Telomerase stimulates ribosomal DNA transcription under hyperproliferative conditions

Abstract

In addition to performing its canonical function, Telomerase Reverse Transcriptase (TERT) has been shown to participate in cellular processes independent of telomerase activity. Furthermore, although TERT mainly localizes to Cajal bodies, it is also present within the nucleolus. Because the nucleolus is the site of rDNA transcription, we investigated the possible role of telomerase in regulating RNA polymerase I (Pol I). Here we show that TERT binds to rDNA and stimulates transcription by Pol I during liver regeneration and Ras-induced hyperproliferation. Moreover, the inhibition of telomerase activity by TERT-or TERC-specific RNA interference, the overexpression of dominant-negative-TERT, and the application of the telomerase inhibitor imetelstat reduce Pol I transcription and the growth of tumour cells. In vitro, telomerase can stimulate the formation of the transcription initiation complex. Our results demonstrate how non-canonical features of telomerase may direct Pol I transcription in oncogenic and regenerative hyperproliferation.

Telomerase regulates MYC-driven oncogenesis independent of its reverse transcriptase activity

“…Notably, consistent results were obtained with independent shRNAs and could be rescued by TERT overexpression (Supplemental Figure 3, H-J). While we observed a significant enrichment in MYC binding and transcriptional increase in some of these ribosomal components, this was also the case for RNA polymerase II-driven genes (49)(50)(51). As such, we believe that, in cancer cells, the effect of MYC stabilization by TERT affects the expression numerous MYC-dependent genes, including ribosomal components.…”

PTENβ is an alternatively translated isoform of PTEN that regulates rDNA transcription

“…Based on previous studies that show imbalance of rDNA transcription closely correlates with tumour progression5152, identification of PTENβ may provide a new track for therapeutic drug design. These results together with our previous observations regarding PTENα illustrate the complexity of PTEN function and enrich our understanding of the PTEN family.…”

The Cajal body and the nucleolus: “In a relationship” or “It's complicated”?

“…102 These ideas, together with the number of telomereindependent roles currently being proposed for TERT, including modulation of gene expression through transcriptional modulation and small interfering RNA (siRNA) processing (for a review see ref. 103 ), make it clear that a dual role for nucleoli and CBs in telomerase biogenesis is far from a certainty.…”