Essential role for the TRF2 telomere protein in adult skin homeostasis

Abstract

TRF2 is a component of shelterin, the protein complex that protects the ends of mammalian chromosomes. TRF2 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 TRF2 are early embryonic lethal. However, the role of TRF2 in later stages of development and in the adult organism remains largely unaddressed, with the exception of liver, where TRF2 was found to be dispensable for maintaining tissue function. Here, we study the impact of TRF2 conditional deletion in stratified epithelia by generating the TRF2∆/∆-K5-Cre mouse model, which targets TRF2 deletion to the skin from embryonic day E11.5. In marked contrast to TRF2 deletion in the liver, TRF2∆/∆-K5-Cre mice show lethality in utero reaching 100% lethality perinataly. At the molecular and cellular level, TRF2 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 53BP1 nor inhibition of DDR by p53 deficiency rescued these severe phenotypes. Instead, TRF2 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 TRF1 and TPP1 in the skin, where p53 deficiency rescued the associated skin phenotypes, highlighting the comparatively more essential role of TRF2 in skin homeostasis.

HULC cooperates with MALAT1 to aggravate liver cancer stem cells growth through telomere repeat-binding factor 2

“…TRF2 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 fusions40. The shelterin protein TIN2 binds to TRF1 and TRF2, improving the telomeric localization of TRF2 and its function41.…”

Mice with reduced expression of the telomere‐associated protein Ft1 develop p53‐sensitive progeroid traits

“…Sections were hydrated with descendant alcohol concentration, stained with Hematoxylin (Carlo Erba) and Eosin (Sigma), cleared, and mounted with DPX Mountant for Histology (Sigma). For γH2AX analysis on paraffin, embedded heart sections were treated as previously described (Martinez, Ferrara‐Romeo, Flores & Blasco, 2014). Tissues were incubated overnight with an anti‐γH2AX (Abcam 2893) diluted in BSA 3%, Triton X‐100 0.1%, and the day after incubated for 1 hr at room temperature with the pertinent secondary antibody (anti‐rabbit‐ALEXA 555, Invitrogen A21430).…”

The crosstalk of telomere dysfunction and inflammation through cell-free TERRA containing exosomes

“…23 It is well known the chronic inflammation leads to a tumorigenic environment. Telomere dysfunction induced inflammation is also observed when TRF2 is depleted in mouse embryonic skin 24 and alveolar stem cells. 25 We suspect that TERRA containing exosomes are a significant component of this inflammatory signaling pathway.…”