  Many organisms possess both a cell cycle to control DNA replication and a
circadian clock to anticipate changes between day and night. In some cases,
these two rhythmic systems are known to be coupled by specific,
cross-regulatory interactions. Here, we use mathematical modeling to show that,
additionally, the cell cycle generically influences circadian clocks in a
non-specific fashion: The regular, discrete jumps in gene-copy number arising
from DNA replication during the cell cycle cause a periodic driving of the
circadian clock, which can dramatically alter its behavior and impair its
function. A clock built on negative transcriptional feedback either phase locks
to the cell cycle, so that the clock period tracks the cell division time, or
exhibits erratic behavior. We argue that the cyanobacterium Synechococcus
elongatus has evolved two features that protect its clock from such
disturbances, both of which are needed to fully insulate it from the cell cycle
and give it its observed robustness: a phosphorylation-based protein
modification oscillator, together with its accompanying push-pull read-out
circuit that responds primarily to the ratios of the different phosphoforms,
makes the clock less susceptible to perturbations in protein synthesis; and the
presence of multiple, asynchronously replicating copies of the same chromosome
diminishes the effect of replicating any single copy of a gene.
