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.