cycle checkpoints, supports the clock’s "integral role in basic
cell biology," conclude the researchers." Their work can help advance
understanding of cancer origins as well as the timing of anti-cancer
Source : Dartmouth Medical School