What question did this study set out to answer?

The aim is to explore the roles of specific rare RNA methylation modifications in disease and therapy.

May 7, 2026Open Access

The Rare RNA Methylations m²G, Cm, m⁵U and ms²i⁶A: Roles in Disease Pathogenesis and Emerging Therapeutic Implications

KWKeyu WanNanchang University TNTiantian NieNanchang University QZqin zhangNanchang University

Key Points

The aim is to explore the roles of specific rare RNA methylation modifications in disease and therapy.
In-depth analysis of N2-methylguanosine, 2-O-methylcytidine, 5-methyluridine, and 2-methylthio-N6-isopentenyladenosine.
Review of current detection methodologies for RNA modifications.
Discussion on the biological functions and disease associations of these modifications.
Elucidated molecular mechanisms for m2G, Cm, m5U, and ms2i6A in various diseases.
Identified potential therapeutic implications for targeting rare RNA methylations.
Highlighted the need for further research on lesser-known RNA modifications.

Abstract

RNA methylation modifications play a central and multifaceted role in various physiological processes by precisely regulating key steps in the RNA life cycle, including nuclear processing, nuclear export, splicing, and cytoplasmic translation.These modifications, which occur on the four nucleotides that constitute RNA strands, are tightly regulated by specific proteins known as "writers," "readers," and "erasers."Advances in high-throughput sequencing and mass spectrometry technologies have progressively unveiled the biological functions of common RNA methylation marks such as N6-methyladenosine (m 6 A), N1-methyladenosine (m 1 A), and 5-methylcytosine (m 5 C).However, our understanding of how RNA modifications influence various cellular processes remains limited, and research focusing on the biological significance of rare RNA methylation modifications is particularly scarce.This review shifts the research focus toward several relatively understudied and less widely recognized RNA methylation modifications, providing an in-depth analysis of four specific modifications: N2-methylguanosine (m 2 G), 2-O-methylcytidine (Cm), 5-methyluridine (m 5 U), and 2-methylthio-N6-isopentenyladenosine (ms 2 i 6 A).It comprehensively elucidates their molecular mechanisms, biological functions, and associations with disease.In addition, this article summarizes the current methodologies available for detecting RNA modifications and discusses the potential applications of these RNA methylation modifications in disease therapy.

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