The long noncoding RNA TERRA controls telomere length homeostasis in human cancers with an activated alternative lengthening of telomeres (ALT) mechanism. Telomeric R-loops formed between TERRA and telomeric DNA (telR-loops) promote telomere elongation through homology-directed repair. However, if not properly regulated, TERRA and telR-loops can lead to rapid cleavage of telomeric DNA and telomere loss.

Eukaryotic telomeres are transcribed into the long noncoding RNA TERRA. A fraction of TERRA remains associated with telomeres by forming RNA:DNA hybrids dubbed telR-loops. TERRA and telR-loops are essential to promote telomere elongation in human cancer cells that maintain telomeres through a homology-directed repair pathway known as alternative lengthening of telomeres or ALT. However, TERRA and telR-loops compromise telomere integrity and cell viability if their levels are not finely tuned. The study of telomere transcription in ALT cells will enormously expand our understanding of the ALT mechanism and of how genome integrity is maintained. Moreover, telomere transcription, TERRA and telR-loops are likely to become exceptionally suited targets for the development of novel anti-cancer therapies.