Mitochondrial reactive oxygen species-mediated genomic instability in low-dose irradiated human cells through nuclear retention of cyclin D1
Mitochondrial reactive oxygen species-mediated genomic instability in low-dose irradiated human cells through nuclear retention of cyclin D1
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DOI：
10.1080/15384101.2016.1170271
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发表时间：
2016-04
期刊：
影响因子：
4.3
通讯作者：
T. Shimura;N. Kunugita
中科院分区：
文献类型：
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作者：
T. Shimura;N. Kunugita
线粒体与各种辐射反应有关，包括适应性反应、线粒体自噬、旁观者效应、基因组不稳定性和细胞凋亡。我们最近在暴露于低剂量长期分次辐射（FR）的人类细胞线粒体中发现了一种独特的辐射反应。这种反复的辐射暴露通过线粒体活性氧（ROS）的持续释放和抗氧化剂谷胱甘肽细胞水平的降低，对照射细胞造成慢性氧化应激。ros诱导的线粒体DNA （mtDNA）氧化损伤在DNA复制过程中产生突变。因此，mtDNA突变和功能障碍可作为评估低剂量辐射影响的标志物。在本研究中，我们概述了线粒体ROS与低剂量辐照细胞基因组不稳定性相关的细胞周期扰动之间的联系。在低剂量长期FR后，过量的线粒体ROS通过蛋白磷酸酶2A的氧化失活干扰AKT/cyclin D1细胞周期信号。由此导致的cyclin D1核异常积累诱导低剂量辐照细胞的基因组不稳定。
ABSTRACT Mitochondria are associated with various radiation responses, including adaptive responses, mitophagy, the bystander effect, genomic instability, and apoptosis. We recently identified a unique radiation response in the mitochondria of human cells exposed to low-dose long-term fractionated radiation (FR). Such repeated radiation exposure inflicts chronic oxidative stresses on irradiated cells via the continuous release of mitochondrial reactive oxygen species (ROS) and decrease in cellular levels of the antioxidant glutathione. ROS-induced oxidative mitochondrial DNA (mtDNA) damage generates mutations upon DNA replication. Therefore, mtDNA mutation and dysfunction can be used as markers to assess the effects of low-dose radiation. In this study, we present an overview of the link between mitochondrial ROS and cell cycle perturbation associated with the genomic instability of low-dose irradiated cells. Excess mitochondrial ROS perturb AKT/cyclin D1 cell cycle signaling via oxidative inactivation of protein phosphatase 2A after low-dose long-term FR. The resulting abnormal nuclear accumulation of cyclin D1 induces genomic instability in low-dose irradiated cells.