  In eukaryotes, DNA replication is initiated along each chromosome at multiple
sites called replication origins. Locally, each replication origin is
"licensed", or specified, at the end of the M and the beginning of G1 phases of
the cell cycle. During S phase when DNA synthesis takes place, origins are
activated in stages corresponding to early and late replicating domains. The
staged and progressive activation of replication origins reflects the need to
maintain a strict balance between the number of active replication forks and
the rate at which DNA synthesis procedes. This suggests that origin densities
(frequency of intiation) and replication fork movement (rates of elongation)
must be co-regulated in order to guarantee the efficient and complete
duplication of each subchromosomal domain. Emerging evidence supports this
proposal and suggests that the ATM/ATR intra-S phase checkpoint plays an
important role in the co-regulation of initiation frequencies and rates of
elongation. In the following, we review recent results concerning the
mechanisms governing the global regulation of DNA replication and discuss the
roles these mechanisms play in maintaining genome stability during both a
normal and perturbed S phase.
