A two-step mechanism for TRF2-mediated chromosome end protection

Mammalian telomeres repress DNA damage activation at natural chromosome ends by recruiting specific inhibitors of the DNA damage machinery that form a protective complex termed shelterin. Within this complex, TRF2 plays a crucial role in end-protection as it is required to suppress ATM activation and the formation of end-to-end chromosome fusions(1, 2). Here, we address the molecular properties of TRF2 that are both necessary and sufficient to protect chromosome ends. Our data support a two-step mechanism for TRF2-mediated end protection. First, the dimerization domain of TRF2 is required to inhibit ATM activation, the key initial step involved in activation of a DNA damage response. Next, TRF2 independently suppresses the propagation of DNA damage signaling downstream of ATM activation. This novel modulation of the DNA damage response at telomeres occurs at the level of the E3 ubiquitin ligase RNF168 (3). Inhibition of RNF168 at telomeres involves the de-ubiquitinating enzyme BRCC3 and the ubiquitin ligase UBR5 and is sufficient to suppress chromosome end-to-end fusions. This two-step mechanism for TRF2-mediated end protection helps to explain the apparent paradox of frequent localization of DNA damage response proteins at functional telomeres without concurrent induction of detrimental DNA repair activities.