Herpesvirus telomerase RNA(vTR)-dependent lymphoma formation does not require interaction of vTR with telomerase reverse transcriptase (TERT)

PLoS Pathog. 2010 Aug 26;6(8):e1001073. doi: 10.1371/journal.ppat.1001073.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Catalytic Domain / genetics
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Chickens
  • Chromosomes, Artificial, Bacterial
  • Herpesvirus 2, Gallid / enzymology*
  • Herpesvirus 2, Gallid / genetics
  • Marek Disease / enzymology*
  • Marek Disease / genetics
  • Marek Disease / pathology
  • Mutation
  • RNA / metabolism*
  • RNA, Viral / adverse effects
  • RNA, Viral / genetics
  • RNA, Viral / metabolism*
  • Telomerase / genetics
  • Telomerase / metabolism*

Substances

  • RNA, Viral
  • telomerase RNA
  • RNA
  • Telomerase