Work

Nucleobase Coordination With Mg 2 + Facilitates RNA Cleavage via Internal Transesterification

Year: 2026

Type: article

Abstract: ABSTRACT Internal transesterification is a fundamental chemical process underlying both spontaneous RNA degradation and biologically regulated RNA cleavage by RNases and ribozymes. Although Mg 2 + and ribose conformation are known to influence this reaction, the mechanistic role of nucleobases remains poorly understood. Here, by combining density functional theory calculations with kinetic and NMR experiments, we demonstrate that Mg 2 + promotes RNA cleavage through synergistic tridentate coordination with the nucleobase, the 2′‐hydroxyl group, and the phosphate moiety. This coordination drives the ribose toward the South conformation, enabling activation of the 2′‐OH nucleophile and stabilization of the transition state during internal transesterification. Notably, O 2 of rU coordinates Mg 2 + more strongly than N 3 of rA, leading to lower activation barriers and faster cleavage kinetics, thereby rationalizing the preferential alkali‐catalyzed RNA cleavage at pyrimidine sites. These findings uncover a previously unrecognized mechanistic role of nucleobases in RNA backbone scission and provide new insights into spontaneous RNA degradation and RNase‐ and ribozyme‐catalyzed RNA cleavage.

Source: Chemistry - A European Journal

DOI: 10.1002/chem.71102