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Abstract
Telomerase is a ribonucleoprotein complex involved in the maintenance of telomeres, a protective structure at the distal ends of chromosomes. The enzyme complex contains two main components, telomerase reverse transcriptase (TERT), the catalytic subunit, and telomerase RNA (TR), which serves as a template for the addition of telomeric repeats (TTAGGG)n. Marek's disease virus (MDV), an oncogenic herpesvirus inducing fatal lymphoma in chickens, encodes a TR homologue, viral TR (vTR), which significantly contributes to MDV-induced lymphomagenesis. As recent studies have suggested that TRs possess functions independently of telomerase activity, we investigated if the tumor-promoting properties of MDV vTR are dependent on formation of a functional telomerase complex. The P6.1 stem-loop of TR is known to mediate TR-TERT complex formation and we show here that interaction of vTR with TERT and, consequently, telomerase activity was efficiently abrogated by the disruption of the vTR P6.1 stem-loop (P6.1mut). Recombinant MDV carrying the P6.1mut stem-loop mutation were generated and tested for their behavior in the natural host in vivo. In contrast to viruses lacking vTR, all animals infected with the P6.1mut viruses developed MDV-induced lymphomas, but onset of tumor formation was significantly delayed. P6.1mut viruses induced enhanced metastasis, indicating functionality of non-complexed vTR in tumor dissemination. We discovered that RPL22, a cellular factor involved in T-cell development and virus-induced transformation, directly interacts with wild-type and mutant vTR and is, consequently, relocalized to the nucleoplasm. Our study provides the first evidence that expression of TR, in this case encoded by a herpesvirus, is pro-oncogenic in the absence of telomerase activity.
Highlights
One of its functions is dependent on vTRTERT interaction, while the other is independent of the formation of an active telomerase complex
The rapid onset of lymphoma formation seems dependent on viral TR (vTR)-mediated telomerase activity because a delay in the development of tumors was observed when vTR-telomerase reverse transcriptase (TERT) interaction was abrogated
The documented increase in telomerase activity mediated by the presence of vTR in complex with TERT when compared to the presence of cellular telomerase RNA (TR) likely plays an important role in the initial establishment and maintenance of Marek’s disease virus (MDV)-transformed cells
Summary
We hypothesize that the observed delay in the development of lymphomas is caused by curtailing telomerase activity mediated by vTR and, the absence of enhanced telomere maintenance Such enhanced telomere maintenance, which was shown in MDV-infected animals [27] and is thought to play an important role for the survival of rapidly dividing MDV-transformed cells early in the transformation process, is probably mediated mainly by an interaction between vTR and cellular chTERT. In the absence of the P6.1 stem-loop, the interaction can no longer occur, and, the pool of transformed cancer stem cells surviving the initial crisis may be reduced It was notable, that, in contrast to viruses lacking vTR [14], all animals infected with v6.1mut succumbed to MD before termination of the experiment, indicating that vTR has functions independent of the formation of an active telomerase complex. Under the conditions used here, efficiency of relocalization of RPL22 was comparable between EBER-1 and the vTR and chTR constructs (Fig. 6), which may suggest that EBER-1 and vTR serve similar purposes in the process of transformation of human and chicken lymphocytes
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