Beyond reader proteins: RNA binding proteins and RNA modifications in conversation to regulate gene expression

Abstract Post‐transcriptional mRNA modifications play diverse roles in gene expression and RNA function. In many cases, RNA modifications function by altering how cellular machinery such as RNA binding proteins (RBPs) interact with RNA substrates. For instance, N6‐methyladenosine (m6A) is recognized by the well‐characterized YTH domain‐containing family of “reader” proteins. For other mRNA modifications, similar global readers of modification status have not been clearly defined. Rather, most interactions between RBPs and RNA modifications have a more complicated dependence on sequence context and binding modality. The current handful of studies that demonstrate modifications impacting protein binding likely represent only a fraction of the full landscape. In this review, we dissect the known instances of RNA modifications altering RBP binding, specifically m6A, N1‐methyladenosine (m1A), 5‐methylcytosine (m5C), pseudouridine (Ψ), and internal N7‐methylguanosine. We then review the biochemical properties of these and other identified mRNA modifications including dihydrouridine (D), N4 ‐ acetylcytosine (ac4C), and 2′‐O‐Methylation (Nme). We focus on how these properties would be likely to impact RNA:RBP interactions, including by changes to hydrogen bond potential, base‐stacking efficiency, and RNA conformational preferences. The effects of RNA modifications on secondary structure have been well‐studied, and we briefly discuss how structural effects imparted by modifications can lead to protein binding changes. Finally, we discuss strategies for uncovering as‐yet‐to‐be identified modification‐sensitive RBP:RNA Interactions. Coordinating future efforts to intersect the epitranscriptome and the RNA–protein interactome will illuminate the rules governing RNA modification recognition and the mechanisms responsible for the biological consequences of mRNA modification. This article is categorized under: RNA Structure and Dynamics > RNA Structure, Dynamics and Chemistry RNA Interactions with Proteins and Other Molecules > Protein‐RNA Recognition RNA Processing > RNA Editing and Modification