Temporal and spatial regulation of eukaryotic DNA replication: from regulated initiation to genome-scale timing program.

Replication origins are where pre-replication complexes are assembled during G1 phase. However, only a subset of the origins is actually "fired" to initiate DNA synthesis during S phase. Whereas factors involved in these steps are relatively well understood now, the mechanisms behind the origin specification, the choice of origins to be fired and determination of their timing are still under active investigation. Recent data show that the origin positions as well as the selection of those to be fired may be determined by multiple factors including sequences, chromatin context, epigenetic information, and some specific genomic features, but that the choice is surprisingly plastic and opportunistic. Timing regulation of firing, on the other hand, appears to be related to cell type-specific intrinsic chromatin architecture in nuclei. The conserved Rif1 protein appears to be a major global regulator of the genome-wide replication timing. Replication timing is regulated also by other factors including checkpoint signals, local chromatin structures, timing and quantity of pre-RC formation, and availability of limiting initiation factors.