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. 2022 Nov;44(11):e2200097.
doi: 10.1002/bies.202200097. Epub 2022 Sep 20.

DNA replication timing: Biochemical mechanisms and biological significance

Nicholas Rhind  1
Affiliations

DNA replication timing: Biochemical mechanisms and biological significance

Nicholas Rhind. Bioessays. 2022 Nov.

Abstract

The regulation of DNA replication is a fascinating biological problem both from a mechanistic angle-How is replication timing regulated?-and from an evolutionary one-Why is replication timing regulated? Recent work has provided significant insight into the first question. Detailed biochemical understanding of the mechanism and regulation of replication initiation has made possible robust hypotheses for how replication timing is regulated. Moreover, technical progress, including high-throughput, single-molecule mapping of replication initiation and single-cell assays of replication timing, has allowed for direct testing of these hypotheses in mammalian cells. This work has consolidated the conclusion that differential replication timing is a consequence of the varying probability of replication origin initiation. The second question is more difficult to directly address experimentally. Nonetheless, plausible hypotheses can be made and one-that replication timing contributes to the regulation of chromatin structure-has received new experimental support.

Keywords: DNA replication origin; DNA replication timing; MCM; ORC; Origin activation; S-phase regulation; Stochastic model.

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Conflict of interest statement

Conflict of Interest Statement

The author declares no conflict of interest.

Figures

Figure 1:
Figure 1:. Replication initiation site usage in bacteria, budding yeast and mammals
A) Genomic maps showing the circular E. coli chromosome opened in a linear format, Chromosome VI of S. cerevisiae, and the Top1 region of Human Chromosome 20. The blue bars depict the bacterial and yeast origins and the human initiation zones. For yeast, only the seven most efficient origins are shown. The red lines depict three genes in the Top1 region. The numbers indicate the length of the maps. B) The probability of firing in early S phase (approximately the first 10% for yeast and the first 2% for human) for each genomic region. For yeast and humans, replication continues to initiate throughout S phase, so more initiations events will occur later in these regions, if they are not passively replicated first. For yeast, because the available long-fiber, single-molecule initiation data is sparse[23], the initiation-probability graph is approximate and the efficiency of only the 7 most efficient origins on Chromosome VI are shown. However, bulk[119] and nanopore-based single-molecule data[120] show similar probabilities of firing. For humans, the experimentally determined initiation probability of the region is shown[30]. C) The distribution of early initiation events on 25 different genomes of each species. As in B, the yeast distribution is from Czajkowsky et al.[23] and the human distribution is from Wang et al.[30]. Note that about 10% of budding yeast initiations are not at the 7 indicated origins, but presumably initiate at lower-probability origins, a result consistent with nanopore-based single-molecule data[120].
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