Integrated Stochastic Model of DNA Damage Repair by Non-homologous End Joining and p53/p21-Mediated Early Senescence Signalling.
Integrated Stochastic Model of DNA Damage Repair by Non-homologous End Joining and p53/p21-Mediated Early Senescence Signalling.
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DOI：
10.1371/journal.pcbi.1004246
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发表时间：
2015-05
影响因子：
4.3
通讯作者：
Shanley DP
中科院分区：
文献类型：
--
作者：
Dolan DW;Zupanic A;Nelson G;Hall P;Miwa S;Kirkwood TB;Shanley DP
未修复或不准确修复的DNA损伤可导致一系列细胞命运，如细胞凋亡、细胞衰老或癌症，这取决于DNA损伤修复的效率和准确性以及下游DNA损伤信号传导。DNA损伤修复和信号传导已经分别进行了详细的研究和建模，但尚不清楚它们如何相互整合以控制细胞命运。在这项研究中，我们已经创建了一个集成的随机模型的DNA损伤修复的非同源末端连接和γ辐射诱导的细胞衰老的人类细胞中，是不容易发生凋亡。综合模型成功地解释了辐射后DNA损伤修复动力学发生的变化。辐照后的p53/p21动力学模拟与先前发表的实验研究一致，进一步验证了该模型。此外，该模型预测，我们提供了一些实验支持，低剂量分次照射的细胞导致p53/p21的时间模式，导致显着的细胞衰老。该模型对于研究DNA损伤诱导细胞命运的过程以及在细胞水平上预测DNA损伤相关的医学干预措施的有效性具有重要意义。所有的细胞都会受到损伤，DNA是最重要的保护分子。细胞通过p53（基因组的守护者）传递DNA损伤，p53信号传导的动力学是决定细胞结果的主要机制之一。在检测到DNA损伤时，p53被激活并诱导细胞周期停滞：如果DNA损伤被快速修复，则信号传导结束，细胞恢复正常功能;如果DNA损伤持续存在，则信号传导继续，细胞可能经历衰老或凋亡。在这里，我们开发了一个计算模型，可以模拟DNA损伤发生，DNA损伤修复，p53信号传导和细胞命运的整个过程，并成功地预测持续的DNA损伤如何导致细胞衰老。该模型预测，使用重复低剂量照射作为损伤源与单次大剂量照射一样有效，这可能对放射治疗具有重要意义。
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.
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影响因子：
3.7
作者：
Dolan D;Nelson G;Zupanic A;Smith G;Shanley D
通讯作者：
Shanley D
影响因子：
5.3
作者：
Fragkos, Michalis;Jurvansuu, Jaana;Beard, Peter
通讯作者：
Beard, Peter
影响因子：
3.7
作者：
Chatterjee P;Choudhary GS;Sharma A;Singh K;Heston WD;Ciezki J;Klein EA;Almasan A
通讯作者：
Almasan A
影响因子：
2.6
作者：
Cmielova, Jana;Havelek, Radim;Rezacova, Martina
通讯作者：
Rezacova, Martina
影响因子：
30.8
作者：
Lahav, G;Rosenfeld, N;Alon, U
通讯作者：
Alon, U