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Mathematical modelling of DNA replication reveals a trade-off between coherence of origin activation and robustness against rereplication.

ABSTRACT: Eukaryotic genomes are duplicated from multiple replication origins exactly once per cell cycle. In Saccharomyces cerevisiae, a complex molecular network has been identified that governs the assembly of the replication machinery. Here we develop a mathematical model that links the dynamics of this network to its performance in terms of rate and coherence of origin activation events, number of activated origins, the resulting distribution of replicon sizes and robustness against DNA rereplication. To parameterize the model, we use measured protein expression data and systematically generate kinetic parameter sets by optimizing the coherence of origin firing. While randomly parameterized networks yield unrealistically slow kinetics of replication initiation, networks with optimized parameters account for the experimentally observed distribution of origin firing times. Efficient inhibition of DNA rereplication emerges as a constraint that limits the rate at which replication can be initiated. In addition to the separation between origin licensing and firing, a time delay between the activation of S phase cyclin-dependent kinase (S-Cdk) and the initiation of DNA replication is required for preventing rereplication. Our analysis suggests that distributive multisite phosphorylation of the S-Cdk targets Sld2 and Sld3 can generate both a robust time delay and contribute to switch-like, coherent activation of replication origins. The proposed catalytic function of the complex formed by Dpb11, Sld3 and Sld2 strongly enhances coherence and robustness of origin firing. The model rationalizes how experimentally observed inefficient replication from fewer origins is caused by premature activation of S-Cdk, while premature activity of the S-Cdk targets Sld2 and Sld3 results in DNA rereplication. Thus the model demonstrates how kinetic deregulation of the molecular network governing DNA replication may result in genomic instability.

SUBMITTER: Brummer A

PROVIDER: S-EPMC2869307 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Mathematical modelling of DNA replication reveals a trade-off between coherence of origin activation and robustness against rereplication.

Brümmer Anneke A Salazar Carlos C Zinzalla Vittoria V Alberghina Lilia L Höfer Thomas T

PLoS computational biology 20100513 5

Eukaryotic genomes are duplicated from multiple replication origins exactly once per cell cycle. In Saccharomyces cerevisiae, a complex molecular network has been identified that governs the assembly of the replication machinery. Here we develop a mathematical model that links the dynamics of this network to its performance in terms of rate and coherence of origin activation events, number of activated origins, the resulting distribution of replicon sizes and robustness against DNA rereplication ...[more]

PMID: 20485558

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Project description:ObjectivesTo investigate the impact of targeted vaccination strategies on morbidity and mortality due to COVID-19, as well as on the incidence of SARS-CoV-2, in India.DesignMathematical modelling.SettingsIndian epidemic of COVID-19 and vulnerable population.Data sourcesCountry-specific and age-segregated pattern of social contact, case fatality rate and demographic data obtained from peer-reviewed literature and public domain.ModelAn age-structured dynamical model describing SARS-CoV-2 transmission in India incorporating uncertainty in natural history parameters was constructed.InterventionsComparison of different vaccine strategies by targeting priority groups such as keyworkers including healthcare professionals, individuals with comorbidities (24-60 years old) and all above 60.Main outcome measuresIncidence reduction and averted deaths in different scenarios, assuming that the current restrictions are fully lifted as vaccination is implemented.ResultsThe priority groups together account for about 18% of India's population. An infection-preventing vaccine with 60% efficacy covering all these groups would reduce peak symptomatic incidence by 20.6% (95% uncertainty intervals (UI) 16.7-25.4) and cumulative mortality by 29.7% (95% CrI 25.8-33.8). A similar vaccine with ability to prevent symptoms (but not infection) will reduce peak incidence of symptomatic cases by 10.4% (95% CrI 8.4-13.0) and cumulative mortality by 32.9% (95% CrI 28.6-37.3). In the event of insufficient vaccine supply to cover all priority groups, model projections suggest that after keyworkers, vaccine strategy should prioritise all who are >60 and subsequently individuals with comorbidities. In settings with weakest transmission, such as sparsely populated rural areas, those with comorbidities should be prioritised after keyworkers.ConclusionsAn appropriately targeted vaccination strategy would witness substantial mitigation of impact of COVID-19 in a country like India with wide heterogeneity. 'Smart vaccination', based on public health considerations, rather than mass vaccination, appears prudent.

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Mathematical modelling of DNA replication reveals a trade-off between coherence of origin activation and robustness against rereplication.

Publications

Mathematical modelling of DNA replication reveals a trade-off between coherence of origin activation and robustness against rereplication.

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