Pseudouridylation Found to Occur Naturally in mRNA

The so-called central dogma of molecular biology—that DNA makes RNA which makes protein—has long provided a simplified explanation for how genetic information is deciphered and translated in living organisms. In reality, of course, the process is vastly more complicated than the schema first articulated nearly 60 years ago by Nobel Laureate Francis Crick, co-discoverer of the DNA’s double-helix structure. For one, there are multiple types of RNA, three of which—messenger RNA (mRNA), transfer RNA (tRNA), and ribosomal RNA (rRNA)—are essential for proper protein production. Moreover, RNAs that are synthesized during the process known as transcription often undergo subsequent changes, which are referred to as “post-transcriptional modifications.” Multiple such RNA modifications have been documented over the years, although the precise functions and significance of many of these have been shrouded in mystery. Among the most common post-transcriptional modifications is pseudouridylation, during which the base nucleoside uridine—the ‘U’ of the four base RNA nucleosides abbreviated as A, C, G, and U—has its chemical structure altered to form a molecule known as pseudouridine (ψ) (see image). To date, ψ has been found in abundance in tRNA, rRNA, and small nuclear or snRNA, but was thought not to exist in mRNA. Deploying sophisticated high-throughput sequencing technology, dubbed ψ-seq, a team of Whitehead Institute and Broad Institute researchers collaborated on a comprehensive, high-resolution mapping of ψ sites that confirms that pseudouridylation does indeed occur naturally in mRNA. This somewhat surprising finding and the novel approach that led to it were revealed online on September 13, 2014 in Cell.