Telomere-specific regulation of TERRA and its impact on telomere stability

TERRA is a class of telomeric repeat-containing RNAs that are expressed from telomeres in multiple organisms. TERRA transcripts play key roles in telomere maintenance and their physiological levels are essential to maintain the integrity of telomeric DNA. Indeed, deregulated TERRA expression or its altered localization can impact telomere stability by multiple mechanisms including fueling transcription-replication conflicts, promoting resection of chromosome ends, altering the telomeric chromatin, and supporting homologous recombination. Therefore, a fine-tuned control of TERRA is important to maintain the integrity of the genome. Several studies have reported that different cell lines express substantially different levels of TERRA. Most importantly, TERRA levels markedly vary among telomeres of a given cell type, indicating the existence of telomere-specific regulatory mechanisms which may help coordinate TERRA functions. TERRA molecules contain distinct subtelomeric sequences, depending on their telomere of origin, which may instruct specific post-transcriptional modifications or mediate distinct functions. In addition, all TERRA transcripts share a repetitive G-rich sequence at their 3' end which can form DNA:RNA hybrids and fold into G-quadruplex structures. Both structures are involved in TERRA functions and can critically affect telomere stability. In this review, we examine the mechanisms controlling TERRA levels and the impact of their telomere-specific regulation on telomere stability. We compare evidence obtained in different model organisms, discussing recent advances as well as controversies in the field. Furthermore, we discuss the importance of DNA:RNA hybrids and G-quadruplex structures in the context of TERRA biology and telomere maintenance.