2-Methylthio Conversion of N6-Isopentenyladenosine in Mitochondrial tRNAs by CDK5RAP1 Promotes the Maintenance of Glioma-Initiating Cells

Takahiro Yamamoto; Atsushi Fujimura; Fan-Yan Wei; Naoki Shinojima; Jun-Ichiro Kuroda; Akitake Mukasa; Kazuhito Tomizawa

doi:10.1016/j.isci.2019.10.012

2-Methylthio Conversion of N6-Isopentenyladenosine in Mitochondrial tRNAs by CDK5RAP1 Promotes the Maintenance of Glioma-Initiating Cells

iScience. 2019 Nov 22:21:42-56. doi: 10.1016/j.isci.2019.10.012. Epub 2019 Oct 8.

Authors

Takahiro Yamamoto¹, Atsushi Fujimura², Fan-Yan Wei³, Naoki Shinojima⁴, Jun-Ichiro Kuroda⁴, Akitake Mukasa⁴, Kazuhito Tomizawa⁵

Affiliations

¹ 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.
² 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.
³ Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
⁴ Department of Neurosurgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
⁵ Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; Center for Metabolic Regulation of Healthy Aging, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; Neutron Therapy Research Center, Okayama University, Okayama 700-8558, Japan. Electronic address: tomikt@kumamoto-u.ac.jp.

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.