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Universal temporal profile of replication origin activation in eukaryotes.

Goldar A, Marsolier-Kergoat MC, Hyrien O - PLoS ONE (2009)

Bottom Line: We have identified a universal behavior of eukaryotic replication initiation that transcends the mechanisms of origin specification.The population-averaged efficiency of replication origin usage changes during S phase in a strikingly similar manner in a highly diverse set of eukaryotes.The quantitative model previously proposed for origin activation in X. laevis can be generalized to explain this evolutionary conservation.

View Article: PubMed Central - PubMed

Affiliation: Commissariat à l'Energie Atomique (CEA), iBiTec-S, Gif-sur-Yvette, France. arach.goldar@cea.fr

ABSTRACT
Although replication proteins are conserved among eukaryotes, the sequence requirements for replication initiation differ between species. In all species, however, replication origins fire asynchronously throughout S phase. The temporal program of origin firing is reproducible in cell populations but largely probabilistic at the single-cell level. The mechanisms and the significance of this program are unclear. Replication timing has been correlated with gene activity in metazoans but not in yeast. One potential role for a temporal regulation of origin firing is to minimize fluctuations in replication end time and avoid persistence of unreplicated DNA in mitosis. Here, we have extracted the population-averaged temporal profiles of replication initiation rates for S. cerevisiae, S. pombe, D. melanogaster, X. laevis and H. sapiens from genome-wide replication timing and DNA combing data. All the profiles have a strikingly similar shape, increasing during the first half of S phase then decreasing before its end. A previously proposed minimal model of stochastic initiation modulated by accumulation of a recyclable, limiting replication-fork factor and fork-promoted initiation of new origins, quantitatively described the observed profiles without requiring new implementations.The selective pressure for timely completion of genome replication and optimal usage of replication proteins that must be imported into the cell nucleus can explain the generic shape of the profiles. We have identified a universal behavior of eukaryotic replication initiation that transcends the mechanisms of origin specification. The population-averaged efficiency of replication origin usage changes during S phase in a strikingly similar manner in a highly diverse set of eukaryotes. The quantitative model previously proposed for origin activation in X. laevis can be generalized to explain this evolutionary conservation.

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Collapse of all I(t').All curves were shifted horizontally so that their starting points coincide with zero. The similarity distance (dsim) between the I(t') of other eukaryotes and the I(t') of X. laevis (Black) was measured using the Continuous Dynamic Time Warping method (see Material and Methods). By using the X. laevis data dispersion (gray error bars) we set the condition that if the measured distance between two curves is smaller than 0.94, the two curves are similar. In all cases we found dsim<0.94, therefore all I(t'), including the one generated by the numerical model, could be considered as similar. However, its possible to define a sequence of decreasing similarity between considered I(t') as: H. sapiens ‘s chromosome 6 (dsim = 0.27, Dark yellow)>D. melanogaster (dsim = 0.38, Orange)>numerical model (dsim = 0.41, Magenta)>S. pombe from Heichinger et al (dsim = 0.43, Olive)>H. sapiens (dsim = 0.44, Purple)>S. pombe from Eshaghi et al (dsim = 0.55, Blue)>S. cerevisiae (dsim = 0.85, Red).
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pone-0005899-g003: Collapse of all I(t').All curves were shifted horizontally so that their starting points coincide with zero. The similarity distance (dsim) between the I(t') of other eukaryotes and the I(t') of X. laevis (Black) was measured using the Continuous Dynamic Time Warping method (see Material and Methods). By using the X. laevis data dispersion (gray error bars) we set the condition that if the measured distance between two curves is smaller than 0.94, the two curves are similar. In all cases we found dsim<0.94, therefore all I(t'), including the one generated by the numerical model, could be considered as similar. However, its possible to define a sequence of decreasing similarity between considered I(t') as: H. sapiens ‘s chromosome 6 (dsim = 0.27, Dark yellow)>D. melanogaster (dsim = 0.38, Orange)>numerical model (dsim = 0.41, Magenta)>S. pombe from Heichinger et al (dsim = 0.43, Olive)>H. sapiens (dsim = 0.44, Purple)>S. pombe from Eshaghi et al (dsim = 0.55, Blue)>S. cerevisiae (dsim = 0.85, Red).

Mentions: The time-dependent rate of replication origin activation, I(t), is defined as an average over the whole genome. Therefore it is independent of chromosomal position and represents the population-averaged dynamic process that controls origin usage and replication fork density, whether calculated from DNA combing or replication timing profiles. The theoretical I(t) calculated using the previously developed stochastic model is also an average of 500 simulations. The I(t) calculated either way can thus be compared. To compare the I(t) of different organisms, plots had to be normalized. S phase length and initiation frequency depend on many parameters that can vary among organisms and according to growth conditions. For example HU-treated S. cerevisiae cells exhibit an extended S phase compared to untreated cells although their rate of origin initiation is unaffected when related to the fraction of replicated DNA [27]. We therefore normalized replication time with respect to S phase length. Similarly, the maximum value of I(t) depends on the concentration of factors limiting origin efficiency [29]–[31]. Each I(t) was thus normalized by its maximum value and plotted as a function of reduced time t' (t' = t/tend). As shown in Figure 3, all the I(t') collapse together and have a maximum value at mid S-phase. The calculated agreement with the X. laevis data (see legend to Fig 3) appears particularly good for S. pombe, which relies on a largely stochastic mechanism for origin initiation, and for H. sapiens and D. melanogaster. The curve appears broader for S. cerevisiae, perhaps because cell synchrony was less tight, or because there is a clearer demarcation of early and late replicating domains in this organism [32]. Importantly, the I(t') calculated using the minimal stochastic model that we have previously developed [26] could account for all these observations.


