Integrated Stochastic Model of DNA Damage Repair by Non-homologous End Joining and p53/p21- Mediated Early Senescence Signalling
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 modell...
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| Published in | PLoS computational biology Vol. 11; no. 5; p. e1004246 |
|---|---|
| Main Authors | , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Public Library of Science
01.05.2015
Public Library of Science (PLoS) |
| Subjects | |
| Online Access | Get full text |
| ISSN | 1553-7358 1553-734X 1553-7358 |
| DOI | 10.1371/journal.pcbi.1004246 |
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| 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. |
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| AbstractList | 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.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. 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. All cells are subject to damage and DNA is the most important molecule to protect. Cells communicate DNA damage through p53—‘the guardian of the genome’—and the dynamics of p53 signalling is one the main mechanisms that determine the outcome for the cell. On detection of DNA damage, p53 is activated and cell cycle arrest is induced: if the DNA damage is repaired quickly then the signalling ends and the cell returns to normal function; if the DNA damage persists then the signalling continues and cells may undergo senescence or apoptosis. Here, we develop a computational model that can simulate the whole process of DNA damage occurrence, DNA damage repair, p53 signalling and cell fate and successfully predict how persistent DNA damage can lead to cellular senescence. The model predicts that using repeating low dose irradiation as a source of damage is as effective as a single large dose, which could have important implications for radiation therapy. 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. 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. |
| Audience | Academic |
| Author | Nelson, Glyn Dolan, David W. P. Miwa, Satomi Hall, Philip Zupanic, Anze Kirkwood, Thomas B. L. Shanley, Daryl P. |
| AuthorAffiliation | 1 School of Biological and Biomedical Biosciences, Durham University, Durham, United Kingdom 3 Eawag—Swiss Federal Institute of Aquatic Science and Technology, Dübendorf, Switzerland 2 Centre for Integrative Systems Biology of Ageing and Nutrition, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, United Kingdom McGill University, CANADA |
| AuthorAffiliation_xml | – name: McGill University, CANADA – name: 1 School of Biological and Biomedical Biosciences, Durham University, Durham, United Kingdom – name: 2 Centre for Integrative Systems Biology of Ageing and Nutrition, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, United Kingdom – name: 3 Eawag—Swiss Federal Institute of Aquatic Science and Technology, Dübendorf, Switzerland |
| Author_xml | – sequence: 1 givenname: David W. P. surname: Dolan fullname: Dolan, David W. P. – sequence: 2 givenname: Anze surname: Zupanic fullname: Zupanic, Anze – sequence: 3 givenname: Glyn surname: Nelson fullname: Nelson, Glyn – sequence: 4 givenname: Philip surname: Hall fullname: Hall, Philip – sequence: 5 givenname: Satomi surname: Miwa fullname: Miwa, Satomi – sequence: 6 givenname: Thomas B. L. surname: Kirkwood fullname: Kirkwood, Thomas B. L. – sequence: 7 givenname: Daryl P. surname: Shanley fullname: Shanley, Daryl P. |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/26020242$$D View this record in MEDLINE/PubMed |
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| Copyright | COPYRIGHT 2015 Public Library of Science 2015 Dolan et al 2015 Dolan et al 2015 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Dolan DWP, Zupanic A, Nelson G, Hall P, Miwa S, Kirkwood TBL, et al. (2015) Integrated Stochastic Model of DNA Damage Repair by Non-homologous End Joining and p53/p21- Mediated Early Senescence Signalling. PLoS Comput Biol 11(5): e1004246. doi:10.1371/journal.pcbi.1004246 |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Conceived and designed the experiments: AZ DWPD GN PH SM DPS. Performed the experiments: DWPD GN PH SM. Analyzed the data: AZ DWPD. Contributed reagents/materials/analysis tools: GN SM. Wrote the paper: DWPD AZ GN PH SM TBLK DPS. Constructed the models: AZ DWPD. Performed the simulations and the analysis: DWPD AZ. The authors have declared that no competing interests exist. |
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| SubjectTerms | Aging (Biology) Cell cycle Cell Line Cellular Senescence - radiation effects Cellular signal transduction Computational Biology Computer Simulation Cyclin-Dependent Kinase Inhibitor p21 - metabolism DNA Damage DNA End-Joining Repair DNA repair Genetic aspects Humans Models, Biological Signal Transduction Stochastic models Stochastic Processes Studies Tumor Suppressor Protein p53 - metabolism |
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| Title | Integrated Stochastic Model of DNA Damage Repair by Non-homologous End Joining and p53/p21- Mediated Early Senescence Signalling |
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