When it comes to our telomeres, we are often left with the feeling that a little bit extra is better. However, a new article which just crossed our paths had a little bit of “extra” that turned our heads: a study of the extra-telomeric functions of the human telomerase RNA component (hTR).
hTR contains a short internal template that the human telomerase reverse transcriptase (hTERT) enzyme employs to maintain or extend telomere sequences when required. However, the relative overexpression of hTR compared to hTERT and the persistent expression of hTR in normal cells in the absence of hTERT expression suggests that “free” hTR may have an extra-telomeric function, with some reports hinting at roles in cell survival, apoptosis, and cell proliferation.
To begin to understand the extra-telomeric roles of hTR, researchers from the laboratories of Roland Ivanyi-Nagy and Peter Dröge (Nanyang Technological University, Singapore) mapped the RNA interactome of hTR in human cells by employing a previously described targeted RNA pull-down approach, given the lack of extracurricular knowledge about the moonlighting roles of hTR.
Here are the details of this extra-ordinary headline-grabbing new study:
- Mapping of the RNA interactome of hTR identified a set of non-coding and coding hTR-interacting RNAs
- o ~80 RNA species interact directly or indirectly with hTR and verified hits included the histone 1C mRNA (HIST1H1C – codes for histone H1.2)
- o The authors named the 15-nucleotide-long region of direct RNA-RNA interaction between hTR and HIST1H1C “the telomerase RNA interacting genetic element” (TRIAGE)
- Disruption of hTR-HIST1H1C RNA association (through the application of hTR variants) leads to increased telomere elongation in the absence of effects on telomerase enzymatic activity
- o Furthermore, over-expression of HIST1H1C reduces telomere length, suggesting a crucial role for HIST1H1C in telomere homeostasis
- The deciphering of HIST1H1C function employed hTR variants and HIST1H1C mutants containing either silent mutations (disrupting hTR complementarity without interfering with H1.2 protein expression) or a frameshift at the start of the HIST1H1C open reading frame (abolishes protein production without limiting RNA expression)
- o Overall, the analysis suggests that alterations to H1.2 protein expression do not affect telomere homeostasis and that a non-coding RNA function of HIST1H1C mediates telomere homeostasis
- o HIST1H1C RNA might act at a step following the assembly of the telomerase complex, possibly as a telomerase sponge that prevents the recruitment of the enzymatically active telomerase complex to telomeres
- Additional hTR-interacting RNA partners code for proteins involved in cytoskeleton organization and/or the regulation of apoptosis as well as small Cajal body-specific RNAs (scaRNAs)
Overall, this extra-special study defines a non-coding RNA role for HIST1H1C in telomere homeostasis, and in doing so, offers us a glimpse into the mostly uncharted realm of non-canonical messenger RNA functions. Indeed, the authors believe that a significant fraction of the cellular RNA interactome remains unexplored, leaving plenty more moonlighting roles of hTR left to be discovered.
Fancy a paper with a little bit extra? Read all about it at eLife, October 2018.