2-Methylthio Conversion of N6-Isopentenyladenosine in Mitochondrial tRNAs by CDK5RAP1 Promotes the Maintenance of Glioma-Initiating Cells
2-Methylthio Conversion of N6-Isopentenyladenosine in Mitochondrial tRNAs by CDK5RAP1 Promotes the Maintenance of Glioma-Initiating Cells
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CDK5RAP1 对线粒体 tRNA 中 N6-异戊烯基腺苷的 2-甲硫基转化促进胶质瘤起始细胞的维持
DOI：
10.1016/j.isci.2019.10.012
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发表时间：
2019
期刊：
影响因子：
5.8
通讯作者：
Tomizawa Kazuhito
中科院分区：
文献类型：
--
作者：
Yamamoto Takahiro;Fujimura Atsushi;Wei Fan-Yan;Shinojima Naoki;Kuroda Jun-ichiro;Mukasa Akitake;Tomizawa Kazuhito
腺苷的2-甲硫基-N6-异戊烯基修饰（ms 2 i6 A）是在线粒体（mt）-tRNA中发现的进化保守修饰。Cdk 5调节亚基相关蛋白1（CDK 5 RAP 1）特异性地将N6-异戊烯基腺苷（i6 A）转化为四种线粒体DNA编码的tRNA的A37位的ms 2 i6 A，并且该修饰调节哺乳动物中有效的线粒体翻译和能量代谢。在这里，我们报告说，ms 2转换介导的CDK 5 RAP 1在mt-tRNA是必需的，以维持胶质瘤起始细胞（GIC）相关的性状。CDK 5 RAP 1维持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。CDK 5 RAP 1通过将i6 A转化为ms 2 i6 A来消除i6 A的抗肿瘤作用，并保护GIC免于由i6 A触发的过度自噬。CDK 5 RAP 1活性的升高有助于改善i6 A的肿瘤抑制作用并促进GIC维持。这项工作表明，CDK 5 RAP 1对于内源性i6 A的解毒至关重要，并且GIC很容易利用这种机制来存活。
2-Methylthio-N6-isopentenyl modification of adenosine (ms2i6A) is an evolutionally conserved modification found in mitochondrial (mt)-tRNAs. Cdk5 regulatory subunit-associated protein 1 (CDK5RAP1) specifically converts N6-isopentenyladenosine (i6A) to ms2i6A 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 ms2conversion 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 i6A by converting i6A to ms2i6A and protected GICs from excessive autophagy triggered by i6A. The elevated activity of CDK5RAP1 contributed to the amelioration of the tumor-suppressive effect of i6A and promoted GIC maintenance. This work demonstrates that CDK5RAP1 is crucial for the detoxification of endogenous i6A and that GICs readily utilize this mechanism for survival.
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影响因子：
--
作者：
Jalota A;Kumar M;Das BC;Yadav AK;Chosdol K;Sinha S
通讯作者：
Sinha S
有丝分裂中的目标基因书签：表型转录因子和癌基因的共同表观遗传特征？
影响因子：
11.2
作者：
Zaidi,SayyedK;Grandy,RodrigoA;Lopez-Camacho,Cesar;Montecino,Martin;vanWijnen,AndreJ;Lian,JaneB;Stein,JanetL;Stein,GaryS
通讯作者：
Stein,GaryS
DOI：
10.1016/j.bbagrm.2011.11.009
发表时间：
2012-09
影响因子：
4.7
作者：
Christian, Brooke E.;Spremulli, Linda L.
通讯作者：
Spremulli, Linda L.
影响因子：
50.3
作者：
Brien GL;Valerio DG;Armstrong SA
通讯作者：
Armstrong SA
影响因子：
4.8
作者：
Fujimura, Atsushi;Michiue, Hiroyuki;Matsui, Hideki
通讯作者：
Matsui, Hideki