Interconnections between m6A RNA modification, RNA structure, and protein-RNA complex assembly

Protein-RNA complexes exist in many forms within the cell, from stable machines such as the ribosome to transient assemblies like the spliceosome. All protein-RNA assemblies rely on spatially and temporally coordinated interactions between specific proteins and RNAs to achieve a functional form. RNA folding and structure are often critical for successful protein binding and protein-RNA complex formation. RNA modifications change the chemical nature of a given RNA and often alter its folding kinetics. Both these alterations can affect how and if proteins or other RNAs can interact with the modified RNA and assemble into complexes. N6-methyladenosine (m6A) is the most common base modification on mRNAs and regulatory noncoding RNAs and has been shown to impact RNA structure and directly modulate protein-RNA interactions. In this review, focusing on the mechanisms and available quantitative information, we discuss first how the METTL3/14 m6A writer complex is specifically targeted to RNA assisted by protein-RNA and other interactions to enable site-specific and cotranscriptional RNA modification and, once introduced, how the m6A modification affects RNA folding and protein-RNA interactions.