TERRA: an induced responder to telomere dysfunction

Abstract Telomeric repeat-containing RNA (TERRA) has long been viewed as a constitutive component of telomeres. However, accumulating experimental evidence suggests that TERRA is instead a stress-responsive signal produced specifically at dysfunctional telomeres. Across yeasts and mammals, TERRA abundance changes as telomeres shorten or become damaged, engaging the appropriate maintenance pathway through interactions with shelterin, chromatin regulators and DNA repair factors, and through the controlled formation of RNA:DNA hybrids (R-loops). In telomerase-negative cells, transient accumulation of TERRA and R-loops promotes homology-directed telomere elongation. In telomerase-positive cells, TERRA appears to direct telomerase activity selectively toward short telomeres. When telomere damage remains unresolved, sustained TERRA expression and persistent R-loops drive cells toward senescence, inflammatory signaling and crisis-associated cell death. We propose here that TERRA functions as a molecular rheostat at damaged telomeres: transient and spatially controlled induction restores chromosome-end integrity, whereas persistent accumulation results in the removal of compromised cells from the proliferative pool. Defining how cells set these switch points will be essential for elucidating how TERRA shapes ageing and disease and for harnessing its therapeutic potential.