The Role of Human Satellite II in Human Cytomegalovirus Infection

Abstract

Human cytomegalovirus (HCMV) is an opportunistic pathogen that is highly prevalent throughout the world. For newborns and individuals with a compromised immune system, the virus represents a severe threat to health. Although healthy individuals are generally asymptomatic, increasing evidence suggests that the persistent nature of the virus is associated with chronic disease. In order to accomplish its ubiquitous tissue manifestation, HCMV must manipulate diverse aspects of cellular biology. In this study, we investigate the viral regulation of cellular noncoding RNA. Specifically, we determined the role of and mechanism by which HCMV induces expression of human satellite II (HSATII), a noncoding RNA that is highly overexpressed in tumor cells. Preliminary RNA sequencing data revealed that many noncoding RNAs, especially HSATII, are upregulated upon HCMV infection. Investigation into the role of HSATII revealed that the RNA is important for efficient viral replication by impacting a later stage of HCMV’s lifecycle. Furthermore, our results implicate the activation of the main transducer in the double stranded DNA break damage response, ataxia telangiectasia mutated (ATM), as a mechanism for HSATII overexpression. Here, we show that activated ATM during HCMV infection or treatment with DNA damaging agents results in the induction of HSATII expression. Moreover, our investigation of HSATII in a monocytic cell line suggested that HSATII acts as an immunoinhibitory element that promotes cell motility during HCMV infection. Based on these results, we conclude that HCMV induces HSATII expression via ATM activation in order to create an environment that encourages viral replication. This study has implications for antiviral therapy as well as for cancer biology by offering an inducible system for studying the biological roles of HSATII and other highly expressed repeat elements.