Abstract
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.
Highlights
Telomeres are nucleoprotein structures assembled at the end of eukaryotic chromosomes, protecting them from degradation, fusion, and erroneous recombination events [1,2,3,4]
Downregulation of TERRA transcripts achieved by siRNA [74] or antisense oligonucleotides (ASO)-locked nucleic acids (LNA) [78,93] results in the activation of DNA damage responses at chromosome ends and in the consequent formation of “Telomere dysfunction-induced foci” (TIFs)
The TERRA20q-KO clones showed increased DNA damage at chromosome ends, telomere fusions, and decreased telomere length. These findings suggest that TERRA-20q transcripts act in trans by participating in telomere protection at multiple chromosome ends in U2OS
Summary
Telomeres are nucleoprotein structures assembled at the end of eukaryotic chromosomes, protecting them from degradation, fusion, and erroneous recombination events [1,2,3,4]. The shelterin complex consists of six proteins that are recruited to telomeres through the direct binding of the shelterin subunits TRF1 and TRF2 to the double-stranded telomeric repeats [16,17,18,19]. A key function of telomeres is to enable the cell to discriminate the natural ends of chromosomes from harmful double-strand breaks (DSBs) [16,17] This function is mainly mediated by TRF2 and POT1, which prevent chromosome ends from activating DNA damage signaling and DSB repair pathways [16,23]. In order to counteract telomere shortening, most eukaryotic cells express a dedicated reverse transcriptase enzyme called telomerase, which adds telomeric repeats to the 30 end of chromosomes by reverse transcription of the template region of its associated RNA moiety [39,40]. We discuss recent findings on the emerging roles of TERRA in telomere maintenance and genome stability and their implications in human diseases
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