Goldar A et al. (2009), Universal temporal profile of replication origi...

XB-ART-40672

PLoS One 2009 Jun 12;46:e5899. doi: 10.1371/journal.pone.0005899.

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Universal temporal profile of replication origin activation in eukaryotes.

Goldar A , Marsolier-Kergoat MC , Hyrien O .

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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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Species referenced: Xenopus laevis
Genes referenced: tbx2

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	Figure 1. I(t) in X. laevis, S. cerevisiae, S. pombe and D. melanogaster.A. I(t) in X. laevis. I(t) was determined from DNA combing data (open circles) as described in Materials and Methods in [26]. The data points were binned into 40 points and the dispersion in data value of each bin was determined (gray standard deviation bars). The red line is the best fit of the numerical model [26] to the data (χ2 = 0.89). The values of free parameters as described in [26] are: P0 = 1.05×10−4±1.07×10−7 kb−1 s−1, P1 = 2.1×10−3±2×10−5 kb−1 s−1, J = 5±0.5 s−1 and N0 = 1000±3. B. I(t) in S. cerevisiae was determined from the replication timing profiles of Raghuraman et al. [3] as described in the Materials and Methods. C. I(t) in S. pombe. Only the 401 strong origins defined by Heichinger et al. [4] (blue circles) and 516 potential origins defined by Eshaghi et al. [5] (black triangles) were considered. D. I(t/tend) for D. melanogaster determined from replication timing profile of chromosome 2L [28].
	Figure 2. I(t) in Homo sapiens.I(t) was determined from the replication timing profiles determined by Woodfine et al. [6], [7] for: (A) the whole genome, at 1 Mb resolution [7] or (B) chromosome 6, at 94 kb resolution [6], as described in the Materials and Methods.
	Figure 3. 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).

References [+] :

Alexandrow, Chromatin decondensation in S-phase involves recruitment of Cdk2 by Cdc45 and histone H1 phosphorylation. 2005, Pubmed