Biography
Biography: Bryan R Cullen
Abstract
While it has been known for almost 40 years that a wide range of virally encoded RNAs, including mRNAs, are extensively modified by addition of a methyl group to the N6 position of adenosine (m6A), the functional consequences of this epitranscriptomic modification had remained unclear. However, the prevalence of m6A across multiple different viral species, and the recently demonstrated conservation of m6A residues in several distinct isolates of HIV-1, clearly implies that m6A favors some aspect of the viral replication cycle. More recently, the identification of the factors that add m6A to mRNAs, especially the m6A “writer” METTL3, and the definition of factors that bind m6A on mRNAs, including the key m6A “reader” YTHDF2, have recently allowed the phenotypic consequences of m6A addition to be more fully characterized. Using overexpression and/or genetic ablation strategies, as well as by mapping and mutationally inactivating specific viral mRNA m6A addition sites, we have now examined the effect of m6A in the context of three distinct viral families: the lentivirus HIV-1, the paramyxovirus influenza A virus (IAV) and the polyomavirus SV40. In all three cases, we observe that addition of m6A strongly enhances viral mRNA and protein expression, and hence replication, and, in the case of IAV, increases pathogenicity in vivo. In this presentation, I will discuss our current understanding of the mechanistic basis for this phenomenon.