No DDRama at chromosome ends: TRF2 takes centre stage

• Distinct molecular properties of TRF2 dictate different states of telomere protection.
• TRF2 promotes assembly of higher-order structures at telomeres.
• TRF2 remodels the telomeric chromatin environment.
• TRF2 regulates TERRA transcription.

Telomeres are nucleoprotein structures capping the natural termini of eukaryotic linear chromosomes. Telomeres possess an inherent ability to circumvent the activation of a full-blown DNA damage response (DDR), and hence fusion reactions, by limiting inappropriate double-strand break (DSB) repair and processing activities at eukaryotic chromosome ends. A telomere-specific protein complex, termed shelterin, has a crucial function in safeguarding and securing telomere integrity. Within this complex, TRF2 has emerged as the key player, dictating different states of telomere protection during the replicative lifespan of a cell. How TRF2 prevents activation of DSB repair activities at functional telomeres has now been extensively investigated. In this review we aim at exploring the complex and multi-faceted mechanisms underlying the TRF2-mediated protection of eukaryotic chromosome ends.