Ciardo D , Haccard O , Narassimprakash H , Arbona JM , Hyrien O , Audit B , Marheineke K , Goldar A .

FRM DEI201512344404 Fondation pour la Recherche Médicale, PLBIO16-302 Institut National Du Cancer

             DNA replication

	Figure 1 Characteristics of combed DNA molecules. (a). Example of combed DNA molecule. The top panel is a fluorescence microscopy of a representative, stretched DNA fiber (green) containing replication eyes (red). The bottom panel is a schematic illustration of measured parameters in replication studies using DNA combing. (b). Molecular length distribution (global replicated fraction of 8%) of combed DNA fibre. The black open circles are the experimentally measured and the red curve is the simulated cut molecular length distributions, respectively.
	Figure 2 Chk1 does not control origin clustering. The black symbols are experimental data and the red curves are simulations. (a,c) Fitting of If data extracted from raw data published in [35] as described in material and methods for control and Chk1 inhibition experiments, respectively. The discrepancy in values between the extracted data and those published in [35] are due to difference in thresholding and the lack of smoothing of the extracted data in this work. (b,d) Discrepancy between experimental and simulated distributions of eye-to-eye distances in control and Chk1 inhibition experiments, respectively.
	Figure 3 Schematic representation of MM5. Potential replication origins located in a fraction θ of the genome (not necessary contiguous) have a probability of firing Pin higher than probability of firing Pout of potential origins located in the complementary genome fraction 1−θ. The firing of a potential origins requires its encounter with limiting factors which number Nt=N0+Jt increases as S phase progresses. Potential origins fire with a probability Plocal over a distance d ahead of a replication fork.
	Figure 4 MM5 captures the essential processes necessary to model the regulation of DNA replication by Chk1. (a,b). Unchallenged (8% global replication fraction) and Chk1 inhibited samples (22% global replication fraction) corresponding to the same experiment and harvested at same time. (c,d). Unchallenged (46% global replication fraction) and Chk1 over expressed samples (22% global replication fraction) corresponding to the same experiment and harvested at same time. The black open circles are experimental data and the dashed red lines are the fit obtained by MM5 model.
	Figure 5 Inferred model parameters by fitting unchallenged S phase data as global replicated fraction increases. The black circles are the averaged value of the parameter over 100 independent fitting processes and the error bars are standard-deviations. The green dashed line is the mean value among consecutive parameters which differences are not statistically significant (Supplementary Material S3 Figure S3).
	Figure 6 J, θ, and the Pout are the only parameters that change when comparing unchallenged, (a) Chk1 inhibited and (b) Chk1 over-expressed S phase The black circle is the averaged value of the parameter over 100 independent fitting processes of unchallenged S phase and the error bars are standard-deviations. The red star (a) is the averaged value of the parameter over 100 independent fitting processes of Chk1 inhibited sample and the error bars represent the standard-deviations. The green star (b) is the averaged value of the parameter over 100 independent fitting processes of Chk1 over-expressed sample and the error bars represent the standard-deviations.
	Figure 7 Replication timing profile generated by MM5. (a) The replication timing profile of a fictitious chromosome L=200 Mbp (N0=1231, J=287s−1, θ=0.46, Pin=0.34, Plocal=0.34, Pout=0.01, d=138 kb). The grey dots are raw data and the blue line is the loess-smoothed curve. The green filled circles represent early firing origins and the red filled circles the late ones. (b) Replication timing profile for chromosomal positions 1.515,1.56×105 kb. The profile can be segmented into plateaus of early and late constant timing regions separated by timing transition regions.

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