Mechanistic modelling of slow and fast NHEJ DNA repair pathways following radiation for G0/G1 normal tissue cells
Warmenhoven, John W
Xu, X. G.
Kirkby, Karen J
Merchant, Michael J
AffiliationSchool of Nuclear Science and Technology, University of Science and Technology of China, Hefei 230026, China.
MetadataShow full item record
AbstractMechanistic in silico models can provide insight into biological mechanisms and highlight uncertainties for experimental investigation. Radiation-induced double-strand breaks (DSBs) are known to be toxic lesions if not repaired correctly. Non-homologous end joining (NHEJ) is the major DSB-repair pathway available throughout the cell cycle and, recently, has been hypothesised to consist of a fast and slow component in G0/G1. The slow component has been shown to be resection-dependent, requiring the nuclease Artemis to function. However, the pathway is not yet fully understood. This study compares two hypothesised models, simulating the action of individual repair proteins on DSB ends in a step-by-step manner, enabling the modelling of both wild-type and protein-deficient cell systems. Performance is benchmarked against experimental data from 21 cell lines and 18 radiation qualities. A model where resection-dependent and independent pathways are entirely separated can only reproduce experimental repair kinetics with additional restraints on end motion and protein recruitment. However, a model where the pathways are entwined was found to effectively fit without needing additional mechanisms. It has been shown that DaMaRiS is a useful tool when analysing the connections between resection-dependent and independent NHEJ repair pathways and robustly matches with experimental results from several sources.
CitationQi Y, Warmenhoven JW, Henthorn NT, Ingram SP, Xu XG, Kirkby KJ, et al. Mechanistic Modelling of Slow and Fast NHEJ DNA Repair Pathways Following Radiation for G0/G1 Normal Tissue Cells. Cancers. 2021 May 3;13(9):2202.
- The influence of heterochromatin on DNA double strand break repair: Getting the strong, silent type to relax.
- Authors: Goodarzi AA, Jeggo P, Lobrich M
- Issue date: 2010 Dec 10
- Roles for 53BP1 in the repair of radiation-induced DNA double strand breaks.
- Authors: Shibata A, Jeggo PA
- Issue date: 2020 Sep
- A Process of Resection-Dependent Nonhomologous End Joining Involving the Goddess Artemis.
- Authors: Löbrich M, Jeggo P
- Issue date: 2017 Sep
- Role for Artemis nuclease in the repair of radiation-induced DNA double strand breaks by alternative end joining.
- Authors: Moscariello M, Wieloch R, Kurosawa A, Li F, Adachi N, Mladenov E, Iliakis G
- Issue date: 2015 Jul
- Mechanisms of DNA double strand break repair and chromosome aberration formation.
- Authors: Iliakis G, Wang H, Perrault AR, Boecker W, Rosidi B, Windhofer F, Wu W, Guan J, Terzoudi G, Pantelias G
- Issue date: 2004