Essential role for the TRF2 telomere protein in adult skin homeostasis.
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.
Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Melchor Fernández Almagro 3, E-28029, Madrid, Spain.
Paula
P
Martínez
Iole
I
Ferrara-Romeo
Juana M
JM
Flores
Maria A
MA
Blasco
D000375:Aging / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002868:Chromosomal Proteins, Non-Histone / Q000172:deficiency / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism; D020964:Embryo Loss / Q000378:metabolism / Q000473:pathology; D047108:Embryonic Development; D004817:Epidermis / Q000378:metabolism / Q000473:pathology; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D006706:Homeostasis; D019426:Integrases / Q000378:metabolism; D053555:Keratin-5 / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D012867:Skin / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D016615:Telomere / Q000378:metabolism*; D059505:Telomere Homeostasis; D034501:Telomere-Binding Proteins; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1
C544060:Acd protein, mouse; D002868:Chromosomal Proteins, Non-Histone; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D053555:Keratin-5; D034501:Telomere-Binding Proteins; D035341:Telomeric Repeat Binding Protein 2; C498302:Trp53bp1 protein, mouse; D016159:Tumor Suppressor Protein p53; D000071857:Tumor Suppressor p53-Binding Protein 1; C045073:Cre recombinase; D019426:Integrases
53BP1; DNA damage; TRF2; Telomeres; p53; skin embryonic development