A tumor-specific endogenous repetitive element is induced by herpesviruses

Maciej T Nogalski,Alexander Solovyov,Arnold J Levine,David T Ting,Benjamin D Greenbaum,Adam Oberstein,Thomas Shenk,Niyati Desai,Anupriya S Kulkarni

doi:10.1038/s41467-018-07944-x

Abstract

Tandem satellite repeats account for 3% of the human genome. One of them, Human Satellite II (HSATII), is highly expressed in several epithelial cancers and cancer cell lines. Here we report an acute induction of HSATII RNA in human cells infected with two herpes viruses. We show that human cytomegalovirus (HCMV) IE1 and IE2 proteins cooperate to induce HSATII RNA affecting several aspects of the HCMV replication cycle, viral titers and infected-cell processes. HSATII RNA expression in tissue from two chronic HCMV colitis patients correlates with the strength of CMV antigen staining. Thus, endogenous HSATII RNA synthesis after herpesvirus infections appears to have functionally important consequences for viral replication and may provide a novel insight into viral pathogenesis. The HSATII induction seen in both infected and cancer cells suggests possible convergence upon common HSATII-based regulatory mechanisms in these seemingly disparate diseases.

Highlights

Tandem satellite repeats account for 3% of the human genome
In the case of human cytomegalovirus (HCMV), we report that accumulation of Human Satellite II (HSATII) RNA requires the combined action of the viral IE1 and IE2 proteins and that HSATII RNA is important for efficient viral protein expression and localization, viral replication, and release of infectious particles
With a focus on non-coding RNAs whose levels changed with infection, we found the majority of transcripts (74%) were downregulated at 48 hpi, and this tendency was the most profound for repetitive elements as 87% of them were decreased in HCMV-infected cells

Summary

Introduction

Tandem satellite repeats account for 3% of the human genome. One of them, Human Satellite II (HSATII), is highly expressed in several epithelial cancers and cancer cell lines. We show that human cytomegalovirus (HCMV) IE1 and IE2 proteins cooperate to induce HSATII RNA affecting several aspects of the HCMV replication cycle, viral titers and infected-cell processes. 1234567890():,; Repetitive sequences account for more than 50% of the human genome with tandem satellite repeats comprising approximately 3%1. Human satellite repeat II (HSATII) and its mouse counterpart (GSAT) were further shown to be highly expressed in several epithelial cancers but not corresponding normal tissue[4,5]. The sequence motifs of HSATII RNA mimic some zoonotic viruses by containing CpG motifs within an AU-rich sequence context These types of sequences are vastly under-represented in the human genome, avoided in viruses[10], immune-stimulatory in cells[5,11], and sensed by the antiviral protein ZAP if present in viral RNA12. Our work depicts HSATII RNA as a regulator of several cellular processes, such as cellular motility, and provides a potential link between increased HSATII expression and virus-mediated pathobiology in CMV colitis

Methods

Results

Conclusion