Transcription–replication conflicts at telomeres: the emerging role of telomeric repeat-containing RNA (TERRA) R-loops in genome instability and cancer

Telomeres are complex chromosomal components that are crucial for genome integrity but frequently experience replication stress due to their repetitive, G-rich nature and active transcription. TERRA is a mediator of telomere homeostasis but is also a causative factor of RNA-DNA hybrid (R-loop) formation, which can give rise to transcription-replication conflicts (TRCs). Telomeric R-loops that persist in the genome can act as a barrier to replication fork movement, cause reversal or collapse of replication forks, and result in fragile telomeres, break-induced replication, and telomere dysfunction. Although normal cells undergo senescence in response to this stress, cancer cells, especially those with alternative lengthening of telomeres (ALT), exploit telomeric TRCs to facilitate recombination-mediated telomere elongation.