Essential role for the TRF2 telomere protein in adult skin homeostasis

Aging Cell

Paula Martínez¹  Iole Ferrara-Romeo¹  Juana M. Flores² 

[1] Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Madrid, Spain;Animal Surgery and Medicine Department, Facultad de Veterinaria, Complutense University of Madrid, Madrid, Spain

关键词: 53BP1;    DNA damage;    p53;    skin embryonic development;    Telomeres;    TRF2;   

DOI  :  10.1111/acel.12221

来源: Wiley

【 摘 要 】

Summary

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.

【 授权许可】

CC BY   
© 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.