Conservation of an intricate circuit for crucial modifications of the tRNAPhe anticodon loop in eukaryotes.
Conservation of an intricate circuit for crucial modifications of the tRNAPhe anticodon loop in eukaryotes.
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DOI：
10.1261/rna.047639.114
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发表时间：
2015-01
期刊：
影响因子：
--
通讯作者：
Phizicky EM
中科院分区：
文献类型：
--
作者：
Guy MP;Phizicky EM
转录后tRNA修饰对于高效和准确的翻译至关重要，并且具有多种不同的作用。缺乏修饰往往导致不同生物体的不同生物学后果，在人类中经常与神经系统疾病有关。在这里，我们调查的保护一个独特的电路反密码子环的修改所需的健康生长的酵母酿酒酵母。S.酿酒酵母Trm 7分别与Trm 732和Trm 734相互作用，在反密码子环残基C32和N34处2′-O-甲基化三种底物tRNA，这些修饰是tRNAPhe的m1 G37处有效形成wybutosine所必需的。此外，由于缺乏功能性tRNAPhe，trm 7 Δ和trm 732 Δ trm 734 Δ突变体生长不良。目前尚不清楚这种电路是否是保守的，并且对于其他真核生物中的tRNAPhe修饰是重要的，但可能的人类TRM 7直系同源物与非综合征性X连锁智力残疾有关。我们发现，远亲的酵母裂殖酵母（Schizoschiomycespombe）保留了这种反密码子环修饰的电路，即S。pombe trm 7 Δ和trm 734 Δ突变体的表型比S.酿酒酵母突变体，和tRNAPhe是主要的生物学目标。此外，我们提供的证据表明，Trm 7和Trm 732的功能在整个真核生物中是广泛保守的，因为人FTSJ 1和THADA，分别补充S. trm 732 Δ trm 734 Δ突变体，分别与相应的S.酿酒酵母伴侣蛋白。这些结果表明tRNA反密码子环的2′-O-甲基化具有广泛的重要性，暗示tRNAPhe是关键底物，并表明这种修饰电路对人类神经元发育很重要。
Post-transcriptional tRNA modifications are critical for efficient and accurate translation, and have multiple different roles. Lack of modifications often leads to different biological consequences in different organisms, and in humans is frequently associated with neurological disorders. We investigate here the conservation of a unique circuitry for anticodon loop modification required for healthy growth in the yeast Saccharomyces cerevisiae. S. cerevisiae Trm7 interacts separately with Trm732 and Trm734 to 2′-O-methylate three substrate tRNAs at anticodon loop residues C32 and N34, and these modifications are required for efficient wybutosine formation at m1G37 of tRNAPhe. Moreover, trm7Δ and trm732Δ trm734Δ mutants grow poorly due to lack of functional tRNAPhe. It is unknown if this circuitry is conserved and important for tRNAPhe modification in other eukaryotes, but a likely human TRM7 ortholog is implicated in nonsyndromic X-linked intellectual disability. We find that the distantly related yeast Schizosaccharomyces pombe has retained this circuitry for anticodon loop modification, that S. pombe trm7Δ and trm734Δ mutants have more severe phenotypes than the S. cerevisiae mutants, and that tRNAPhe is the major biological target. Furthermore, we provide evidence that Trm7 and Trm732 function is widely conserved throughout eukaryotes, since human FTSJ1 and THADA, respectively, complement growth defects of S. cerevisiae trm7Δ and trm732Δ trm734Δ mutants by modifying C32 of tRNAPhe, each working with the corresponding S. cerevisiae partner protein. These results suggest widespread importance of 2′-O-methylation of the tRNA anticodon loop, implicate tRNAPhe as the crucial substrate, and suggest that this modification circuitry is important for human neuronal development.
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