Cross-regulation of RNA methylation modifications and R-loops: from molecular mechanisms to clinical implications.

Abstract

R-loops, RNA-DNA hybrid structures, are integral to key cellular processes such as transcriptional regulation, DNA replication, and repair. However, aberrant accumulation of R-loops can compromise genomic integrity, leading to the development of various diseases. Emerging evidence underscores the pivotal role of RNA methylation modifications, particularly N6-methyladenosine (m⁶A) and 5-methylcytosine (m⁵C), in orchestrating the formation, resolution, and stabilization of R-loops. These modifications dynamically regulate R-loop metabolism, exerting bidirectional control by either facilitating or resolving R-loop structures during gene expression regulation and DNA damage repair. Dysregulation of RNA methylation and the resultant imbalance in R-loop homeostasis are closely linked to the pathogenesis of diseases such as cancer and neurodegenerative disorders. Thus, deciphering the cross-talk between RNA methylation and R-loops is essential for understanding the mechanisms underlying genomic stability and identifying novel therapeutic targets. This review provides a comprehensive analysis of the role of RNA methylation in R-loop dynamics, examines their physiological and pathological implications, and proposes future directions for therapeutic intervention targeting these processes.