Regulated expression of the lncRNA TERRA and its impact on telomere biology

The telomere protects against genomic instability by minimizing the accelerated end resection of the genetic material, a phenomenon that results in severe chromosome instability that could favor the transformation of a cell by enabling the emergence of tumor-promoting mutations. Some mechanisms that avoid this fate, such as capping and loop formation, have been very well characterized; however, telomeric non-coding transcripts, such as long non-coding RNAs (lncRNAs), should also be considered in this context because they play roles in the organization of telomere dynamics, involving processes such as replication, degradation, extension, and heterochromatin stabilization. Although the mechanism through which the expression of telomeric transcripts regulates telomere dynamics is not yet clear, a non-coding RNA component opens the research options in telomere biology and the impact that it can have on telomere-associated diseases such as cancer.


A) Topology of telomeric and sub-telomeric chromatin. The telomeric region is protected by the Shelterin complex, which stabilizes the T-loop, and by the G-quads that form on ththe D-loops. The loci of TERRA’s TSSs (shown in yellow) are located in the sub-telomeric region of chromosomes and bear chromatin marks associated with a state of active transcription (H3K4me3, H3ac and H4ac). Some of these loci are flanked by CTCF and cohesin, forming a barrier that prevents heterochromatin expansion (shown in green) and the subsequent silencing of this lncRNA. B) TERRA/protein interactions at telomeres. This lncRNA is able to associate with the telomeric repeat as it is transcribed and can also diffuse and associate with several proteins to bring them in proximity to the telomeric region. The figure schematizes the interactions that have already been described for TERRA. Arrows indicate the possible interactions that can take place once the lncRNA binds to a protein. Direct interactions have been reported between the lncRNA and ORC (a complex that promotes the heterochromatin state of the telomeric locus), TRF2 (the protein that stabilizes the T-loop at chromosome ends), hnRNPA1 (the ribonucleoprotein that promotes the interchange between RPA and POT1 at telomeric ssDNA) and hTERT (the enzyme that extends the telomeric tract of the chromosome arm it was recruited to). Further indirect interactions can take place once TERRA has bound some of the proteins mentioned above. In this way, TERRA will first bind either ORC or TRF2 so it can then recruit HP1α; Pol-II can be recruited to TERRA’s TSS by the lncRNA itself, but only via the previous association between TRF2 and TERRA; finally CTCF/Cohesin will keep the chromatin at TERRA’s TSS poised for Poll-II transcription, while the flanking sequences remain inaccessible due to the presence of HP1α and the SUV methyltransferases, this is possible due to the interaction between TERRA, TRF2 and Pol-II. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Oliva-Rico D, Herrera LA. (2017) Regulated expression of the lncRNA TERRA and its impact on telomere biology. Mech Ageing Dev [Epub ahead of print]. [article]

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