title: Integrated Stochastic Model of DNA Damage Repair by Non-homologous End Joining and p53/p21-Mediated Early Senescence Signalling.
abstract: Unrepaired or inaccurately repaired DNA damage can lead to a range of cell fates, such as apoptosis, cellular senescence or cancer, depending on the efficiency and accuracy of DNA damage repair and on the downstream DNA damage signalling. DNA damage repair and signalling have been studied and modelled in detail separately, but it is not yet clear how they integrate with one another to control cell fate. In this study, we have created an integrated stochastic model of DNA damage repair by non-homologous end joining and of gamma irradiation-induced cellular senescence in human cells that are not apoptosis-prone. The integrated model successfully explains the changes that occur in the dynamics of DNA damage repair after irradiation. Simulations of p53/p21 dynamics after irradiation agree well with previously published experimental studies, further validating the model. Additionally, the model predicts, and we offer some experimental support, that low-dose fractionated irradiation of cells leads to temporal patterns in p53/p21 that lead to significant cellular senescence. The integrated model is valuable for studying the processes of DNA damage induced cell fate and predicting the effectiveness of DNA damage related medical interventions at the cellular level.
authors.affiliation: School of Biological and Biomedical Biosciences, Durham University, Durham, United Kingdom; Centre for Integrative Systems Biology of Ageing and Nutrition, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: David W P
authors.initials: DW
authors.lastname: Dolan
authors.affiliation: Centre for Integrative Systems Biology of Ageing and Nutrition, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, United Kingdom; Eawag-Swiss Federal Institute of Aquatic Science and Technology, Dübendorf, Switzerland.
authors.forename: Anze
authors.initials: A
authors.lastname: Zupanic
authors.affiliation: Centre for Integrative Systems Biology of Ageing and Nutrition, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Glyn
authors.initials: G
authors.lastname: Nelson
authors.affiliation: Centre for Integrative Systems Biology of Ageing and Nutrition, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Philip
authors.initials: P
authors.lastname: Hall
authors.affiliation: Centre for Integrative Systems Biology of Ageing and Nutrition, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Satomi
authors.initials: S
authors.lastname: Miwa
authors.affiliation: Centre for Integrative Systems Biology of Ageing and Nutrition, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Thomas B L
authors.initials: TB
authors.lastname: Kirkwood
authors.affiliation: Centre for Integrative Systems Biology of Ageing and Nutrition, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Daryl P
authors.initials: DP
authors.lastname: Shanley
mesh_terms: D002460:Cell Line; D016922:Cellular Senescence / Q000528:radiation effects; D019295:Computational Biology; D003198:Computer Simulation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage; D059766:DNA End-Joining Repair; D006801:Humans; D008954:Models, Biological; D015398:Signal Transduction; D013269:Stochastic Processes; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53