Arbona JM et al. (2018), The eukaryotic bell-shaped temporal rate of DNA...

XB-ART-55923

Elife 2018 Jun 01;7. doi: 10.7554/eLife.35192.

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The eukaryotic bell-shaped temporal rate of DNA replication origin firing emanates from a balance between origin activation and passivation.

Arbona JM , Goldar A , Hyrien O , Arneodo A , Audit B .

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The time-dependent rate [Formula: see text] of origin firing per length of unreplicated DNA presents a universal bell shape in eukaryotes that has been interpreted as the result of a complex time-evolving interaction between origins and limiting firing factors. Here, we show that a normal diffusion of replication fork components towards localized potential replication origins (p-oris) can more simply account for the [Formula: see text] universal bell shape, as a consequence of a competition between the origin firing time and the time needed to replicate DNA separating two neighboring p-oris. We predict the [Formula: see text] maximal value to be the product of the replication fork speed with the squared p-ori density. We show that this relation is robustly observed in simulations and in experimental data for several eukaryotes. Our work underlines that fork-component recycling and potential origins localization are sufficient spatial ingredients to explain the universality of DNA replication kinetics.

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GO keywords: DNA replication origin binding [+]

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Figure 1. Emergence of a bell-shaped I(t).(a) Sketch of the different steps of our modeling of replication initiation and propagation. (b) IS(t) (Equation 1) obtained from numerical simulations (Materials and methods) of one chromosome of length 3000 kb, with a fork speed v=0.6 kb/min. The firing factors are loaded with a characteristic time of 3 min. From blue to green to red the interaction is increased and the number of firing factors is decreased: blue (kon=5×10−5 min−1, NDT=1000, ρ0=0.3 kb−1), green (kon=6×10−4 min−1, NDT=250, ρ0=0.5 kb−1), red (kon=6×10−3 min−1, NDT=165, ρ0=0.28 kb−1). (c) Corresponding normalized densities of p-oris (solid lines), and corresponding normalized numbers of free diffusing firing factors (dashed line): blue (NFD∗=3360), green (NFD∗=280), red (NFD∗=28); the horizontal dotted-dashed line corresponds to the critical threshold value NFD(t)=NFD∗. (d) Corresponding number of passivated origins over the number of activated origins (solid lines). Corresponding probability distribution functions (PDF) of replication time (dashed lines).

Figure 2. Model validation by experimental data.(a) Xenopus embryo: Simulated IS(t) (Equation (1), Materials and methods) for a chromosome of length L=3000 kb and a uniform distribution of p-oris (blue: v=0.6 kb/min, kon=3.×10−3 min−1, NDT=187, ρ0=0.70 kb−1) or a periodic distribution of p-oris (red: v=0.6 kb/min, kon=6×10−3 min−1, NDT=165, ρ0=0.28 kb−1); (red squares) 3D simulations with the same parameter values as for periodic p-ori distribution; (black) experimental I(t): raw data obtained from Goldar et al. (2009) were binned in groups of 4 data points; the mean value and standard error of the mean of each bin were represented. (b) S. cerevisiae: Simulated IS(t) (Materials and methods) for the 16 chromosomes with the following parameter values: v=1.5 kb/min, NDT=143, kon=3.6×10−3 min-1, when considering only Confirmed origins (light blue), Confirmed and Likely origins (yellow) and Confirmed, Likely and Dubious origins (purple); the horizontal dashed lines mark the corresponding predictions for Imax (Equation 5); (purple squares) 3D simulations with the same parameter values considering Confirmed, Likely and Dubious origins; (black) experimental I(t) from Goldar et al. (2009). (c) Eukaryotic organisms: Imax as a function of vρ02; (squares and bullets) simulations performed for regularly spaced origins (blue) and uniformly distributed origins (green) (Materials and methods) with two sets of parameter values: L=3000 kb, v=0.6 kb/min, kon=1.2×10−2 min−1 and NDT=12 (dashed line) or 165 (solid line); (black diamonds) experimental data points for Xenopus embryo, S. cerevisiae, S. cerevisae grown in Hydroxyurea (HU), S. pombe, D. melanogaster, human (see text and Table 1). The following figure supplement is available for Figure 2.10.7554/eLife.35192.006Figure 2—source data 1. Data file for the experimental Xenopus I(t) in Figure 2 (a).Figure 2—source data 2. Data file for the experimental S.cerevisae I(t) in Figure 2 (b).Figure 2—source data 3. Data file for the experimental parameters used in Figure 2 (c).Figure 2—figure supplement 1. Different steps of the interaction between diffusing elements and origins of replication.(a) Definition of the color coding; (b) once in the vicinity of an origin of replication, a firing factor can be captured; (c) it is then splitted; (d) the two forks then travel in opposite direction, each carrying half of the diffusing firing factor.

References [+] :

Alvino, Replication in hydroxyurea: it's a matter of time. 2007, Pubmed