1. Chromosomes and Gene Expression
  2. Computational and Systems Biology
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The eukaryotic bell-shaped temporal rate of DNA replication origin firing emanates from a balance between origin activation and passivation

  1. Jean-Michel Arbona
  2. Arach Goldar
  3. Olivier Hyrien
  4. Alain Arneodo
  5. Benjamin Audit  Is a corresponding author
  1. Laboratoire de Physique, Université de Lyon, Ens de Lyon, Université Claude Bernard Lyon 1, CNRS, France
  2. Ibitec-S, CEA, France
  3. Ecole Normale Supérieure, CNRS, INSERM, PSL Research University, France
  4. Univ de Bordeaux, CNRS, UMR 5798, France
Short Report
Cite this article as: eLife 2018;7:e35192 doi: 10.7554/eLife.35192
2 figures, 1 table and 2 additional files

Figures

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=5×105 min1, NDT=1000, ρ0=0.3 kb1), green (kon=6×104 min1, NDT=250, ρ0=0.5 kb1), red (kon=6×103 min1, NDT=165, ρ0=0.28 kb1). (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).

https://doi.org/10.7554/eLife.35192.003
Figure 2 with 1 supplement
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.×103 min1, NDT=187, ρ0=0.70 kb1) or a periodic distribution of p-oris (red: v=0.6 kb/min, kon=6×103 min1, NDT=165, ρ0=0.28 kb1); (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=3.6×103 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=1.2×102 min1 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.

https://doi.org/10.7554/eLife.35192.004
Figure 2—source data 1

Data file for the experimental Xenopus I(t) in Figure 2 (a).

https://doi.org/10.7554/eLife.35192.006
Figure 2—source data 2

Data file for the experimental S.

cerevisae I(t) in Figure 2 (b).

https://doi.org/10.7554/eLife.35192.007
Figure 2—source data 3

Data file for the experimental parameters used in Figure 2 (c).

https://doi.org/10.7554/eLife.35192.008
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.

https://doi.org/10.7554/eLife.35192.005

Tables

Table 1
Experimental data for various eukaryotic organisms with genome length L (Mb), replication fork velocity v (kb/min), number of p-oris (Npori(t=0)), ρ0=Npori(t=0)/L (kb1) and Imax (Mb1min1).

All Imax data are from Goldar et al. (2009), except for S. cerevisiae grown in presence or absence of hydroxyurea (HU) which were computed from the replication profile of Alvino et al. (2007). For S. cerevisiae and S. pombe, Confirmed, Likely, and Dubious origins were taken into account. For D. melanogaster, Npori(t=0) was obtained from the same Kc cell type as the one used to estimate Imax. For Xenopus embryo, we assumed that a p-ori corresponds to a dimer of MCM2-7 hexamer so that Npori(t=0) was estimated as a half of the experimental density of MCM3 molecules reported for Xenopus sperm nuclei DNA in Xenopus egg extract (Mahbubani et al., 1997). For human, we averaged the number of origins experimentally identified in K562 (62971) and in MCF7 (94195) cell lines.

https://doi.org/10.7554/eLife.35192.009

L

v

Npori

ρ0

Imax

Ref.
S. cerevisiae12.51.608290.0666.0Sekedat et al. (2010) and Siow et al. (2012)
S. cerevisiae in presence of HU12.50.058290.0660.24Alvino et al. (2007). Same Npori and ρ0 as S. cerevisiae in normal growth condition.
S. pombe12.52.807410.05910.0Siow et al. (2012) and Kaykov and Nurse (2015)
D. melanogaster143.60.6361840.0430.5Ananiev et al. (1977) and Cayrou et al. (2011)
human6469.01.46780000.0120.3Conti et al. (2007) and Martin et al. (2011)
Xenopus sperm2233.00.527443330.33370.0Mahbubani et al. (1997) and Loveland et al. (2012)

Additional files

Supplementary file 1

This file provides: the parameter values used for all the simulations in Figures 1 and 2; the list of all the symbols used in the main text and their meanings.

https://doi.org/10.7554/eLife.35192.010
Transparent reporting form
https://doi.org/10.7554/eLife.35192.011

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