Herpesvirus telomerase rna(vtr)-dependent lymphoma formation does not require interaction of vtr with telomerase reverse transcriptase (tert)

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. © 2010 kaufer et al.