DALRD3 encodes a protein mutated in epileptic encephalopathy that targets arginine tRNAs for 3-methylcytosine modification
DALRD3 encodes a protein mutated in epileptic encephalopathy that targets arginine tRNAs for 3-methylcytosine modification
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DOI：
10.1038/s41467-020-16321-6
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发表时间：
2020-05-19
影响因子：
16.6
通讯作者：
Fu, Dragony
中科院分区：
文献类型：
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作者：
Lentini, Jenna M.;Alsaif, Hessa S.;Fu, Dragony
在哺乳动物中，精氨酸tRNA异源受体的一个子集在反密码子环中被胃L2甲基转移酶甲基化，形成3-甲基胞嘧啶（m3 C）修饰。然而，胃L2鉴定m3 C形成的特定tRNA精氨酸种类的机制以及m3 C在哺乳动物中的生物学作用尚不清楚。在这里，我们表明，人胃L2形成一个复合物与DALR反密码子结合域3（DALRD 3）蛋白识别特定的精氨酸tRNA注定为m3 C修饰。DALRD 3缺陷型人细胞表现出几乎完全丧失tRNA-Arg种类中的m3 C修饰。值得注意的是，我们确定了DALRD 3基因中的纯合无义突变，该突变损害了表现出发育迟缓和早发性癫痫性脑病的人类患者的m3 C形成。这些发现揭示了DALRD 3蛋白在靶向不同的精氨酸tRNA进行m3 C修饰中的意想不到的功能，并表明DALRD 3依赖性tRNA修饰在适当的神经发育中具有关键的生物学作用。
In mammals, a subset of arginine tRNA isoacceptors are methylated in the anticodon loop by the METTL2 methyltransferase to form the 3-methylcytosine (m3C) modification. However, the mechanism by which METTL2 identifies specific tRNA arginine species for m3C formation as well as the biological role of m3C in mammals is unknown. Here, we show that human METTL2 forms a complex with DALR anticodon binding domain containing 3 (DALRD3) protein to recognize particular arginine tRNAs destined for m3C modification. DALRD3-deficient human cells exhibit nearly complete loss of the m3C modification in tRNA-Arg species. Notably, we identify a homozygous nonsense mutation in the DALRD3 gene that impairs m3C formation in human patients exhibiting developmental delay and early-onset epileptic encephalopathy. These findings uncover an unexpected function for the DALRD3 protein in the targeting of distinct arginine tRNAs for m3C modification and suggest a crucial biological role for DALRD3-dependent tRNA modification in proper neurological development.