TY - JOUR
T1 - Tyrosine pre-transfer RNA fragments are linked to p53-dependent neuronal cell death via PKM2
AU - Inoue, Masanori
AU - Hada, Kazumasa
AU - Shiraishi, Hiroshi
AU - Yatsuka, Hiroyuki
AU - Fujinami, Hiroyuki
AU - Morisaki, Ikuko
AU - Nishida, Yoshihiro
AU - Matsubara, Etsuro
AU - Ishitani, Tohru
AU - Hanada, Reiko
AU - Matsumoto, Masaki
AU - Penninger, Josef M.
AU - Ihara, Kenji
AU - Hanada, Toshikatsu
N1 - Funding Information:
We thank M. Nakamura-Ota, M. Oda, E. Koba, and T. Nitta for their excellent technical assistance. T.H. was supported by the Japan Society for the Promotion of Science [ 17K19919 ], Takeda Science Foundation , Astellas Foundation for Research on Metabolic Disorders , The Uehara Memorial Foundation , Japan Foundation for Applied Enzymology , Mitsubishi Foundation , and Mizoguchi Urology Clinic . Parts of this work were performed as part of the Cooperative Research Project Program of the Medical Institute of Bioregulation, Kyushu University, and the Institute for Molecular and Cellular Regulation, Gunma University.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/5/7
Y1 - 2020/5/7
N2 - Fragments of transfer RNA (tRNA), derived either from pre-tRNA or mature tRNA, have been discovered to play an essential role in the pathogenesis of various disorders such as neurodegenerative disease. CLP1 is an RNA kinase involved in tRNA biogenesis, and mutations in its encoding gene are responsible for pontocerebellar hypoplasia type-10. Mutation of the CLP1 gene results in the accumulation of tRNA fragments of several different kinds. These tRNA fragments are expected to be associated with the disease pathogenesis. However, it is still unclear which of the tRNA fragments arising from the CLP1 gene mutation has the greatest impact on the onset of neuronal disease. We found that 5′ tRNA fragments derived from tyrosine pre-tRNA (5′ Tyr-tRF) caused p53-dependent neuronal cell death predominantly more than other types of tRNA fragment. We also showed that 5′ Tyr-tRF bound directly to pyruvate kinase M2 (PKM2). Injection of zebrafish embryos with PKM2 mRNA ameliorated the neuronal defects induced in zebrafish embryos by 5′ Tyr-tRF. Our findings partially uncovered a mechanistic link between 5′ Tyr-tRF and neuronal cell death that is regulated by PKM2.
AB - Fragments of transfer RNA (tRNA), derived either from pre-tRNA or mature tRNA, have been discovered to play an essential role in the pathogenesis of various disorders such as neurodegenerative disease. CLP1 is an RNA kinase involved in tRNA biogenesis, and mutations in its encoding gene are responsible for pontocerebellar hypoplasia type-10. Mutation of the CLP1 gene results in the accumulation of tRNA fragments of several different kinds. These tRNA fragments are expected to be associated with the disease pathogenesis. However, it is still unclear which of the tRNA fragments arising from the CLP1 gene mutation has the greatest impact on the onset of neuronal disease. We found that 5′ tRNA fragments derived from tyrosine pre-tRNA (5′ Tyr-tRF) caused p53-dependent neuronal cell death predominantly more than other types of tRNA fragment. We also showed that 5′ Tyr-tRF bound directly to pyruvate kinase M2 (PKM2). Injection of zebrafish embryos with PKM2 mRNA ameliorated the neuronal defects induced in zebrafish embryos by 5′ Tyr-tRF. Our findings partially uncovered a mechanistic link between 5′ Tyr-tRF and neuronal cell death that is regulated by PKM2.
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U2 - 10.1016/j.bbrc.2020.02.157
DO - 10.1016/j.bbrc.2020.02.157
M3 - Article
C2 - 32143824
AN - SCOPUS:85081031862
VL - 525
SP - 726
EP - 732
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 3
ER -