CRISPR-like properties of eukaryotic ribosomal 45S RNA gene clusters
As viruses lack their own ribosomes, they have evolved various strategies of cellular mimicry and deception to usurp and repurpose host cell ribosomes toward viral protein production 1. This omnipresent challenge posed by viruses results in virus-host coevolution, with ribosomes and ribosomal RNA (rRNA) gene clusters locked in genetic conflict with viral genomes. In addition to their tandem repeat redundancy, eukaryotic 45S rRNA gene clusters have a number of striking, CRISPR-like features, such as palindromic organization 2 of highly conserved sequences (18S, 5.8S, and 28S rDNA) separated by unique, internal transcribed spacers 1 (ITS1) and 2 (ITS2). ITS sequences are highly dissimilar between species but tend to preserve RNA secondary structure that includes a stem-loop 3,4. We discovered that, not unlike bacterial and archaeal CRISPRs 5, eukaryotic ITS regions contain ancient fragments of integrated virus-like sequences, predominantly homologous to DNA viruses, such as herpesviruses in vertebrates. Human ITS2 sequences not only exhibit homologies to herpesvirus sequences but also exert potent immunostimulatory and antiviral properties against herpesvirus infection. These findings will help establish the groundwork for a new paradigm in antiviral immunity and treatment.