Rationalizing the Effects of RNA Modifications on Protein Interactions

AbstractRNA modifications play a crucial role in regulating gene expression by altering RNA structure and modulating interactions with RNA-binding proteins (RBPs). In this study, we explore the impact of specific RNA chemical modifications—N6-methyladenosine (m⁶A), A-to-I editing, and pseudouridine (Ψ)—on RNA secondary structure and protein-RNA interactions. Utilizing genome-wide data, including RNA secondary structure predictions and protein-RNA interaction datasets, we classify proteins into distinct categories based on their binding behaviors: modification-specific and structure-independent, or modification-promiscuous and structure-dependent. For instance, m⁶A readers like YTHDF2 exhibit modification-specific and structure-independent binding, consistently attaching to m⁶A regardless of structural changes. Conversely, proteins such as U2AF2 display modification-promiscuous and structure-dependent behavior, altering their binding preferences in response to structural changes induced by different modifications. A-to-I editing, which causes significant structural changes, typically reduces protein interactions, while Ψ enhances RNA structural stability, albeit with variable effects on protein binding. To better predict these interactions, we developed the catRAPID 2.0 RNA modifications algorithm, which forecasts the effects of RNA modifications on protein-RNA binding propensities. This algorithm serves as a valuable tool for researchers, enabling the prediction and analysis of RNA modifications’ impact on protein interactions, thus offering new insights into RNA biology and engineering. The catRAPID 2.0 RNA modifications tool is available athttp://service.tartaglialab.com/new_submission/catrapid_omicsv2_rna_mod.Abstract Figure