Abstract
RNA polymerase II transcribes the physical ends of linear eukaryotic chromosomes into a variety of long non-coding RNA molecules including telomeric repeat-containing RNA (TERRA). Since TERRA discovery, advances have been made in the characterization of TERRA biogenesis and regulation; on the contrary its associated functions remain elusive. Most of the biological roles so far proposed for TERRA are indeed based on in vitro experiments carried out using short TERRA-like RNA oligonucleotides. In particular, it has been suggested that TERRA inhibits telomerase activity. We have exploited two alternative cellular systems to test whether TERRA and/or telomere transcription influence telomerase-mediated telomere elongation in human cancer cells. In cells lacking the two DNA methyltransferases DNMT1 and DNMT3b, TERRA transcription and steady-state levels are greatly increased while telomerase is able to elongate telomeres normally. Similarly, telomerase can efficiently elongate transgenic inducible telomeres whose transcription has been experimentally augmented. Our data challenge the current hypothesis that TERRA functions as a general inhibitor of telomerase and suggest that telomere length homeostasis is maintained independently of TERRA and telomere transcription.
Highlights
The physical ends of linear eukaryotic chromosomes are transcribed into a variety of non-coding RNA species constituting the ‘telomeric transcriptome’
By using independent yet complementary cellular systems, we have shown that telomerase-mediated telomere elongation is not substantially affected by the transcriptional activity associated to telomeres in human cancer cells
These observations argue against the currently accepted notion that telomeric repeat-containing RNA (TERRA) might function as a general telomerase inhibitor, thereby contributing to maintain telomere length homeostasis
Summary
The physical ends of linear eukaryotic chromosomes are transcribed into a variety of non-coding RNA (ncRNA) species constituting the ‘telomeric transcriptome’. Among these species, the long ncRNA TERRA (telomeric repeat-containing RNA) was first discovered in mammalian cells and successively described in non-mammalian eukaryotes including zebrafish, Arabidopsis thaliana, the budding yeast Saccharomyces cerevisiae and the fission yeast Schizosaccharomyces pombe [1,2,3,4,5,6,7]. Other RNA species transcribed from chromosome ends comprise ARIA, a C-rich telomeric RNA so far identified only in fission yeast and plants, and two complementary subtelomeric transcripts devoid of detectable telomeric repeats named ARRET, identified in budding and fission yeasts, and aARRET, identified only in fission yeast [1,4,5,7]
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