Replicating by the clock

Abstract

The genome is organized into distinct 1–2 Mb bands that contain numerous origins, which are coordinated to replicate in a programmed manner during S phase. These bands represent subunits of chromosome structure and function. There is a general correlation between replication timing and gene expression. Housekeeping genes replicate early in S phase, whereas many tissue-specific genes are developmentally regulated — they replicate late in most cell types and early in the tissue of expression. Genes that are expressed monoallelically replicate asynchronously in S phase, with one allele copied earlier than the other. This mechanism functions as an epigenetic mark for distinguishing between the alleles, and it is used both for genomic imprinting and for setting up allelic exclusion in the immune system and at olfactory-receptor gene loci. Asynchronous replication timing at several regions on each autosome is coordinated, and this might be carried out by individual control centres in a way that is similar to X inactivation. The genomic replication-timing pattern is set up during the G1 stage of the cell cycle through interactions between cis-acting sequences and trans-acting factors that bring about epigenetic changes that have an impact on the firing of nearby replication origins during S phase. This process is probably controlled by cell-cycle-regulated factors. Late replication might function as a mechanism for maintaining gene repression through many cell generations by causing DNA to be repackaged with deacetylated histones after passage through the replication fork. By contrast, early-replicating DNA is assembled with acetylated histones. In this way, replication time might influence gene accessibility.