Temporal regulation of DNA replication in mammalian cells

Eukaryotic cells follow a temporal program to duplicate their genomes. Chromosomes are divided into domains with a specific DNA replication timing (RT), not dictated by DNA sequence alone, which is conserved from one cell cycle to the next. Timing of replication correlates with gene density, transcriptional activity, chromatin structure and nuclear position, making it an intriguing epigenetic mark. The differentiation from embryonic stem cells to specialized cell types is accompanied by global changes in the RT program. This review covers our current understanding of the mechanisms that determine RT in mammalian cells, its possible biological significance and how unscheduled alterations of the RT program may predispose to human disease.