ion maps in the NETWORK database, as well as with conserved functional units of KEGG modules and reaction modules in the MODULE database. The KO database for functional orthologs continues to be improved and virus KOs are being expanded for better understanding of virus-cell interactions and for enabling prediction of viral perturbations.20:T43c,N⁶-methyladenosine (m⁶A) is an RNA modification well-known for its contribution to different processes controlling RNA metabolism, including splicing, stability, and translation of mRNA. Conversely, the role of m⁶A on the biogenesis and function of circular RNAs (circRNAs) has yet to be addressed. circRNAs belong to a class of covalently closed transcripts produced via a back-splicing reaction whereby a downstream 5' splice donor site fuses to an upstream 3' splice acceptor site. Starting from circ-ZNF609 as a study case, we discover that specific m⁶As control its accumulation and that METTL3 and YTHDC1 are required to direct the back-splicing reaction. This feature is shared with other circRNAs because we find a significant direct correlation among METTL3 requirement, YTHDC1 binding, and the ability of m⁶A exons to undergo back-splicing. Finally, because circ-ZNF609 displays the ability to be translated, we show that m⁶A modifications, through recognition by YTHDF3 and eIF4G2, modulate its translation.21:T532,N⁶-Methyladenosine (m⁶A) is the most common internal modification of eukaryotic messenger RNA (mRNA) that occurred on the N⁶ nitrogen of adenosine. However, the roles of m⁶A in oral squamous cell carcinoma (OSCC) are still elusive. Here, we investigate the function and mechanism of methyltransferase-like 3 (METTL3) in OSCC tumorigenesis. Clinically, METTL3 was significantly upregulated in tissue samples and correlated with the poor prognosis of OSCC patients. Functionally, loss and gain studies illustrated that METTL3 promoted the proliferation, invasion, and migration of OSCC cells in vitro, and METTL3 knockdown inhibited tumor growth in vivo. Mechanistically, methylated RNA immunoprecipitation sequencing (MeRIP-seq) illustrated that METTL3 targeted the 3' UTR (near to stop codon) of the c-Myc transcript to install the m⁶A modification, thereby enhancing its stability. Furthermore, results revealed that YTH N⁶-methyladenosine RNA binding protein 1 (YTH domain family, member 1 [YTHDF1]) mediated the m⁶A-increased stability of c-Myc mRNA catalyzed by METTL3. In conclusion, our findings herein identify that METTL3 accelerates the c-Myc stability via YTHDF1-mediated m⁶A modification, thereby giving rise to OSCC tumorigenesis.

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