Regulation and functions of non-m6A mRNA modifications

Abstract

Nucleobase modifications are prevalent in eukaryotic mRNA and their discovery has resulted in the emergence of epitranscriptomics as a research field. The most abundant internal (non-cap) mRNA modification is N⁶-methyladenosine (m⁶A), the study of which has revolutionized our understanding of post-transcriptional gene regulation. In addition, numerous other mRNA modifications are gaining great attention because of their major roles in RNA metabolism, immunity, development and disease. In this Review, we focus on the regulation and function of non-m⁶A modifications in eukaryotic mRNA, including pseudouridine (Ψ), N⁶,2'-O-dimethyladenosine (m⁶Am), N¹-methyladenosine (m¹A), inosine, 5-methylcytidine (m⁵C), N⁴-acetylcytidine (ac⁴C), 2'-O-methylated nucleotide (Nm) and internal N⁷-methylguanosine (m⁷G). We highlight their regulation, distribution, stoichiometry and known roles in mRNA metabolism, such as mRNA stability, translation, splicing and export. We also discuss their biological consequences in physiological and pathological processes. In addition, we cover research techniques to further study the non-m⁶A mRNA modifications and discuss their potential future applications.