Colocalization of m(6)A and G-Quadruplex-Forming Sequences in Viral RNA (HIV, Zika, Hepatitis B, and SV40) Suggests Topological Control of Adenosine N(6)-Methylation

[Image: see text] This Outlook calls attention to two seemingly disparate and emerging fields regarding viral genomics that may be correlated in a way previously overlooked. First, we describe identification of conserved potential G-quadruplex-forming sequences (PQSs) in viral genomes relevant to human health. Studies have demonstrated that PQSs are highly conserved and can fold to G-quadruplexes (G4s) to regulate viral processes. Key examples include G4s as a countermeasure to the host’s immune system or G4-guided regulation of replication or transcription. Second, emerging data are discussed concerning the epitranscriptomic modification N(6)-methyladenosine (m(6)A) in viral RNA installed by host proteins in a consensus sequence favoring 5′-GG(m(6)A)C-3′. The proposed pathways by which m(6)A is written, read, and erased in viral RNA genomes and the impact this has on viral replication are described. The structural reason why certain sites are selected for modification while others are not is still mysterious. Finally, we discuss our new observations regarding these previous sequencing data that identify m(6)A installation within the loops of two-tetrad PQSs in the RNA genomes of the Zika, HIV, hepatitis B, and SV40 viruses. We hypothesize that conserved viral PQSs can provide a framework (sequence and/or structural) for m(6)A installation. We also discuss literature sources suggesting that PQSs as sites of RNA modification could be a general phenomenon. We anticipate our observations will provide ample opportunities for exciting discoveries regarding the interplay between G4 structures and epitranscriptomic modifications of RNA.