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

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Figures

Figure 1

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Emergence of a bell-shaped $I (t)$ .

(a) Sketch of the different steps of our modeling of replication initiation and propagation. (b) $I_{S} (t)$ (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 ( $k_{o n} = 5 \times 10^{- 5}$ min $^{- 1}$ , $N_{D}^{T} = 1000$ , $ρ_{0} = 0.3$ kb $^{- 1}$ ), green ( $k_{o n} = 6 \times 10^{- 4}$ min $^{- 1}$ , $N_{D}^{T} = 250$ , $ρ_{0} = 0.5$ kb $^{- 1}$ ), red ( $k_{o n} = 6 \times 10^{- 3}$ min $^{- 1}$ , $N_{D}^{T} = 165$ , $ρ_{0} = 0.28$ kb $^{- 1}$ ). (c) Corresponding normalized densities of *p-oris* (solid lines), and corresponding normalized numbers of free diffusing firing factors (dashed line): blue ( $N_{F D}^{*} = 3360$ ), green ( $N_{F D}^{*} = 280$ ), red ( $N_{F D}^{*} = 28$ ); the horizontal dotted-dashed line corresponds to the critical threshold value $N_{F D} (t) = N_{F D}^{*}$ . (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

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Model validation by experimental data.

(a) *Xenopus* embryo: Simulated $I_{S} (t)$ (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, $k_{o n} = 3. \times 10^{- 3}$ min $^{- 1}$ , $N_{D}^{T} = 187$ , $ρ_{0} = 0.70$ kb $^{- 1}$ ) or a periodic distribution of *p-oris* (red: $v = 0.6$ kb/min, $k_{o n} = 6 \times 10^{- 3}$ min $^{- 1}$ , $N_{D}^{T} = 165$ , $ρ_{0} = 0.28$ 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 $I_{S} (t)$ (Materials and methods) for the 16 chromosomes with the following parameter values: $v = 1.5$ kb/min, $N_{D}^{T} = 143$ , $k_{o n} = 3.6 \times 10^{- 3}$ 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 $I_{m a x}$ (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:* $I_{m a x}$ as a function of $v ρ_{0}^{2}$ ; (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, $k_{o n} = 1.2 \times 10^{- 2}$ min $^{- 1}$ and $N_{D}^{T} = 12$ (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
Download elife-35192-fig2-data1-v2.csv
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
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Figure 2—source data 3 Data file for the experimental parameters used in Figure 2 (c).: https://doi.org/10.7554/eLife.35192.008
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Figure 2—figure supplement 1

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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 $L$ ( $M b$ ), replication fork velocity $v$ (kb/min), number of p-oris ( $N_{p - ori} (t = 0)$ ), $ρ_{0} = N_{p - ori} (t = 0) / L$ (kb $^{- 1}$ ) and $I_{m a x}$ (Mb $^{- 1}$ min $^{- 1}$ ).

All $I_{m a x}$ 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, $N_{p - ori} (t = 0)$ was obtained from the same Kc cell type as the one used to estimate $I_{m a x}$ . For Xenopus embryo, we assumed that a p-ori corresponds to a dimer of MCM2-7 hexamer so that $N_{p - ori} (t = 0)$ 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

	$L$	$v$	$N_{p - ori}$	$ρ_{0}$	$I_{m a x}$	Ref.
S. cerevisiae	12.5	1.60	829	0.066	6.0	Sekedat et al. (2010) and Siow et al. (2012)
S. cerevisiae in presence of HU	12.5	0.05	829	0.066	0.24	Alvino et al. (2007). Same $N_{p - ori}$ and $ρ_{0}$ as S. cerevisiae in normal growth condition.
S. pombe	12.5	2.80	741	0.059	10.0	Siow et al. (2012) and Kaykov and Nurse (2015)
D. melanogaster	143.6	0.63	6184	0.043	0.5	Ananiev et al. (1977) and Cayrou et al. (2011)
human	6469.0	1.46	78000	0.012	0.3	Conti et al. (2007) and Martin et al. (2011)
Xenopus sperm	2233.0	0.52	744333	0.333	70.0	Mahbubani 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
Download elife-35192-supp1-v2.docx
Transparent reporting form: https://doi.org/10.7554/eLife.35192.011
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Jean-Michel Arbona
Arach Goldar
Olivier Hyrien
Alain Arneodo
Benjamin Audit

(2018)

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

eLife 7:e35192.

https://doi.org/10.7554/eLife.35192

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Emergence of a bell-shaped I(t).

Model validation by experimental data.

Figure 2—source data 1

Figure 2—source data 2

Figure 2—source data 3

Different steps of the interaction between diffusing elements and origins of replication.

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

Supplementary file 1

Transparent reporting form

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Emergence of a bell-shaped $I (t)$ .

Experimental data for various eukaryotic organisms with genome length $L$ ( $M b$ ), replication fork velocity $v$ (kb/min), number of p-oris ( $N_{p - ori} (t = 0)$ ), $ρ_{0} = N_{p - ori} (t = 0) / L$ (kb $^{- 1}$ ) and $I_{m a x}$ (Mb $^{- 1}$ min $^{- 1}$ ).