Mathematical Modelling of DNA Replication Reveals a Trade-off between Coherence of Origin Activation and Robustness against Rereplication
Figure 4
Deregulation of S-Cdk activity reduces origin firing and causes rereplication.
(A) Rapid activation of S-Cdk (upper panel) causes coherent origin firing (lower panel, red curve). Blue and green curves show the kinetics of pre-replicative and pre-initiation complexes. (B) Distribution of replicon size corresponding to the firing kinetics in (A). (C) Slow activation of S-Cdk (upper panel) due to a slow Sic1 degradation, as observed under suboptimal growth conditions, causes delayed origin firing (lower panel, red curve). (D) Distribution of replicon size corresponding to the firing kinetics in (C). (E) Premature and reduced activation of S-Cdk, as suggested for the Δsic1 mutant (upper panel) causes reduced origin licensing and premature origin firing (lower panel). (F) The distribution of replicon sizes corresponding to firing kinetics of (E) is broadened and large replicons (>120 kb) can occur. (G) A constitutive 11-3-2 activator together can bypass the requirement for S-Cdk (using a non-degradable mutant form of Sic1, sic1ΔNT) in replication initiation but causes asynchronous firing and considerable rereplication. (H) Distribution of replicon size corresponding to the firing kinetics in (G). (I) Quantification of the kinetics of origin firing for the conditions shown in (A)–(H). All simulations with reference parameter set; parameter changes for (C)–(H) specified in Text S2.