Essential role for the TRF2 telomere protein in adult skin homeostasis
Article first published online: 14 APR 2014
© 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Volume 13, Issue 4, pages 656–668, August 2014
How to Cite
Martínez, P., Ferrara-Romeo, I., Flores, J. M. and Blasco, M. A. (2014), Essential role for the TRF2 telomere protein in adult skin homeostasis. Aging Cell, 13: 656–668. doi: 10.1111/acel.12221
- Issue published online: 29 JUL 2014
- Article first published online: 14 APR 2014
- Manuscript Accepted: 23 FEB 2014
- European Research Council (ERC) Project TEL STEM CELL. Grant Number: GA#232854
- European Union FP7 Projects (MARK-AGE) and (EuroBATS). Grant Numbers: 2007-A-20088, 2010-259749
- Spanish Ministry of Economy and Competitiveness Projects. Grant Numbers: SAF2008-05384, CSD2007-00017
- Regional of Government of Madrid Project (ReCaRe). Grant Number: S2010/BMD-2303
- AXA Research Fund (Life Risks Project)
- Lilly 2010 Preclinical Biomedicine Research Award (Fundación Lilly, Spain)
- Fundación Botín (Spain)
- DNA damage;
- skin embryonic development;
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.