Replication in context: dynamic regulation of DNA replication patterns in metazoans

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Abstract
In metazoa, the entire genome can replicate once each cell cycle without requiring that replication initiate from particular sequences, suggesting that the role of discrete replication initiation programmes is to coordinate replication with gene expression and chromosome condensation. Specific sequences (replicators) determine the ability to initiate DNA replication in cis. The likelihood of initiation from a particular replicator at a specific time during the cell cycle can be modulated by distal sequences and epigenetic modifications. The location of initiation events is affected by distal sequences that often also affect transcription. The location and timing of initiation events often vary with transcription but it is unclear whether the movement of the transcriptional machinery can, by itself, determine initiation sites. Enzymes that modify chromatin, and proteins that recruit such enzymes to particular genomic loci, can affect the location and the timing of initiation events. In certain organisms, the initiation of DNA replication is not limited to specific regions during early embryogenesis; such regions are specified later in development concurrent with chromatin remodelling. Differentiation of specific cell lineages often alters the location and timing of replication initiation in certain loci, concomitant with changes in gene expression. Flexibility in the location and timing of initiation events might help maintain an appropriate number of replication forks during S phase to help preserve genomic stability.