Universal temporal profile of replication origin activation in eukaryotes.

Goldar A, Marsolier-Kergoat MC, Hyrien O - PLoS ONE (2009)

Collapse of all I(t').All curves were shifted horizontally so that their starting points coincide with zero. The similarity distance (dsim) between the I(t') of other eukaryotes and the I(t') of X. laevis (Black) was measured using the Continuous Dynamic Time Warping method (see Material and Methods). By using the X. laevis data dispersion (gray error bars) we set the condition that if the measured distance between two curves is smaller than 0.94, the two curves are similar. In all cases we found dsim<0.94, therefore all I(t'), including the one generated by the numerical model, could be considered as similar. However, its possible to define a sequence of decreasing similarity between considered I(t') as: H. sapiens ‘s chromosome 6 (dsim = 0.27, Dark yellow)>D. melanogaster (dsim = 0.38, Orange)>numerical model (dsim = 0.41, Magenta)>S. pombe from Heichinger et al (dsim = 0.43, Olive)>H. sapiens (dsim = 0.44, Purple)>S. pombe from Eshaghi et al (dsim = 0.55, Blue)>S. cerevisiae (dsim = 0.85, Red).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2690853&req=5

pone-0005899-g003: Collapse of all I(t').All curves were shifted horizontally so that their starting points coincide with zero. The similarity distance (dsim) between the I(t') of other eukaryotes and the I(t') of X. laevis (Black) was measured using the Continuous Dynamic Time Warping method (see Material and Methods). By using the X. laevis data dispersion (gray error bars) we set the condition that if the measured distance between two curves is smaller than 0.94, the two curves are similar. In all cases we found dsim<0.94, therefore all I(t'), including the one generated by the numerical model, could be considered as similar. However, its possible to define a sequence of decreasing similarity between considered I(t') as: H. sapiens ‘s chromosome 6 (dsim = 0.27, Dark yellow)>D. melanogaster (dsim = 0.38, Orange)>numerical model (dsim = 0.41, Magenta)>S. pombe from Heichinger et al (dsim = 0.43, Olive)>H. sapiens (dsim = 0.44, Purple)>S. pombe from Eshaghi et al (dsim = 0.55, Blue)>S. cerevisiae (dsim = 0.85, Red).
Mentions: The time-dependent rate of replication origin activation, I(t), is defined as an average over the whole genome. Therefore it is independent of chromosomal position and represents the population-averaged dynamic process that controls origin usage and replication fork density, whether calculated from DNA combing or replication timing profiles. The theoretical I(t) calculated using the previously developed stochastic model is also an average of 500 simulations. The I(t) calculated either way can thus be compared. To compare the I(t) of different organisms, plots had to be normalized. S phase length and initiation frequency depend on many parameters that can vary among organisms and according to growth conditions. For example HU-treated S. cerevisiae cells exhibit an extended S phase compared to untreated cells although their rate of origin initiation is unaffected when related to the fraction of replicated DNA [27]. We therefore normalized replication time with respect to S phase length. Similarly, the maximum value of I(t) depends on the concentration of factors limiting origin efficiency [29]–[31]. Each I(t) was thus normalized by its maximum value and plotted as a function of reduced time t' (t' = t/tend). As shown in Figure 3, all the I(t') collapse together and have a maximum value at mid S-phase. The calculated agreement with the X. laevis data (see legend to Fig 3) appears particularly good for S. pombe, which relies on a largely stochastic mechanism for origin initiation, and for H. sapiens and D. melanogaster. The curve appears broader for S. cerevisiae, perhaps because cell synchrony was less tight, or because there is a clearer demarcation of early and late replicating domains in this organism [32]. Importantly, the I(t') calculated using the minimal stochastic model that we have previously developed [26] could account for all these observations.

Bottom Line: We have identified a universal behavior of eukaryotic replication initiation that transcends the mechanisms of origin specification.The population-averaged efficiency of replication origin usage changes during S phase in a strikingly similar manner in a highly diverse set of eukaryotes.The quantitative model previously proposed for origin activation in X. laevis can be generalized to explain this evolutionary conservation.

View Article: PubMed Central - PubMed

Affiliation: Commissariat à l'Energie Atomique (CEA), iBiTec-S, Gif-sur-Yvette, France. arach.goldar@cea.fr

ABSTRACT
Although replication proteins are conserved among eukaryotes, the sequence requirements for replication initiation differ between species. In all species, however, replication origins fire asynchronously throughout S phase. The temporal program of origin firing is reproducible in cell populations but largely probabilistic at the single-cell level. The mechanisms and the significance of this program are unclear. Replication timing has been correlated with gene activity in metazoans but not in yeast. One potential role for a temporal regulation of origin firing is to minimize fluctuations in replication end time and avoid persistence of unreplicated DNA in mitosis. Here, we have extracted the population-averaged temporal profiles of replication initiation rates for S. cerevisiae, S. pombe, D. melanogaster, X. laevis and H. sapiens from genome-wide replication timing and DNA combing data. All the profiles have a strikingly similar shape, increasing during the first half of S phase then decreasing before its end. A previously proposed minimal model of stochastic initiation modulated by accumulation of a recyclable, limiting replication-fork factor and fork-promoted initiation of new origins, quantitatively described the observed profiles without requiring new implementations.The selective pressure for timely completion of genome replication and optimal usage of replication proteins that must be imported into the cell nucleus can explain the generic shape of the profiles. We have identified a universal behavior of eukaryotic replication initiation that transcends the mechanisms of origin specification. The population-averaged efficiency of replication origin usage changes during S phase in a strikingly similar manner in a highly diverse set of eukaryotes. The quantitative model previously proposed for origin activation in X. laevis can be generalized to explain this evolutionary conservation.

Show MeSH
Related in: MedlinePlus