Telomeres and viruses: common themes of genome maintenance

Abstract

Genome maintenance mechanisms actively suppress genetic instability associated with cancer and aging. Some viruses provoke genetic instability by subverting the host's control of genome maintenance. Viruses have their own specialized strategies for genome maintenance, which can mimic and modify host cell processes. Here, we review some of the common features of genome maintenance utilized by viruses and host chromosomes, with a particular focus on terminal repeat (TR) elements. The TRs of cellular chromosomes, better known as telomeres, have well-established roles in cellular chromosome stability. Cellular telomeres are themselves maintained by viral-like mechanisms, including self-propagation by reverse transcription, recombination, and retrotransposition. Viral TR elements, like cellular telomeres, are essential for viral genome stability and propagation. We review the structure and function of viral repeat elements and discuss how they may share telomere-like structures and genome protection functions. We consider how viral infections modulate telomere regulatory factors for viral repurposing and can alter normal host telomere structure and chromosome stability. Understanding the common strategies of viral and cellular genome maintenance may provide new insights into viral-host interactions and the mechanisms driving genetic instability in cancer.

Keywords: EBV; HHV6; KSHV; MDV; replication; telomere; virus.

FIGURE 1

Schematic of Viral Genome Terminal Repeat Structure in Linear and Circular Conformations. Viral terminal repeats (TR) and intergenic repeats (IR) are shown as various colored box, indicating different repetitive sequences. Adenovirus TP and LANA bind to TR of adenovirus and KSHV, respectively. EBNA1 binds to both FR and DS region of EBV OriP. TRFs bind to DS region of EBV OriP and MDV OriS, and TRFs-binding sites are indicated for TR of MDV and HHV6. The terminal hairpin structure for Pox virus is indicated in pink.

FIGURE 2

Model of higher order chromatin structures at telomeres and viral maintenance elements. RNA-dependent recruitment of ORC at telomeres and EBV OriP is indicated. Elevated histone H3K4me3 and CTCF-cohesin enrichment is found at all three maintenance elements. TRFs are localized to the latent origin of both EBV and KSHV.

FIGURE 3

EBV primary infection induces telomere dysfunction in peripheral blood mononuclear cells (PBMCs). (A) Freshly isolated PBMCs (#187 and #225) were infected with viruses isolated from Mutu I cells, and assayed by telomere DNA fluorescence in situ hybridization (FISH) on metaphase spreads at day 50 post-infection using telomeric PNA probe (green). Metaphase chromosomes were stained by Dapi, and shown in blue. (B) Common telomere aberrations in infected cells were shown as enlarged images. Arrows indicate telomere doublets (i–ii), telomere end fusions (iii–iv), and telomeric signal free ends (v–vi).