dc.contributor.author
Kaufer, Benedikt B.
dc.contributor.author
Arndt, Sina
dc.contributor.author
Trapp, Sascha
dc.contributor.author
Osterrieder, Nikolaus
dc.contributor.author
Jarosinski, Keith W.
dc.date.accessioned
2018-06-08T03:04:34Z
dc.date.available
2013-02-01
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/14461
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-18653
dc.description.abstract
Telomerase reverse transcriptase (TERT) and telomerase RNA (TR) represent the
enzymatically active components of telomerase. In the complex, TR provides the
template for the addition of telomeric repeats to telomeres, a protective
structure at the end of linear chromosomes. Human TR with a mutation in the
template region has been previously shown to inhibit proliferation of cancer
cells in vitro. In this report, we examined the effects of a mutation in the
template of a virus encoded TR (vTR) on herpesvirus-induced tumorigenesis in
vivo. For this purpose, we used the oncogenic avian herpesvirus Marek's
disease virus (MDV) as a natural virus-host model for lymphomagenesis. We
generated recombinant MDV in which the vTR template sequence was mutated from
AATCCCAATC to ATATATATAT (vAU5) by two-step Red-mediated mutagenesis.
Recombinant viruses harboring the template mutation replicated with kinetics
comparable to parental and revertant viruses in vitro. However, mutation of
the vTR template sequence completely abrogated virus-induced tumor formation
in vivo, although the virus was able to undergo low-level lytic replication.
To confirm that the absence of tumors was dependent on the presence of mutant
vTR in the telomerase complex, a second mutation was introduced in vAU5 that
targeted the P6.1 stem loop, a conserved region essential for vTR-TERT
interaction. Absence of vTR-AU5 from the telomerase complex restored virus-
induced lymphoma formation. To test if the attenuated vAU5 could be used as an
effective vaccine against MDV, we performed vaccination-challenge studies and
determined that vaccination with vAU5 completely protected chickens from
lethal challenge with highly virulent MDV. Taken together, our results
demonstrate 1) that mutation of the vTR template sequence can completely
abrogate virus-induced tumorigenesis, likely by the inhibition of cancer cell
proliferation, and 2) that this strategy could be used to generate novel
vaccine candidates against virus-induced lymphoma.
de
dc.rights.uri
http://www.fu-berlin.de/sites/refubium/rechtliches/Nutzungsbedingungen
dc.subject.ddc
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::616 Krankheiten
dc.title
Herpesvirus Telomerase RNA (vTR) with a Mutated Template Sequence Abrogates
Herpesvirus-Induced Lymphomagenesis
dcterms.bibliographicCitation
PLOS Pathogens October 2011 ; 7(10)
dcterms.bibliographicCitation.doi
10.1371/journal.ppat.1002333
dcterms.bibliographicCitation.url
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3203187/
refubium.affiliation
Externe Anbieter
de
refubium.mycore.fudocsId
FUDOCS_document_000000015921
refubium.resourceType.isindependentpub
no
refubium.mycore.derivateId
FUDOCS_derivate_000000002294
dcterms.accessRights.openaire
open access