Replication timing and transcriptional control: beyond cause and effect

In general, transcriptionally active euchromatin replicates during the first half of S phase, whereas silent heterochromatin replicates during the second half. Moreover, changes in replication timing accompany key stages of development. Although there is not a strict correlation between replication timing and transcription per se, recent results reveal a strong relationship between heritably repressed chromatin and late replication that is conserved in all eukaryotes. A long-standing question is whether replication timing dictates the structure of chromatin or vice versa. Mounting evidence supports a model in which replication timing is both cause and consequence of chromatin structure by providing a means to inherit chromatin states that, in turn, regulate replication timing in the subsequent cell cycle. Moreover, new findings relating aberrations in replication timing to defects in centromere function, chromosome cohesion and genome instability suggest that the role of replication timing extends beyond its relationship to transcription. Novel systems in both yeasts and mammals are finally beginning to reveal some of the determinants that regulate replication timing, which should pave the way for a long-anticipated molecular dissection of this complex liaison.