YTH Domain: A Family of N6-methyladenosine (m6A) Readers

Shanhui Liao,Hongbin Sun,Chao Xu

doi:10.1016/j.gpb.2018.04.002

Abstract

Like protein and DNA, different types of RNA molecules undergo various modifications. Accumulating evidence suggests that these RNA modifications serve as sophisticated codes to mediate RNA behaviors and many important biological functions. N6-methyladenosine (m6A) is the most abundant internal RNA modification found in a variety of eukaryotic RNAs, including but not limited to mRNAs, tRNAs, rRNAs, and long non-coding RNAs (lncRNAs). In mammalian cells, m6A can be incorporated by a methyltransferase complex and removed by demethylases, which ensures that the m6A modification is reversible and dynamic. Moreover, m6A is recognized by the YT521-B homology (YTH) domain-containing proteins, which subsequently direct different complexes to regulate RNA signaling pathways, such as RNA metabolism, RNA splicing, RNA folding, and protein translation. Herein, we summarize the recent progresses made in understanding the molecular mechanisms underlying the m6A recognition by YTH domain-containing proteins, which would shed new light on m6A-specific recognition and provide clues to the future identification of reader proteins of many other RNA modifications.

Highlights

A splicing, RNA folding, and protein translation
N6-methyladenosine (m6A), which was discovered in a wide range of cellular RNAs in 1970s [5,6,7], is the most prevalent internal RNA modification present in a GAC or AAC motif within almost all types of eukaryotic RNAs examined [8] as well as viral RNAs [9,10,11,12,13,14]
Similar to other epigenetic modifications, m6A is dynamic and reversible, established mainly by the METTL3–METTL14 methyltransferase complex [20,21] and removed by demethylases including the fat mass and obesity-associated protein (FTO) [22] and AlkB homolog 5 RNA demethylase (ALKBH5) [23]. Both METTL3 and METTL14 adopt a canonical fold similar to that of other methyltransferases [20], only METTL3 can bind to the methyl donor Sadenosyl methionine (SAM or AdoMet), whereas METTL14 acts to modulate the activity of METTL3 and binds to the RNA substrate instead [20,24,25]

Summary

Introduction

A splicing, RNA folding, and protein translation. we summarize the recent progresses made in understanding the molecular mechanisms underlying the m6A recognition by YTH domaincontaining proteins, which would shed new light on m6A-specific recognition and provide clues to the future identification of reader proteins of many other RNA modifications. Similar to other epigenetic modifications, m6A is dynamic and reversible, established mainly by the METTL3–METTL14 methyltransferase complex [20,21] and removed by demethylases including the fat mass and obesity-associated protein (FTO) [22] and AlkB homolog 5 RNA demethylase (ALKBH5) [23] Both METTL3 and METTL14 adopt a canonical fold similar to that of other methyltransferases [20], only METTL3 can bind to the methyl donor Sadenosyl methionine (SAM or AdoMet), whereas METTL14 acts to modulate the activity of METTL3 and binds to the RNA substrate instead [20,24,25]. The in vivo biological relevance of 6 mA ssDNA demethylation by ALKBH5 remains unknown, 6 mA has been identified in eukaryotic genomes by several groups [31,32,33]

Objectives

Conclusion