Mechanisms of DNA damage response to targeted irradiation in organotypic 3D skin cultures.
Mechanisms of DNA damage response to targeted irradiation in organotypic 3D skin cultures.
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DOI：
10.1371/journal.pone.0086092
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Schettino G
中科院分区：
文献类型：
--
作者：
Acheva A;Ghita M;Patel G;Prise KM;Schettino G
DNA损伤（由直接细胞照射和旁观者信号传导引起）及其修复所涉及的复杂途径是辐射照射后细胞和组织反应的关键事件。关于皮肤中DNA损伤诱导和修复的动态，特别是在未直接暴露的区域中，数据有限。在这里，我们研究了调节DNA损伤，修复，细胞内信号传导的机制，以及它们对3D器官型皮肤模型的照射区域和周围区域中炎症样反应的过早分化和发展的影响。在局部低LET照射（225 kVp X射线）后，在3D模型中观察到低水平的53 BP 1病灶（3.8±0.28病灶/戈伊/细胞），病灶持续存在并在照射后48小时大小增加。相反，在细胞单层中，观察到14.2±0.6个病灶/戈伊/细胞和双相修复动力学，修复在24小时前完成。这些差异与细胞状态的差异有关，其中2D中p21驱动凋亡信号传导的水平可变，以及3D模型的直接照射和旁观者区域中的加速分化。辐射角质形成细胞诱导皮肤非暴露区域DNA损伤的信号通路涉及NF-κB转录因子及其下游靶点考克斯-2。
DNA damage (caused by direct cellular exposure and bystander signaling) and the complex pathways involved in its repair are critical events underpinning cellular and tissue response following radiation exposures. There are limited data addressing the dynamics of DNA damage induction and repair in the skin particularly in areas not directly exposed. Here we investigate the mechanisms regulating DNA damage, repair, intracellular signalling and their impact on premature differentiation and development of inflammatory-like response in the irradiated and surrounding areas of a 3D organotypic skin model. Following localized low-LET irradiation (225 kVp X-rays), low levels of 53BP1 foci were observed in the 3D model (3.8±0.28 foci/Gy/cell) with foci persisting and increasing in size up to 48 h post irradiation. In contrast, in cell monolayers 14.2±0.6 foci/Gy/cell and biphasic repair kinetics with repair completed before 24 h was observed. These differences are linked to differences in cellular status with variable level of p21 driving apoptotic signalling in 2D and accelerated differentiation in both the directly irradiated and bystander areas of the 3D model. The signalling pathways utilized by irradiated keratinocytes to induce DNA damage in non-exposed areas of the skin involved the NF-κB transcription factor and its downstream target COX-2.
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影响因子：
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