title: tRNA modifying enzymes, NSUN2 and METTL1, determine sensitivity to 5-fluorouracil in HeLa cells.
abstract: Nonessential tRNA modifications by methyltransferases are evolutionarily conserved and have been reported to stabilize mature tRNA molecules and prevent rapid tRNA decay (RTD). The tRNA modifying enzymes, NSUN2 and METTL1, are mammalian orthologs of yeast Trm4 and Trm8, which are required for protecting tRNA against RTD. A simultaneous overexpression of NSUN2 and METTL1 is widely observed among human cancers suggesting that targeting of both proteins provides a novel powerful strategy for cancer chemotherapy. Here, we show that combined knockdown of NSUN2 and METTL1 in HeLa cells drastically potentiate sensitivity of cells to 5-fluorouracil (5-FU) whereas heat stress of cells revealed no effects. Since NSUN2 and METTL1 are phosphorylated by Aurora-B and Akt, respectively, and their tRNA modifying activities are suppressed by phosphorylation, overexpression of constitutively dephosphorylated forms of both methyltransferases is able to suppress 5-FU sensitivity. Thus, NSUN2 and METTL1 are implicated in 5-FU sensitivity in HeLa cells. Interfering with methylation of tRNAs might provide a promising rationale to improve 5-FU chemotherapy of cancer.
authors.affiliation: Department of Life Sciences, Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, Shoubara, Hiroshima, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Okamoto
authors.affiliation: Department of Life Sciences, Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, Shoubara, Hiroshima, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Fujiwara
authors.affiliation: Department of Life Sciences, Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, Shoubara, Hiroshima, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Hori
authors.affiliation: Department of Life Sciences, Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, Shoubara, Hiroshima, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Okada
authors.affiliation: Department of Life Sciences, Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, Shoubara, Hiroshima, Japan.
authors.forename: Futoshi
authors.initials: F
authors.lastname: Yazama
authors.affiliation: Department of Life Sciences, Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, Shoubara, Hiroshima, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Konishi
authors.affiliation: Department of Management Information Systems, Faculty of Management and Information System, Prefectural University of Hiroshima, Minami-ku, Hiroshima, Japan.
authors.forename: Yegui
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Department of Health Sciences, Faculty of Human Culture and Science, Prefectural University of Hiroshima, Minami-ku, Hiroshima, Japan.
authors.forename: Guangying
authors.initials: G
authors.lastname: Qi
authors.affiliation: Department of Health Sciences, Faculty of Human Culture and Science, Prefectural University of Hiroshima, Minami-ku, Hiroshima, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Shimamoto
authors.affiliation: Department of Life Science, Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
authors.forename: Takahide
authors.initials: T
authors.lastname: Ota
authors.affiliation: Department of Neurosurgery, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Temme
authors.affiliation: Department of Life Sciences, Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, Shoubara, Hiroshima, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Tatsuka
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005472:Fluorouracil / Q000494:pharmacology*; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D018869:Heat-Shock Response / Q000235:genetics; D006801:Humans; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation; D020871:RNA Stability / Q000187:drug effects; D012343:RNA, Transfer / Q000235:genetics / Q000378:metabolism*; D014410:Tumor Stem Cell Assay
chemical_list: D000964:Antimetabolites, Antineoplastic; D012343:RNA, Transfer; C120297:METTL1 protein, human; D008780:Methyltransferases; C515610:NSUN2 protein, human; D017239:Paclitaxel; D002945:Cisplatin; D005472:Fluorouracil