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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)42-56
Number of pages15
JournaliScience
Volume21
DOIs
Publication statusPublished - Nov 22 2019

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Isopentenyladenosine
Protein Subunits
Transfer RNA
Glioma
Maintenance
Mitochondrial Proteins
Autophagy
Mitochondrial DNA
Adenosine
Energy Metabolism
Mammals

Keywords

  • Biological Sciences
  • Cancer
  • Cell Biology
  • Molecular Biology
  • Stem Cells Research

ASJC Scopus subject areas

  • General

Cite this

2-Methylthio Conversion of N6-Isopentenyladenosine in Mitochondrial tRNAs by CDK5RAP1 Promotes the Maintenance of Glioma-Initiating Cells. / Yamamoto, Takahiro; Fujimura, Atsushi; Wei, Fan Yan; Shinojima, Naoki; Kuroda, Jun ichiro; Mukasa, Akitake; Tomizawa, Kazuhito.

In: iScience, Vol. 21, 22.11.2019, p. 42-56.

Research output: Contribution to journalArticle

Yamamoto, Takahiro ; Fujimura, Atsushi ; Wei, Fan Yan ; Shinojima, Naoki ; Kuroda, Jun ichiro ; Mukasa, Akitake ; Tomizawa, Kazuhito. / 2-Methylthio Conversion of N6-Isopentenyladenosine in Mitochondrial tRNAs by CDK5RAP1 Promotes the Maintenance of Glioma-Initiating Cells. In: iScience. 2019 ; Vol. 21. pp. 42-56.
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