601. 2-Methylthio Conversion of N6-Isopentenyladenosine in Mitochondrial tRNAs by CDK5RAP1 Promotes the Maintenance of Glioma-Initiating Cells.
- Author
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Yamamoto T, Fujimura A, Wei FY, Shinojima N, Kuroda JI, Mukasa A, and Tomizawa K
- Abstract
2-Methylthio-N
6 -isopentenyl modification of adenosine (ms2 i6 A) is an evolutionally conserved modification found in mitochondrial (mt)-tRNAs. Cdk5 regulatory subunit-associated protein 1 (CDK5RAP1) specifically converts N6-isopentenyladenosine (i6 A) to ms2 i6 A 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 i6 A by converting i6 A to ms2 i6 A and protected GICs from excessive autophagy triggered by i6 A. The elevated activity of CDK5RAP1 contributed to the amelioration of the tumor-suppressive effect of i6 A and promoted GIC maintenance. This work demonstrates that CDK5RAP1 is crucial for the detoxification of endogenous i6 A and that GICs readily utilize this mechanism for survival., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2019
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