Role of TERRA in the regulation of telomere length

Abstract

Telomere dysfunction is closely associated with human diseases such as cancer and ageing. Inappropriate changes in telomere length and/or structure result in telomere dysfunction. Telomeres have been considered to be transcriptionally silent, but it was recently demonstrated that mammalian telomeres are transcribed into telomeric repeat-containing RNA (TERRA). TERRA, a long non-coding RNA, participates in the regulation of telomere length, telomerase activity and heterochromatinization. The correct regulation of telomere length may be crucial to telomeric homeostasis and functions. Here, we summarize recent advances in our understanding of the crucial role of TERRA in the maintenance of telomere length, with focus on the variety of mechanisms by which TERRA is involved in the regulation of telomere length. This review aims to enable further understanding of how TERRA-targeted drugs can target telomere-related diseases.

Keywords: ALT; HDR; TERRA; protection of chromosome end; telomerase; telomere length.

Fig 1

TERRA regulation of telomere length for the protection of chromosome ends involving TRF2. CTCF recruits RNAPII to the CpG-island promoter and promotes TERRA transcription, CTCF and cohesin stabilization and TRF1/TRF2 binding to subtelomeres prevents telomere DNA damage signaling. The binding of TERRA to TRF2 hinders the formation of T-loops and activates the ATM kinase pathway. The THO complex enables the packaging of TERRA into RNPs and inhibits unscheduled TERRA expression, which could avoid the redundant removal of TERRA from the T-loop. TERRA interacts with the Exo1-inhibiting Ku70/80 dimer and promotes Exo1-dependent resection at chromosome ends to shorten the telomere.

Fig 2

Dynamic balance of TERRA sustains telomere length during telomere replication. TERRA acts as an on-switch for RPA-to-POT1 to regulate telomere replication and end protection. Changes in the level of TERRA are in accordance with changes in cell cycle-dependent telomerase activity. During the early to mid S phase, high levels of TERRA bind to hnRNPA1, allowing RPA to bind ssTEL and releasing POT1 to enable telomere extension; at the same time, TERRA binds to TERT or TERC to inhibit telomerase activity. The dynamic balance of TERRA is necessary to regulate these seemingly conflicted processes in order to maintain a normal telomere length.