m^(6)A甲基转移酶家族Fiona/METT-10/METTL16的功能

The Functions of Fiona/Mett10/Mettl16 Family of m~6A Methyltransferases

RNA碱基上的化学修饰在其功能的精准调节中发挥关键作用,其中m~6A是自然界中最普遍的RNA修饰之一,且该修饰在调控RNA稳定性、pre-mRNA剪接、翻译等方面具有重要功能。在真核生物中,m~6A修饰主要由两种甲基转移酶完成,其在哺乳动物中分别命名为METTL3和METTL16。与METTL3相似,METTL16的底物多种多样,包括pre-mRNA、rRNA、snRNA和lncRNA等,因此似乎难以用一种分子机理解释METTL16对不同RNA底物进行m~6A修饰的功能。此外,METTL16还在翻译调控中发挥重要作用,但此过程不依赖其甲基转移酶活性,这进一步增加了高度保守的METTL16的功能复杂性。本综述总结了METTL16及其同源蛋白质的结构域、甲基化底物以及它们的潜在功能,着重阐述了在不同物种中关于METTL16研究结果的矛盾之处,并推测METTL16调控S-腺苷基甲硫氨酸(SAM)代谢的功能是趋同进化的一个潜在案例。

Chemical modifications of RNA bases play essential roles in finetuning the functions of the modified RNA species.The m~6A modification is one of the most prevalent RNA modifications in nature with important functions in RNA stability,pre-mRNA splicing,translational regulations and likely others.m~6A modifications in eukaryotes are believed to be mainly carried out by two related methyltransferases,METTL3 and METTL16 based on mammalian nomenclature.METTL16,similar to METTL3,has a large variety of RNA substrates,including pre-mRNA,rRNA,snRNA and lncRNA.Therefore,a unifying molecular function seems farfetched for the METTL16-installed m~6A modification.In addition,METTL16 carries out important function in translational regulation independent of its methyltransferase activity,adding another layer of functional complexity to this highly conserved enzyme.In this review,we summarize the domain architecture of METTL16 and homologous proteins,indicating the conserved functional domains as well as the mammalian specific VCR domain suggestive of additional function of the higher enzymes.We summarize the confirmed METTL16-methylated RNA substrates as the pre-mRNA for SAM synthetase(MAT) in men and worms,and the U6 small nuclear RNA(snRNA) in yeast,plants,worms and men.Although the role of m~6A modification in regulating SAM levels by alternative splicing might represent a case of convergent evolution,this proposition lacks support from plant studies of METTL16.The lack of m~6A modification on U6 snRNA,an essential component of the spliceosome,has been identified in genome-wide studies as the cause for the splicing defects of specific introns in yeast and plants.How much of this function of U6 modification is conserved remains unclear.Mammalian METTL16 has been shown to carry out methylation-independent function by interacting with the machinery for protein synthesis.In addition,METTL16 was originally identified as the interacting protein of the triple-helix forming MALAT1,a long non-coding RNA highly expressed in certain tumors.However,whether MALAT1 is a methylation substrate of METTL16 and what underlies the biological significance of the METTL16-MALAT1 interaction remain under characterized.While knock-out mutants of METTL3 proteins suffer mild organismal consequences,those of METTL16 cause much more severe physiological abnormalities.How the conserved METTL16 enzymes fulfill an array of diverse and essential functions promises to be one of the fascinating directions in RNA biology.