Roles of Small G protein Ras in regulating mRNA m6A methylation

Abstract: N6-methyladenosine (m6A) methylation, a dynamic epitranscriptomic modification, regulates RNA processing, impacting diverse cellular activities. Meanwhile, in the past decades, evidence has suggested that mRNA m6A methylation and its associated factors are markedly dysregulated in tumours, contributing to carcinogenesis, cancer progression, cancer stem cell renewal, and cancer therapy resistance. However, the mechanisms linking upstream oncogenic signalling pathways to m6A regulation remain limited understood. This study investigates the role of small G protein Ras signalling, a central driver of tumorigenesis, in modulating m6A methylation. By integrating genetic perturbation of Ras signalling with Nanopore sequencing and functional assays, we aim to delineate how Ras-driven signalling cascades (e.g., MAPK, PI3K, Ral/GEF) influence the expression, post-translational modifications, activity, or localization of m6A regulatory proteins, thereby reprogramming the m6A landscape to promote oncogenic mRNA translation or stability. Our findings will uncover novel crosstalk between oncogenic Ras and the epitranscriptome, with critical implications for understanding post-transcriptional regulation in cancer progression, which will potentially reveal the therapeutic vulnerabilities in Ras-mutant cancers and propose novel therapeutic avenues targeting the Ras-m6A axis.