Paradoxes of eukaryotic DNA replication: MCM proteins and the random completion problem

Hyrien, Olivier; Marheineke, Kathrin; Goldar, Arach

doi:10.1002/bies.10208

Cited by 187 publications

(209 citation statements)

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“…An interesting property of the MCM complex is that there is a large excess of this complex compared with the amount of the origin recognition complex on chromatin (14,48,49). In particular, in Xenopus egg extracts, ϳ10 -40 MCM complexes appear to be loaded onto the DNA for each origin recognition complex particle (12).…”

Section: Discussionmentioning

confidence: 99%

Mcm2 Is a Direct Substrate of ATM and ATR during DNA Damage and DNA Replication Checkpoint Responses

Yoo

Shevchenko

Dunphy

2004

Journal of Biological Chemistry

120

107

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Section: Discussionmentioning

confidence: 99%

Mcm2 Is a Direct Substrate of ATM and ATR during DNA Damage and DNA Replication Checkpoint Responses

Yoo

Shevchenko

Dunphy

2004

Journal of Biological Chemistry

120

107

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“…Metazoan origins lack a consensus sequence and often contain cis-regulatory elements embedded in complex genomes (DePamphilis, 2005), which has made it difficult to identify such origins on a genome-wide scale and at the resolution required to investigate origin utilization. In somatic cells, the median replicon size has been estimated to be between 50 and 300 kb (Berezney et al, 2000), but in preblastula embryos of Drosophila or Xenopus DNA replication initiates every 8-15 kb, leading to a reduction in S-phase length compared with somatic cells (Hyrien et al, 2003). The transition from the inefficient replication that takes place in differentiated erythrocyte nuclei in Xenopus egg extracts to efficient replication more typical of early development is dependent on the re-programming of replicon organization during mitosis and results in shorter interorigin distances (Lemaitre et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Genome-wide characterization of fission yeast DNA replication origins

Heichinger

Penkett

Bähler

et al. 2006

EMBO J

197

358

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Eukaryotic DNA replication is initiated from multiple origins of replication, but little is known about the global regulation of origins throughout the genome or in different types of cell cycles. Here, we identify 401 strong origins and 503 putative weaker origins spaced in total every 14 kb throughout the genome of the fission yeast Schizosaccharomyces pombe. The same origins are used during premeiotic and mitotic S-phases. We found that few origins fire late in mitotic S-phase and that activating the Rad3 dependent S-phase checkpoint by inhibiting DNA replication had little effect on which origins were fired. A genome-wide analysis of eukaryotic origin efficiencies showed that efficiency was variable, with large chromosomal domains enriched for efficient or inefficient origins. Average efficiency is twice as high during mitosis compared with meiosis, which can account for their different S-phase lengths. We conclude that there is a continuum of origin efficiency and that there is differential origin activity in the mitotic and meiotic cell cycles.

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“…1) 6,22 . To avoid the random gap problem, it has been argued that there must be some mechanism to coordinate origin firing so as to avoid large random gaps 22 .…”

Section: Introductionmentioning

confidence: 99%

“…Second, stochastic firing of origins leads to the so-called 'random gap' problemrandomly distributed origin firing will occasionally lead to large gaps between replication bubbles that would take an inordinately long time to replicate (Fig. 1) 6,22 . To avoid the random gap problem, it has been argued that there must be some mechanism to coordinate origin firing so as to avoid large random gaps 22 .…”

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confidence: 99%

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DNA replication timing: random thoughts about origin firing

2006

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Regions of metazoan genomes replicate at defined times within S phase. This observation suggests that replication origins fire with a defined timing pattern that remains the same from cycle to cycle. However, an alterative model based on the stochastic firing of origins may also explain replication timing. This model assumes varying origin efficiency instead of a strict origin-timing programme. Here, we discuss the evidence for both models.Models for the organization of eukaryotic DNA replication have to account for two diametrically opposed conceptions of replication. On one side of the spectrum is the replicon paradigm, exemplified by the mechanism of bacterial replication, in which origins are welldefined sites that fire once in each cell cycle, leading to uniform replication that is identical in every cell 1 . At the opposite end of the spectrum is the mechanism of replication in frog and fly embryos, in which replication initiates asynchronously throughout S phase at indiscriminate sites, presumably leading to a different, random pattern of replication in each cell 2,3 . It is clear that neither of these extreme mechanisms reflect the reality of replication in most eukaryotic somatic cells, but it is also clear that both models contain a kernel of truth. So how do we reconcile these apparently competing views of replication? Recent work suggests a way to bridge the gap and to reconcile stochastic origin firing with defined patterns of genome replication.It is useful to first establish which parts of each model generally apply to eukaryotic replication. The replicon paradigm, which serves as the foundation for most textbook models of eukaryotic replication, describes eukaryotic replication reasonably well, with two major exceptions: first, most eukaryotes do not seem to have well-defined, sequence-specific origins4 , 5. Consequently, it has been difficult to identify metazoan replication origins, and in the few cases in which they have been identified, they seem to have no particular sequence specificity. However, too few metazoan origins have been defined to exclude the possibility of origin specific sequences. The question of what constitutes a eukaryotic replication origin remains an active field of research, and as knowledge of the exact location of origins is not necessary for the ideas presented here, we will not pursue it further. Second, eukaryotic origins are inefficient and fire in only a subset of S phases 6 -only a fraction of the origins established in G1 are fired in S phase and it is a different set in each cell. In fission yeast, most origins fire about 30% of the time, whereas in mammals, the well-studied dihydrofolate reductase (DHFR) origins fire approximately 20% of the time 7, 8.In terms of these two exceptions to the replicon paradigm, eukaryotic replication looks more like the example of frog and fly embryos. Frog embryos go to the extreme of establishing origins randomly across the genome, without regard to DNA sequence 2,9 . This is not the case for eukaryotes in general, whi...

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Paradoxes of eukaryotic DNA replication: MCM proteins and the random completion problem

Cited by 187 publications

References 84 publications

Mcm2 Is a Direct Substrate of ATM and ATR during DNA Damage and DNA Replication Checkpoint Responses

Mcm2 Is a Direct Substrate of ATM and ATR during DNA Damage and DNA Replication Checkpoint Responses

Genome-wide characterization of fission yeast DNA replication origins

DNA replication timing: random thoughts about origin firing

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