Nuclear Position Leaves Its Mark on Replication Timing

The multiple replication origins of eukaryotic chromosomes are programmed to replicate at specific times throughout S phase of the cell cycle. The functional significance of this program is not understood, but, in general, transcriptionally active chromatin replicates early in S phase, whereas hypoacetylated, transcriptionally inactive chromatin replicates later. During metazoan development, multiple origins, encompassing megabase domains of chromosomes, exhibit replication timing switches that precede gene activation and accompany changes in chromatin structure (Selig et al. 1992). These early- and late-replicating chromosomal domains are localized to distinct spatial compartments of the metazoan nucleus where DNA synthesis can be observed to take place at defined times during S phase. Recently, it has been shown both in budding yeast (Raghuraman et al. 1997) and in mammalian cells (Dimitrova and Gilbert 1999) that replication origins are marked...