tRNA modifying enzymes, NSUN2 and METTL1, determine sensitivity to 5-fluorouracil in HeLa cells.
tRNA modifying enzymes, NSUN2 and METTL1, determine sensitivity to 5-fluorouracil in HeLa cells.
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tRNA 修饰酶 NSUN2 和 METTL1 决定 HeLa 细胞对 5-氟尿嘧啶的敏感性。
DOI：
10.1371/journal.pgen.1004639
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发表时间：
2014-09
期刊：
影响因子：
4.5
通讯作者：
Tatsuka M
中科院分区：
文献类型：
--
作者：
Okamoto M;Fujiwara M;Hori M;Okada K;Yazama F;Konishi H;Xiao Y;Qi G;Shimamoto F;Ota T;Temme A;Tatsuka M
甲基转移酶的非必需 tRNA 修饰在进化上是保守的，据报道可以稳定成熟的 tRNA 分子并防止 tRNA 快速衰减 (RTD)。 tRNA 修饰酶 NSUN2 和 METTL1 是酵母 Trm4 和 Trm8 的哺乳动物直系同源物，它们是保护 tRNA 免受 RTD 侵害所必需的。在人类癌症中广泛观察到 NSUN2 和 METTL1 同时过度表达，这表明靶向这两种蛋白为癌症化疗提供了一种新颖的强大策略。在这里，我们表明，HeLa 细胞中 NSUN2 和 METTL1 的联合敲低极大地增强了细胞对 5-氟尿嘧啶 (5-FU) 的敏感性，而细胞的热应激却没有显示任何影响。由于 NSUN2 和 METTL1 分别被 Aurora-B 和 Akt 磷酸化，并且它们的 tRNA 修饰活性被磷酸化抑制，因此两种甲基转移酶的组成型去磷酸化形式的过度表达能够抑制 5-FU 敏感性。因此，NSUN2 和 METTL1 与 HeLa 细胞的 5-FU 敏感性有关。干扰 tRNA 的甲基化可能为改善癌症的 5-FU 化疗提供有希望的理由。感知和响应核酸代谢应激或基因毒性应激的细胞机制是基本且古老的进化生物学活动，具有保守且多样化的生物学功能。在酵母中，低修饰的成熟 tRNA 种类在热应激下通过 RTD 途径迅速腐烂。然而，研究表明，tRNA 特异性甲基转移酶 Trm4 和 Trm8 可以防止 tRNA 衰变。 5-FU 是一种用于癌症治疗的嘧啶类似物，通常被认为可作为胸苷酸合酶抑制剂，但也提出了其他作用机制。我们研究了酵母中 Trm4 和 Trm8 的人类直系同源物 NSUN2 和 METTL1，并证明这些 RTD 相关 tRNA 修饰酶参与宫颈癌 HeLa 细胞的 5-FU 敏感性。我们的结论是，tRNA 修饰的进化保守调控是癌细胞化疗耐药的潜在机制。
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. The cellular mechanisms for sensing and responding to stress on nucleic acid metabolism or to genotoxic stress are the fundamental and ancient evolutionary biological activities with conserved and diverse biological functions. In yeast, hypomodified mature tRNA species are rapidly decayed under heat stress by the RTD pathway. Yet, it has been shown that tRNA-specific methyltransferases Trm4 and Trm8 protect from tRNA decay. 5-FU, a pyrimidine analog used for cancer treatment, is generally known to act as a thymidylate synthase inhibitor although other ways for the mechanisms of action are suggested. We studied NSUN2 and METTL1, the human orthologs of Trm4 and Trm8 in yeast, and demonstrated that these RTD-related tRNA modifying enzymes are involved in 5-FU sensitivity in cervical cancer HeLa cells. We conclude that the evolutionarily conserved regulation of tRNA modifications is a potential mechanism of chemotherapy resistance in cancer cells.
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影响因子：
8.8
作者：
Hussain S;Sajini AA;Blanco S;Dietmann S;Lombard P;Sugimoto Y;Paramor M;Gleeson JG;Odom DT;Ule J;Frye M
通讯作者：
Frye M
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影响因子：
4.5
作者：
Blanco S;Kurowski A;Nichols J;Watt FM;Benitah SA;Frye M
通讯作者：
Frye M