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Spatiotemporal modelling of DNA replication


J. Windhager

Master Thesis, SS16

DNA replication ensures the maintenance of genetic information and is thus the basis of biological inheritance. In eukaryotic cells, the replication process initiates at multiple origins in the genome that are activated in a probabilistic manner. Origin activation is driven by the recruitment of specific protein complexes onto origin sites and is thus naturally governed by their abundance and kinetics. As observed recently using chromosome conformation capture (3C) techniques, the efficiency and timing of origin activation is closely related with the three-dimensional structure of the genome, however the exact mechanisms are still poorly understood. Here, a stochastic hybrid model for DNA replication is presented. The model incorporates spatial information on origin locations and protein mobility dynamics within the nucleus. It is based on earlier work on modeling DNA replication (Lygeros et al., 2008) and protein diffusion (Cinquemani et al., 2008), and is tailored to fission yeast using recent 3C data (Pichugina et al., 2016). Origin efficiencies and activation times were computed for a broad range of parameter values by leveraging a high-performance computing (HPC) setup. Model simulations revealed that activation factor diffusion and linear replication dynamics operate on fundamentally different time scales, and that diffusivity does not significantly affect the time until completion of DNA replication. Furthermore, it was shown that the completion time is dominated by the abundance of activation factors within the nucleus. The model is able to capture the main trends of the replication process and can be used to elucidate the role of nuclear organization in the regulation of DNA replication.

Supervisors: Marianna Rapsomaniki, María Rodríguez Martínez, John Lygeros


Type of Publication:

(12)Diploma/Master Thesis

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% Autogenerated BibTeX entry
@PhdThesis { Xxx:2017:IFA_5610
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