tRNA modifying enzymes, NSUN2 and METTL1, determine sensitivity to 5-fluorouracil in HeLa cells

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 protec...

Full description

Saved in:
Bibliographic Details
Published in:PLoS genetics 2014-09, Vol.10 (9), p.e1004639
Main Authors: Okamoto, Mayumi, Fujiwara, Mamoru, Hori, Masato, Okada, Kaoru, Yazama, Futoshi, Konishi, Hiroaki, Xiao, Yegui, Qi, Guangying, Shimamoto, Fumio, Ota, Takahide, Temme, Achim, Tatsuka, Masaaki
Format: Article
Language:English
Subjects:
Analysis
Antimetabolites, Antineoplastic - pharmacology
Biology and life sciences
Cancer
Cancer therapies
Cell cycle
Cell growth
Cell Proliferation
Cisplatin - pharmacology
Cloning
Colleges & universities
Cytotoxicity
Drug Resistance, Neoplasm - genetics
Enzymes
Experiments
Fluorouracil
Fluorouracil - pharmacology
Gene Expression
Gene Knockdown Techniques
Heat-Shock Response - genetics
HeLa Cells
Humans
Kinases
Medicine and Health Sciences
Methylation
Methyltransferases - genetics
Methyltransferases - metabolism
Mutation
Paclitaxel - pharmacology
Phosphorylation
Physiological aspects
RNA Stability - drug effects
RNA, Transfer - genetics
RNA, Transfer - metabolism
Surveillance
Transfer RNA
Tumor Stem Cell Assay
Yeast
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1004639