BOT-02 2-METHYLTHIO MODIFICATION OF N6-ISOPENTENYLADENOSINE IN MITOCHONDRIAL TRNAS BY CDK5RAP1 PROMOTES THE MAINTENANCE OF GLIOMA-INITIATING CELLS. (16th December 2019) - Yamamoto, Takahiro
Abstract: 2-Methylthio-N 6 -isopentenyl modification of adenosine (ms 2 i 6 A) is an evolutionally conserved modification that is found in mitochondrial (mt)-tRNAs. Cdk5 regulatory subunit-associated protein 1 (CDK5RAP1) specifically converts N6-isopentenyladenosine (i 6 A) to ms 2 i 6 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 ms 2 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 i 6 A by converting i 6 A to ms 2 i 6 A and protected GICs from excessive autophagy triggered by i 6 A. The elevated activity of CDK5RAP1 contributed to the amelioration of the cytotoxic effect of i 6 A and promoted GIC maintenance. The hypoxic microenvironment in the tumor core activated CDK5RAP1, whose activity was inversely correlated with the oxygen concentration because of two [4Fe-4S] clusters in the enzyme. This work demonstrates that CDK5RAP1 is crucial for the detoxification of endogenous i 6 A and that GICs readily utilize this mechanism for survival.