@article{ecac87780a1647fb883e7826e349df04,
title = "2-Methylthio Conversion of N6-Isopentenyladenosine in Mitochondrial tRNAs by CDK5RAP1 Promotes the Maintenance of Glioma-Initiating Cells",
abstract = "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 ms2 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 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.",
keywords = "Biological Sciences, Cancer, Cell Biology, Molecular Biology, Stem Cells Research",
author = "Takahiro Yamamoto and Atsushi Fujimura and Wei, {Fan Yan} and Naoki Shinojima and Kuroda, {Jun ichiro} and Akitake Mukasa and Kazuhito Tomizawa",
note = "Funding Information: We thank Nobuko Maeda, Masayo Obata (Kumamoto University), and Masumi Furutani (Okayama University) for their technical assistance. This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Sciences, and Technology of Japan (17905074 and 18959602 to K.T. 16K18989 and 18K15241 to A.F.), the Japan Agency for Medical Research and Development (AMED) (17935694 to K.T. JP18cm0106143 to A.F.), and the Takeda Science Foundation (K.T.). T.Y. A.F. F.-Y.W. and K.T. designed the experiments and wrote the manuscript. T.Y. and A.F. carried out the experiments. N.S. J.K. and A.M. provided GBM samples. The authors declare no conflict of interest. Funding Information: We thank Nobuko Maeda, Masayo Obata (Kumamoto University), and Masumi Furutani (Okayama University) for their technical assistance. This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Sciences, and Technology of Japan ( 17905074 and 18959602 to K.T., 16K18989 and 18K15241 to A.F.), the Japan Agency for Medical Research and Development (AMED) ( 17935694 to K.T., JP18cm0106143 to A.F.), and the Takeda Science Foundation (K.T.). Publisher Copyright: {\textcopyright} 2019 The Author(s)",
year = "2019",
month = nov,
day = "22",
doi = "10.1016/j.isci.2019.10.012",
language = "English",
volume = "21",
pages = "42--56",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier Inc.",
}
