Institute for Ageing and Health, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, United Kingdom.
PLoS One. 2013;8(1):e52989. doi: 10.1371/journal.pone.0052989. Epub 2013 Jan 9.
Most cancer cells express high levels of telomerase and proliferate indefinitely. In addition to its telomere maintenance function, telomerase also has a pro-survival function resulting in an increased resistance against DNA damage and decreased apoptosis induction. However, the molecular mechanisms for this protective function remain elusive and it is unclear whether it is connected to telomere maintenance or is rather a non-telomeric function of the telomerase protein, TERT. It was shown recently that the protein subunit of telomerase can shuttle from the nucleus to the mitochondria upon oxidative stress where it protects mitochondrial function and decreases intracellular oxidative stress. Here we show that endogenous telomerase (TERT protein) shuttles from the nucleus into mitochondria upon oxidative stress in cancer cells and analyzed the nuclear exclusion patterns of endogenous telomerase after treatment with hydrogen peroxide in different cell lines. Cell populations excluded TERT from the nucleus upon oxidative stress in a heterogeneous fashion. We found a significant correlation between nuclear localization of telomerase and high DNA damage, while cells which excluded telomerase from the nucleus displayed no or very low DNA damage. We modeled nuclear and mitochondrial telomerase using organelle specific localization vectors and confirmed that mitochondrial localization of telomerase protects the nucleus from inflicted DNA damage and apoptosis while, in contrast, nuclear localization of telomerase correlated with higher amounts of DNA damage and apoptosis. It is known that nuclear DNA damage can be caused by mitochondrially generated reactive oxygen species (ROS). We demonstrate here that mitochondrial localization of telomerase specifically prevents nuclear DNA damage by decreasing levels of mitochondrial ROS. We suggest that this decrease of oxidative stress might be a possible cause for high stress resistance of cancer cells and could be especially important for cancer stem cells.
大多数癌细胞表达高水平的端粒酶并无限增殖。除了其端粒维持功能外，端粒酶还有促生存功能，导致对 DNA 损伤的抵抗力增加和细胞凋亡诱导减少。然而，这种保护功能的分子机制仍不清楚，也不清楚它是否与端粒维持有关，还是端粒酶蛋白 TERT 的非端粒功能。最近表明，端粒酶的蛋白亚基在氧化应激下可以从核转移到线粒体，在那里它保护线粒体功能并减少细胞内氧化应激。在这里，我们显示内源性端粒酶（TERT 蛋白）在癌细胞的氧化应激下从核转移到线粒体，并分析了不同细胞系中用过氧化氢处理后内源性端粒酶的核排除模式。细胞群体以异质的方式将 TERT 从核中排除。我们发现端粒酶的核定位与高 DNA 损伤之间存在显著相关性，而将端粒酶从核中排除的细胞则没有或只有很少的 DNA 损伤。我们使用细胞器特异性定位载体对核和线粒体端粒酶进行建模，并证实端粒酶的线粒体定位可保护核免受施加的 DNA 损伤和细胞凋亡，而相反，核定位的端粒酶与更高水平的 DNA 损伤和细胞凋亡相关。已知核 DNA 损伤可由线粒体产生的活性氧物质（ROS）引起。我们在这里证明，端粒酶的线粒体定位通过降低线粒体 ROS 水平来特异性防止核 DNA 损伤。我们认为这种氧化应激的降低可能是癌细胞高应激抗性的一个可能原因，对于癌症干细胞尤其重要。
