Abstract
Dyskerin mediates both the modification of uridine on ribosomal and small nuclear RNAs and the stabilization of the telomerase RNA component (TERC). In human tumors dyskerin expression was found to be associated with both rRNA modification and TERC levels. Moreover, dyskerin overexpression has been linked to unfavorable prognosis in a variety of tumor types, however an explanation for the latter association is not available. To clarify this point, we analyzed the connection between dyskerin expression, TERC levels and clinical outcome in two series of primary lung cancers, differing for the presence of TERC gene amplification, a genetic alteration inducing strong TERC overexpression. TERC levels were significantly higher in tumors bearing TERC gene amplification (P = 0.017). In addition, the well-established association between dyskerin expression and TERC levels was observed only in the series without TERC gene amplification (P = 0.003), while it was not present in TERC amplified tumors (P = 0.929). Similarly, the association between dyskerin expression and survival was found in cases not bearing TERC gene amplification (P = 0.009) and was not observed in TERC amplified tumors (P = 0.584). These results indicate that the influence of dyskerin expression on tumor clinical outcome is linked to its role on the maintenance of high levels of TERC.
Highlights
Telomeres are tandem repeats of TTAGGG se quence, protecting the ends of chromosomes from deterioration or from fusion with other chromosomes
Telomerase is a ribonucleoproteic complex composed by the template sequence Telomerase RNA Component (TERC, referred to as human telomerase RNA component, hTR), the enzyme telomerase reverse transcriptase (TERT) and a protein complex with protecting function on TERC, formed by dyskerin, NOP10, NHP2 and GAR1
DKC1 gene product, dyskerin, besides its role of TERC stabilization, is involved in ribosome www.impactjournals.com/oncotarget biogenesis process; when its function is reduced, ribosomes show an altered translation of a subgroup of cellular mRNAs containing internal ribosomal entry site (IRES), whose de-regulation is well-described in cancer development [7]
Summary
Telomeres are tandem repeats of TTAGGG se quence, protecting the ends of chromosomes from deterioration or from fusion with other chromosomes. DKC1 gene product, dyskerin, besides its role of TERC stabilization, is involved in ribosome www.impactjournals.com/oncotarget biogenesis process; when its function is reduced, ribosomes show an altered translation of a subgroup of cellular mRNAs containing internal ribosomal entry site (IRES), whose de-regulation is well-described in cancer development [7]. The list of such genes includes those encoding the tumor suppressors p53 and p27 [8,9], the antiapoptotic factors Bcl-xL and XIAP [9] and the vascular endothelial growth factor (VEGF) [10]. We found that DKC1 expression influence on the clinical outcome is linked to its role on the maintenance of high levels of TERC
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