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

Emilio Cusanelli,Pascal Chartrand

doi:10.3389/fgene.2015.00143

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.

Highlights

Telomeres are nucleoprotein structures assembled at the extremities of eukaryotic chromosomes that protect chromosome ends
While it cannot be formerly excluded that telomeric RNAs containing only telomeric repeats are expressed in mouse, this study reveals that TERRA transcribed from a single telomere can associate with multiple chromosome ends
TERRA expression stabilizes lysine-specific demethylase 1 (LSD1)-MRE11 association in vitro and in vivo (Porro et al, 2014b). These findings suggest that increased expression of TERRA in TRF2depleted cells may contribute to the activation of nonhomologous end joining (NHEJ) by promoting MRE11 activity at uncapped telomeres (Figure 1C) (Porro et al, 2014b)

Summary

Introduction

Telomeres are nucleoprotein structures assembled at the extremities of eukaryotic chromosomes that protect chromosome ends. While it cannot be formerly excluded that telomeric RNAs containing only telomeric repeats are expressed in mouse, this study reveals that TERRA transcribed from a single telomere can associate with multiple chromosome ends This suggests that TERRA can act in trans in mammalian cells and further supports the view of TERRA as an essential player for the overall maintenance of telomeres and/or telomere function (de Silanes et al, 2014). Depletion of components of the nonsense mediated RNA decay (NMD) pathway or members of the heterogeneous nuclear ribonucleoprotein family (hnRNPs) which bind TERRA, increases localization of TERRA at chromosome ends without affecting its overall levels or stability (Azzalin et al, 2007; Lopez de Silanes et al, 2010) These findings suggest that TERRA molecules are actively displaced from telomeres and may be recruited at chromosome ends through interaction with stable constituents of the telomeric structure. These findings support the emerging role of TERRA acting as a scaffold molecule to promote recruitment of proteins and enzymatic activities at telomeres

Connecting Telomere Biology and Genome Integrity

TERRA and DNA Damage Response at Telomeres

TERRA and Telomerase

Findings

Concluding Remarks