Lee et al. report a mechanism regulating mRNP export mediated by N6-adenosine methylation, METTL3 and NUP93 with potential implications for nephrotic syndrome and other human diseases.

Beyond its role as RNA m6A writer, METTL3-METTL14 can mediate 5mC deposition on DNA by recruiting the DNA methyltransferase DNMT1 to chromatin. The two marks co-orchestrate the expression of key genes...

Chen, Xu, Zhou, Wu et al. report that a citric acid cycle enzyme OGDH regulates METTL3 succinylation and its activation as an m6A reader, thereby modulating NRF2 translation, disulfidptosis evasion an...

Beyond its role as RNA m6A writer, METTL3-METTL14 can mediate 5mC deposition on DNA by recruiting the DNA methyltransferase DNMT1 to chromatin. The two marks co-orchestrate the expression of key genes...

AbstractRNA N6-methyladenosine (m6A) deposition by the METTL3–METTL14 complex regulates RNA metabolism and thereby influences cell differentiation and stress responses. Dysregulated m6A deposition has been implicated in multiple cancers, where METTL3–METTL14 supports oncogenic programs. Yet the molecular basis of RNA recognition by this complex remains unclear, in part due to the lack of an RNA-bound structure of the full assembly. Here, we combined native mass spectrometry (MS), molecular modeling, biochemical assays, and cell-based studies to define how METTL3–METTL14 engages RNA and how this process can be perturbed through interface targeting. Native MS of the intact heterodimer revealed simultaneous binding of multiple RNA molecules, with RNA-dependent stoichiometries and higher-occupancy states consistent with cooperative interactions. Molecular dynamics simulations identified a structured RNA-bound assembly in which the METTL14 C-terminal RGG-rich region stabilizes two RNA molecules, supporting a pre-engaged substrate configuration. We further developed a focused library of METTL14-derived peptides that bind METTL3 and interfere with protein–protein interactions, identifying the minimal METTL14 epitope for interface engagement. The most potent peptide, R8–14, binds with submicromolar affinity, disrupts both METTL3–METTL14 association and higher-order RNA-bound states, and reduces m6A levels, c-Myc expression, and cancer cell viability. Together, these findings demonstrate that RNA recognition by METTL3–METTL14 is governed by multivalent, higher-order interactions that enhance binding avidity. Notably, this assembly can be perturbed allosterically through protein–protein interface targeting rather than active-site inhibition, highlighting multivalent RNA recognition as a mechanistically and pharmacologically actionable feature of the RNA m6A writer complex.

He and colleagues develop a METTL3-based RNA base-editing screening strategy to identify functional N6-methyladenosine (m6A) sites that are important for prostate cancer cells and validate the role of...

Wu et al. reveal that METTL3-mediated m6A modification downregulates the lncRNA MALAT1, which sponges miR-23c to elevate IDH1 expression and α-ketoglutarate production. This axis promotes mitophagy and alleviates oxidative stress, thereby protecting against intervertebral disc degeneration.

Lee et al. report a mechanism regulating mRNP export mediated by N6-adenosine methylation, METTL3 and NUP93 with potential implications for nephrotic syndrome and other human diseases.

Cell Death & Disease - TRIM21-mediated METTL3 degradation promotes PDAC ferroptosis and enhances the efficacy of Anti-PD-1 immunotherapy

The mechanisms governing kidney nephrogenic capacity are incompletely understood. Here, the authors reveal that METTL3-dependent RNA transmethylation is both necessary and sufficient to promote nephro...

Akçaöz-Alasar et al. reveal that the mitotic kinase CDK1 phosphorylates the m6A methyltransferase METTL3, which then methylates 7SK RNA to release P-TEFb and promote RNA polymerase II clearance during mitosis, ensuring proper chromosome segregation.

In this issue, Huang et al. report the acetylation of METTL3 as a negative regulator of m6A deposition of chromatin-associated regulatory RNAs from enhancers and promoters. This acetylation is mediated by p300 and positively regulated by PAK2.