Crosstalk between m6A modification and alternative splicing during cancer progression

Abstract

BackgroundN6‐methyladenosine (m6A), the most prevalent internal mRNA modification in eukaryotes, is added by m6A methyltransferases, removed by m6A demethylases and recognised by m6A‐binding proteins. This modification significantly influences carious facets of RNA metabolism and plays a pivotal role in cellular and physiological processes.Main bodyPre‐mRNA alternative splicing, a process that generates multiple splice isoforms from multi‐exon genes, contributes significantly to the protein diversity in mammals. Moreover, the presence of crosstalk between m6A modification and alternative splicing, with m6A modifications on pre‐mRNAs exerting regulatory control, has been established. The m6A modification modulates alternative splicing patterns by recruiting specific RNA‐binding proteins (RBPs) that regulate alternative splicing or by directly influencing the interaction between RBPs and their target RNAs. Conversely, alternative splicing can impact the deposition or recognition of m6A modification on mRNAs. The integration of m6A modifications has expanded the scope of therapeutic strategies for cancer treatment, while alternative splicing offers novel insights into the mechanistic role of m6A methylation in cancer initiation and progression.ConclusionThis review aims to highlight the biological functions of alternative splicing of m6A modification machinery and its implications in tumourigenesis. Furthermore, we discuss the clinical relevance of understanding m6A‐dependent alternative splicing in tumour therapies.

Endogenous labeling empowers accurate detection of m6A from single long reads of direct RNA sequencing

“…Recent studies have unveiled the pivotal roles of m 6 A in the process of epithelial-mesenchymal transition (EMT) 43, 44 , which is also a process critically regulated by alternative RNA splicing 45 . To investigate whether m 6 A can be dynamically regulated in an isoform-specific manner, we performed ONT DRS to examine the m 6 A changes on specific RNA isoforms in HeLa cells upon TGF-β induced EMT.…”

Unveiling the Impact of ApoF Deficiency on Liver and Lipid Metabolism: Insights from Transcriptome-Wide m6A Methylome Analysis in Mice

“…MeRIP-Seq is a high-throughput sequencing technique that uses RNA–protein immunoprecipitation to analyze m6A modification levels in RNA. These modifications affect the metabolism of target RNAs, including their maturation, splicing, export, folding, translation, and stability, thereby influencing downstream signaling pathways and physiological functions [ 48 , 49 , 50 ]. The m6A modifications primarily occur on adenines within the RRACH sequence.…”

The functions and mechanisms of RNA modification in prostate: Current status and future perspectives

“…They can recruit heat-responsive protein 12-RNase for mitochondrial RNA processing complex, carbon catabolite repression-negative on TATA-less deenylase complex, and interact with UPF1, playing a key role in mRNA degradation. Additionally, m6A modification is closely related to chromatin accessibility, histone modification, and homologous recombination repair (Zhu et al, 2023). However, the role of these complex regulatory mechanisms in determining the fate of tumor cells is often contradictory due to differences in tumor types, warranting further investigation.…”