Oncogenic herpesvirus KSHV triggers hallmarks of alternative lengthening of telomeres

• Published in: Nature communications Vol. 12; no. 1; pp. 512 - 11
• Main Authors: Lippert, Timothy P., Marzec, Paulina, Idilli, Aurora I., Sarek, Grzegorz, Vancevska, Aleksandra, Bower, Mark, Farrell, Paul J., Ojala, Päivi M., Feldhahn, Niklas, Boulton, Simon J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.01.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/106; 14; 14/1; 14/19; 631/337/103/560; 631/67/68; Biotechnology; Cancer; Carcinogenesis; Cell Line; Cell Line, Tumor; DNA Damage; DNA Replication - genetics; HeLa Cells; Herpes viruses; Herpesvirus 8, Human - physiology; Host-Pathogen Interactions; Humanities and Social Sciences; Humans; In Situ Hybridization, Fluorescence; Infections; Kaposi's sarcoma; Latency; Maintenance; multidisciplinary; Neoplasms - genetics; Neoplasms - pathology; Neoplasms - virology; Proteome - genetics; Proteome - metabolism; Recombination; Sarcoma; Science; Science (multidisciplinary); Telomerase; Telomerase - genetics; Telomerase - metabolism; Telomere - genetics; Telomere Homeostasis - genetics; Telomere Shortening - genetics; Telomeres; Tumors; Yeast
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-20819-4

To achieve replicative immortality, cancer cells must activate telomere maintenance mechanisms to prevent telomere shortening. ~85% of cancers circumvent telomeric attrition by re-expressing telomerase, while the remaining ~15% of cancers induce alternative lengthening of telomeres (ALT), which relies on break-induced replication (BIR) and telomere recombination. Although ALT tumours were first reported over 20 years ago, the mechanism of ALT induction remains unclear and no study to date has described a cell-based model that permits the induction of ALT. Here, we demonstrate that infection with Kaposi’s sarcoma herpesvirus (KSHV) induces sustained acquisition of ALT-like features in previously non-ALT cell lines. KSHV-infected cells acquire hallmarks of ALT activity that are also observed in KSHV-associated tumour biopsies. Down-regulating BIR impairs KSHV latency, suggesting that KSHV co-opts ALT for viral functionality. This study uncovers KSHV infection as a means to study telomere maintenance by ALT and reveals features of ALT in KSHV-associated tumours. ~15% of cancers induce alternative lengthening of telomeres (ALT) to activate telomere maintenance. Here, the authors reveal that infection with Kaposi’s sarcoma herpesvirus (KSHV) induces acquisition of ALT-like features in previously non-ALT cell lines.