Global and local regulation of replication origin activity

Eukaryotic genomes are replicated from multiple initiation sites called DNA replication origins. Different origins fire at different times during S phase, giving rise to a characteristic temporal order to genome replication. However, the physiological role for temporal regulation of the order of genome replication remains largely unknown. Powerful genomic approaches have allowed genome replication dynamics to be characterised in various mutants and a range of species. Work in several organisms has revealed that limiting levels of trans-acting replication initiation factors are likely to play a role in determining origin firing time. This raises the question of how the initiation factors distinguish between origins. Recent work has started to identify cis-acting elements at origins that might be responsible for characteristic firing times. The identification of mechanisms that regulate the temporal order of genome replication is starting to allow investigation of potential physiological roles for temporally regulated replication.