Essential role for the TRF 2 telomere protein in adult skin homeostasis

Summary TRF 2 is a component of shelterin, the protein complex that protects the ends of mammalian chromosomes. TRF 2 is essential for telomere capping owing to its roles in suppressing an ATM ‐dependent DNA damage response ( DDR ) at chromosome ends and inhibiting end‐to‐end chromosome fusions. Mice deficient for TRF 2 are early embryonic lethal. However, the role of TRF 2 in later stages of development and in the adult organism remains largely unaddressed, with the exception of liver, where TRF 2 was found to be dispensable for maintaining tissue function. Here, we study the impact of TRF 2 conditional deletion in stratified epithelia by generating the TRF 2 ∆/∆ ‐K5‐Cre mouse model, which targets TRF 2 deletion to the skin from embryonic day E11.5. In marked contrast to TRF 2 deletion in the liver, TRF 2 ∆/∆ ‐K5‐Cre mice show lethality in utero reaching 100% lethality perinataly. At the molecular and cellular level, TRF 2 deletion provokes induction of an acute DDR at telomeres, leading to activation of p53 signaling pathways and to programed cell death since the time of Cre expression at E11.5. Unexpectedly, neither inhibition of the NHEJ pathway by abrogation of 53 BP 1 nor inhibition of DDR by p53 deficiency rescued these severe phenotypes. Instead, TRF 2 deletion provokes an extensive epidermal cell death accompanied by severe inflammation already at E16.5 embryos, which are independent of p53. These results are in contrast with conditional deletion of TRF 1 and TPP 1 in the skin, where p53 deficiency rescued the associated skin phenotypes, highlighting the comparatively more essential role of TRF 2 in skin homeostasis.