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Review
. 2015 Apr 14:6:143.
doi: 10.3389/fgene.2015.00143. eCollection 2015.

Telomeric repeat-containing RNA TERRA: a noncoding RNA connecting telomere biology to genome integrity

Emilio Cusanelli  1 , Pascal Chartrand  2
Affiliations
Review

Telomeric repeat-containing RNA TERRA: a noncoding RNA connecting telomere biology to genome integrity

Emilio Cusanelli et al. Front Genet. .

Abstract

Telomeres are dynamic nucleoprotein structures that protect the ends of chromosomes from degradation and activation of DNA damage response. For this reason, telomeres are essential to genome integrity. Chromosome ends are enriched in heterochromatic marks and proper organization of telomeric chromatin is important to telomere stability. Despite their heterochromatic state, telomeres are transcribed giving rise to long noncoding RNAs (lncRNA) called TERRA (telomeric repeat-containing RNA). TERRA molecules play critical roles in telomere biology, including regulation of telomerase activity and heterochromatin formation at chromosome ends. Emerging evidence indicate that TERRA transcripts form DNA-RNA hybrids at chromosome ends which can promote homologous recombination among telomeres, delaying cellular senescence and sustaining genome instability. Intriguingly, TERRA RNA-telomeric DNA hybrids are involved in telomere length homeostasis of telomerase-negative cancer cells. Furthermore, TERRA transcripts play a role in the DNA damage response (DDR) triggered by dysfunctional telomeres. We discuss here recent developments on TERRA's role in telomere biology and genome integrity, and its implication in cancer.

Keywords: DNA damage response; R-loops; TERRA; cancer; genome integrity; telomerase; telomere.

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Figures

Figure 1
Figure 1
Proposed functions of TERRA at functional and dysfunctional telomeres. (A) TERRA expression promotes heterochromatin formation at telomeres. TERRA interacts with several proteins at telomeres including TRF2, H3K9me3, origin replication complex 1 (ORC1), HP1, and MORF4L2 proteins. TERRA molecules act as scaffold recruiting chromatin remodeling factors to chromosome ends. (B) Expression of TERRA is required for proper capping of telomeres. hnRNPA1 displaces RPA from telomeric single-stranded overhangs. TERRA transcripts interact with hnRNPA1. TERRA-hnRNPA1 interaction removes hnRNPA1 from chromosome ends allowing POT1 to bind the telomeric single-stranded overhangs. (C) TERRA participates to DNA damage response triggered by dysfunctional telomeres. Depletion of TRF2 results in dysfunctional telomeres and increased TERRA expression. TERRA interacts with lysine-specific demethylase 1 (LSD1). Elevated TERRA levels in TRF2-depleted cells promote nucleolytic processing of uncapped telomeres by favoring the recruitment of a LSD1-MRE11 complex at telomeres (1). TERRA molecules interact with SUV39H1 histone methyltransferase. TERRA-SUV39H1 interaction promotes H3K9 methylation (H3K9me3) at dysfunctional telomeres and chromosome end-to-end fusions (2).
Figure 2
Figure 2
Proposed roles of TERRA in telomere length homeostasis of telomerase-negative and telomerase-positive cells. (A) In telomerase-negative cells, TERRA molecules form DNA:RNA hybrids, or R-loops, at telomeres. Telomeric R-loop formation is inhibited by RNase H1 and 2, and the THO complex in budding yeast, and is repressed by RNase H1 in ALT cancer cells. Telomeric R-loops promote homologous recombination among telomeres, which maintains telomere length homeostasis in ALT cancer cells and delays senescence of telomerase-negative yeast cells. (B) In telomerase-positive yeast cells, TERRA transcripts promote the formation of telomerase clusters at short telomeres in yeast. TERRA expression is induced when a telomere shortens and TERRA transcripts accumulate in a single focus localizing at the nuclear periphery. During S phase, a TERRA focus acts as a scaffold to bind and aggregate telomerase molecules (TLC1) into a TERRA/T-Rec cluster. TERRA/T-Rec cluster relocates to the short telomere expressing TERRA to mediate telomere elongation.
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