Replication timing regulation of eukaryotic replicons: Rif1 as a global regulator of replication timing

Origins of DNA replication on eukaryotic genomes have been observed to fire during S phase in a coordinated manner. Studies in yeast indicate that origin firing is affected by several factors, including checkpoint regulators and chromatin modifiers. However, it is unclear what the mechanisms orchestrating this coordinated process are. Recent studies have identified factors that regulate the timing of origin activation, including Rif1 which plays crucial roles in the regulation of the replication timing program in yeast as well as in higher eukaryotes. In mammalian cells, Rif1 appears to regulate the structures of replication timing domains through its ability to organize chromatin loop structures. Regulation of chromatin architecture by Rif1 may be linked to other chromosome transactions including recombination, repair, or transcription. This review summarizes recent progress in the effort to elucidate the regulatory mechanisms of replication timing of eukaryotic replicons.