Mathematical Modelling of DNA Replication Reveals a Trade-off between Coherence of Origin Activation and Robustness against Rereplication
Figure 2
Optimized parameter sets required for rapid and coherent origin activation.
(A) Admissible parameter sets (n = 109) show synchronous activation of replication origins without rereplication (red curve, reference parameter set as given in Table S2). (B) Correlation of the duration of origin firing Δ and the mean time to firing τ. (C) The distribution of firing times for the early replication origins predicted by the model (red bars, reference parameter set) closely matches the measured replication profile of potential early replication origins in budding yeast (black bars, redrawn from Fig 5, +HU, Yabuki et al. [11]). The simulated distribution was scaled to the same total number of fired origins as in the experiment. (D) Typical kinetics of the model (reference parameter set): activation time course of G1-Cdk as an input function (blue curve), followed by delayed activation of S-Cdk (orange curve). S-Cdk triggers formation of the 11-3-2 activator (red curve) and the firing of replication origins (black curve). (E) Mean affinities for binding reactions (both binding partners indicated) in the admissible parameter sets. The rather high binding affinities of Cdc45, the 11-3-2 activator and the GINS/DNA polymerase complex to the origins as well as those of phospho-Sld2 and phospho-Sld3 to Dpb11 support fast origin firing. There is hierarchy in regulatory phosphorylations by S-Cdk, with rather high S-Cdk affinity for Sld2 (mean Kd = 250 nM), and lower for Orc6 (mean Kd = 1.18 µM). The affinity of the phosphatase for Sld2 and Sld3, counteracting origin firing, is also moderate (mean Kd = 3.36 µM).