The finding that transcription occurs at chromosome ends has opened new fields of study on the roles of telomeric transcripts in chromosome end maintenance and genome stability. Indeed, the ends of chromosomes are required to be protected from activation of DNA damage response and DNA repair pathways. Chromosome end protection is achieved by the activity of specific proteins that associate with chromosome ends, forming telomeres. Telomeres need to be constantly maintained as they are in a heterochromatic state and fold into specific structures (T-loops), which may hamper DNA replication. In addition, in the absence of maintenance mechanisms, chromosome ends shorten at every cell division due to limitations in the DNA replication machinery, which is unable to fully replicate the extremities of chromosomes. Altered telomere structure or critically short chromosome ends generate dysfunctional telomeres, ultimately leading to replicative senescence or chromosome instability. Telomere biology is thus implicated in multiple human diseases, including cancer. Emerging evidence indicates that a class of long noncoding RNAs transcribed at telomeres, known as TERRA for “TElomeric Repeat-containing RNA,” actively participates in the mechanisms regulating telomere maintenance and chromosome end protection. However, the molecular details of TERRA activities remain to be elucidated. In this review, we discuss recent findings on the emerging roles of TERRA in telomere maintenance and genome stability and their implications in human diseases.

The function of TERRA in the regulation of telomerase in human cells is still debated. While TERRA interacts with telomerase, how it regulates telomerase function remains unknown. Here, we show that TERRA colocalizes with the telomerase RNA subunit hTR in the nucleoplasm and at telomeres during different phases of the cell cycle. We report that TERRA transcripts relocate away from chromosome ends during telomere lengthening, leading to a reduced number of telomeric TERRA-hTR molecules and consequent increase in “TERRA-free” telomerase molecules at telomeres. Using live-cell imaging and super-resolution microscopy, we show that upon transcription, TERRA relocates from its telomere of origin to long chromosome ends. Furthermore, TERRA depletion by antisense oligonucleotides promoted hTR localization to telomeres, leading to increased residence time and extended half-life of hTR molecules at telomeres. Overall, our findings indicate that telomeric TERRA transcripts inhibit telomere elongation by telomerase acting in trans, impairing telomerase access to telomeres that are different from their chromosome end of origin.