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Review
. 2019 Mar 15;8(3):246.
doi: 10.3390/cells8030246.

The Emerging Roles of TERRA in Telomere Maintenance and Genome Stability

Nicole Bettin  1 , Claudio Oss Pegorar  2 , Emilio Cusanelli  3
Affiliations
Review

The Emerging Roles of TERRA in Telomere Maintenance and Genome Stability

Nicole Bettin et al. Cells. .

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.

Keywords: DNA damage response; TERRA; chromatin; genome stability; human diseases; long noncoding RNA; telomeres.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Proposed roles of TERRA in chromatin regulation at telomeres. (A) TERRA interacts with various proteins at telomeres including TRF2, Suv39h1, and origin replication complex 1 (ORC1). TERRA transcripts can act as scaffold molecules to promote the recruitment of proteins, histone modifying enzymes and chromatin remodeling complexes to chromosome ends. (B) TERRA forms DNA-RNA hybrid structures (R-loops) at telomeres. Telomeric R-loops can influence heterochromatin formation at telomeres by inhibiting DNA methylation or promoting the recruitment of HP1 proteins at chromosome ends.
Figure 2
Figure 2
Proposed TERRA functions in telomere maintenance. (A) TERRA transcripts may facilitate DNA replication at telomeres by promoting the recruitment of the origin replication complex 1 (ORC1) at chromosome ends or through the formation of DNA-RNA hybrids (R-loops) at chromosome ends. Telomeric R-loops promote homologous recombination among telomeres, which protects replication forks from collapsing and becoming dysfunctional during replication stress. (B) TERRA sustains DNA damage response at dysfunctional telomeres. Depletion of TRF2 results in increased TERRA levels. TERRA transcripts promote the recruitment of LSD1-Mre11 complex at chromosome ends, which can fuel DNA damage response at dysfunctional telomeres. TERRA also interacts with Suv39h1 histone methyltransferase. In TRF2-depleted cells, TERRA-Suv39h1 interaction promotes H3K9me3 accumulation at dysfunctional telomeres, sustaining the DNA damage response.
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