Yamamoto Takahiro, Fujimura Atsushi, Wei Fan-Yan, Shinojima Naoki, Kuroda Jun-Ichiro, Mukasa Akitake, Tomizawa Kazuhito
Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; Department of Neurosurgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; Neutron Therapy Research Center, Okayama University, Okayama 700-8558, Japan.
iScience. 2019 Nov 22;21:42-56. doi: 10.1016/j.isci.2019.10.012. Epub 2019 Oct 8.
2-Methylthio-N-isopentenyl modification of adenosine (msiA) is an evolutionally conserved modification found in mitochondrial (mt)-tRNAs. Cdk5 regulatory subunit-associated protein 1 (CDK5RAP1) specifically converts N6-isopentenyladenosine (iA) to msiA at position A37 of four mt-DNA-encoded tRNAs, and the modification regulates efficient mitochondrial translation and energy metabolism in mammals. Here, we report that the ms conversion mediated by CDK5RAP1 in mt-tRNAs is required to sustain glioma-initiating cell (GIC)-related traits. CDK5RAP1 maintained the self-renewal capacity, undifferentiated state, and tumorigenic potential of GICs. This regulation was not related to the translational control of mt-proteins. CDK5RAP1 abrogated the antitumor effect of iA by converting iA to msiA and protected GICs from excessive autophagy triggered by iA. The elevated activity of CDK5RAP1 contributed to the amelioration of the tumor-suppressive effect of iA and promoted GIC maintenance. This work demonstrates that CDK5RAP1 is crucial for the detoxification of endogenous iA and that GICs readily utilize this mechanism for survival.
腺苷的2-甲硫基-N-异戊烯基修饰（msiA）是一种在线粒体（mt）-tRNA中发现的进化保守修饰。细胞周期蛋白依赖性激酶5调节亚基相关蛋白1（CDK5RAP1）特异性地将四种线粒体DNA编码的tRNA第37位的N6-异戊烯基腺苷（iA）转化为msiA，这种修饰调节哺乳动物中高效的线粒体翻译和能量代谢。在此，我们报告mt-tRNA中由CDK5RAP1介导的ms转化是维持胶质瘤起始细胞（GIC）相关特征所必需的。CDK5RAP1维持了GIC的自我更新能力、未分化状态和致瘤潜力。这种调节与mt蛋白的翻译控制无关。CDK5RAP1通过将iA转化为msiA消除了iA的抗肿瘤作用，并保护GIC免受iA触发的过度自噬。CDK5RAP1活性的升高有助于减轻iA的肿瘤抑制作用并促进GIC的维持。这项工作表明CDK5RAP1对内源性iA的解毒至关重要，并且GIC很容易利用这种机制来生存。
