The Molecular Interplay between Human Oncoviruses and Telomerase in Cancer Development

SIMPLE SUMMARY: The expression of the telomerase reverse transcriptase (TERT) gene is commonly repressed in terminally differentiated somatic cells and becomes reactivated in the large majority of tumors. Oncogenic viruses have evolved multiple strategies to subvert the telomerase function in the host cells. Viruses may promote TERT transcription through the binding of their oncoproteins to cis-regulatory elements in the gene promoter or by integrating their genomes nearby TERT locus. Other viruses cause telomerase activation via epigenetic mechanisms that contribute to the maintenance of long telomeres and cellular immortality. This review will outline recent findings on the strategies employed by viruses to deregulate telomerase activity and telomere length and to promote cancer development. ABSTRACT: Human oncoviruses are able to subvert telomerase function in cancer cells through multiple strategies. The activity of the catalytic subunit of telomerase (TERT) is universally enhanced in virus-related cancers. Viral oncoproteins, such as high-risk human papillomavirus (HPV) E6, Epstein–Barr virus (EBV) LMP1, Kaposi’s sarcoma-associated herpesvirus (HHV-8) LANA, hepatitis B virus (HBV) HBVx, hepatitis C virus (HCV) core protein and human T-cell leukemia virus-1 (HTLV-1) Tax protein, interact with regulatory elements in the infected cells and contribute to the transcriptional activation of TERT gene. Specifically, viral oncoproteins have been shown to bind TERT promoter, to induce post-transcriptional alterations of TERT mRNA and to cause epigenetic modifications, which have important effects on the regulation of telomeric and extra-telomeric functions of the telomerase. Other viruses, such as herpesviruses, operate by integrating their genomes within the telomeres or by inducing alternative lengthening of telomeres (ALT) in non-ALT cells. In this review, we recapitulate on recent findings on virus–telomerase/telomeres interplay and the importance of TERT-related oncogenic pathways activated by cancer-causing viruses.