Global effects of mistranslation from an editing defect in mammalian cells
Global effects of mistranslation from an editing defect in mammalian cells
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DOI：
10.1016/j.chembiol.2006.08.011
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发表时间：
2006-10-01
影响因子：
--
通讯作者：
Schimmel, Paul
中科院分区：
文献类型：
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作者：
Nangle, Leslie A.;Motta, Candace M.;Schimmel, Paul
氨酰-tRNA合成酶通过特殊的编辑反应防止误翻译或遗传密码歧义。扰乱细菌编辑的突变对细胞生长和活性产生不利影响，最近在老鼠身上的研究支持这样一种观点，即编辑缺陷引起的翻译错误会导致神经疾病样的表型。为了进一步研究误翻译与细胞病理学的关系，我们将一种表达编辑缺陷的valyl-tRNA合成酶的可诱导转基因引入哺乳动物细胞。引入错误翻译导致细胞形态的破坏和膜的起泡，伴随着caspase-3的激活，这与细胞的凋亡反应一致。添加一种被编辑缺陷酶错误激活但未被清除的非规范氨基酸，加剧了这些影响。一种特殊的歧义检测传感器提供了体内错误翻译的直接读数，支持翻译保真度降低可能与疾病有关的可能性。
Aminoacyl-tRNA synthetases prevent mistranslation, or genetic code ambiguity, through specialized editing reactions. Mutations that disrupt editing in bacteria adversely affect cell growth and viability, and recent work in the mouse supports the idea that translational errors caused by an editing defect lead to a neurological disease-like phenotype. To further investigate the connection of mistranslation to cell pathology, we introduced an inducible transgene expressing an editing-deficient valyl-tRNA synthetase into mammalian cells. Introducing mistranslation precipitated a disruption of cell morphology and membrane blebbing, accompanied by activation of caspase-3, consistent with an apoptotic response. Addition of a noncanonical amino acid that is misactivated, but not cleared, by the editing-defective enzyme exacerbated these effects. A special ambiguity-detecting sensor provided direct readout of mistranslation in vivo, supporting the possibility that decreased translational fidelity could be associated with disease.