Telomeres and Telomerase: Role in Marek’s Disease Virus Pathogenesis, Integration and Tumorigenesis

Abstract

Telomeres protect the ends of vertebrate chromosomes from deterioration and consist of tandem nucleotide repeats (TTAGGG)n that are associated with a number of proteins. Shortening of the telomeres occurs during genome replication, thereby limiting the replication potential of somatic cells. To counteract this shortening, vertebrates encode the telomerase complex that maintains telomere length in certain cell types via de novo addition of telomeric repeats. Several herpesviruses, including the highly oncogenic alphaherpesvirus Marek’s disease virus (MDV), harbor telomeric repeats (TMR) identical to the host telomere sequences at the ends of their linear genomes. These TMR facilitate the integration of the MDV genome into host telomeres during latency, allowing the virus to persist in the host for life. Integration into host telomeres is critical for disease and tumor induction by MDV, but also enables efficient reactivation of the integrated virus genome. In addition to the TMR, MDV also encodes a telomerase RNA subunit (vTR) that shares 88% sequence identity with the telomerase RNA in chicken (chTR). vTR is highly expressed during all stages of the virus lifecycle, enhances telomerase activity and plays an important role in MDV-induced tumor formation. This review will focus on the recent advances in understanding the role of viral TMR and vTR in MDV pathogenesis, integration and tumorigenesis.

Latest Insights into Marek’s Disease Virus Pathogenesis and Tumorigenesis

“…Previous research has largely focused on the role of those viral protein-coding genes. However, MDV also encodes a rich repertoire of non-coding RNAs (ncRNAs) including micro RNAs (miRNAs) and a viral telomerase RNA (vTR) [53][54][55][56][57][58][59][60]. vTR shares 88% sequence identity and the conserved stem-loop structure with its cellular homolog in the chicken (cTR) [54].…”

The Complete Genome of an Endogenous Nimavirus (Nimav-1_LVa) From the Pacific Whiteleg Shrimp Penaeus (Litopenaeus) Vannamei

“…Little is known about the molecular mechanism underlying such integration because we cannot exclude the possibility that circular Nimav-1_LVa could harbor one short tract of variable length of (TAACC/GGTTA) n microsatellites somewhere between g002 and g276. If so, the integration of Nimav-1_LVa would be through the homology-based recombination, which is adopted in the telomere-specific integration of human herpesvirus HHV-6A, HHV-6B [40][41][42], and chicken lymphotropic alphaherpesvirus Marek's disease virus (MDV) [43,44].…”

“…However, the molecular mechanism underlying such a site-specific integration cannot be excluded and is worthwhile for future investigations. In the scope of DNA virus, it is known that HHV-6A and HHV-6B and the chicken lymphotropic alphaherpesvirus Marek's disease virus (MDV) can insert specifically into telomere site via the homology-dependent recombination, where the linear double-stranded DNA viruses have variable length of telomere-like repeat regions at either genome end [40,[42][43][44]. As shown in Figure 1B, it remains to be determined if the circular Nimav-1_LVa genome does harbor one or two tracts of telomeric pentanucleotide (TAACC/GGTTA) n .…”

Drosophila: Retrotransposons Making up Telomeres

“…Indeed, several herpesviruses are able to integrate their genome at the telomeres in humans [ 67 ]. Integration happens during the latency phase and in some cases reaches through germ cells, which will allow not only their presence in the host for life, but also being vertically transmitted to the next generation [ 68 , 69 , 70 ].…”

“…As a part of a special issue dedicated to telomere integration with more specialized authors in viral integration, I will not revise here the specific mechanisms that have been recently elucidated [ 67 ], but I would like to summarize some components that have been shown to be of importance for such integration. The viral genomes with telomere specificity are flanked by direct repeats, telomeric repeats (TMR) and perfect telomeric repeats (pTMR), which at least in one side are highly identical to human telomerase repeats [ 70 ].…”