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      An In Silico Model of DNA Repair for Investigation of Mechanisms in Non-Homologous End Joining

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          Abstract

          In human cells, non-homologous end joining is the preferred process to repair radiation induced DNA double strand breaks. The complex nature of such biological systems involves many individual actions that combine to produce an overall behaviour. As such, experimentally determining the mechanisms involved, their individual roles, and how they interact is challenging. An in silico approach to radiobiology is uniquely suited for detailed exploration of these complex interactions and the unknown effects of specific mechanisms on overall behaviour. We detail the construction of a mechanistic model by combination of several, experimentally supported, hypothesised mechanisms. Compatibility of these mechanisms was tested by fitting to results reported in the literature. To avoid over fitting, individual mechanisms within this pathway were sequentially fitted. We demonstrate that using this approach the model is capable of reproducing published protein kinetics and overall repair trends. This process highlighted specific biological mechanisms which are not clearly defined experimentally, and showed that the assumed motion of individual double strand break ends plays a crucial role in determining overall system behaviour.

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          Author and article information

          Journal
          bioRxiv
          May 09 2018
          Article
          10.1101/318139
          © 2018
          Product

          Quantitative & Systems biology

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