Abstract SY33-04: Role of shelterin in cancer and aging: Generation of conditional knockout mice for TRF1, TPP1, and RAP1

Abstract

Abstract Shelterin is a highly conserved chromosome end-capping complex, which encompasses TRF1, TRF2, TPP1, POT1, TIN2 and RAP1. Although extensive cell culture studies suggest that shelterin is essential for telomere regulation, its role in telomere biology and disease in the context of the organism remained elusive due to lack of viable loss-of-function mouse models. I will report on mice and cells conditionally deleted for TRF1, TPP1 and RAP1. While deletion of TRF1 and TPP1 in mouse stratified epithelia results in perinatal mortality, severe skin atrophy and hyperpigmentation, and widespread epithelial dysplasia and tumors in the absence of p53, RAP1 deletion does not affect mouse viability and only leads to mild skin hyperpigmentation at aduldhood. This differential impact of TPP1 and TRF1 deletion compared to RAP1 deletion is in agreement with severe telomere uncapping produced by either TPP1 or TRF1 abrogation, which is not observed upon RAP1 deletion. These results argue that RAP1 is not an essential telomere capping protein in mammals. Instead, we show here that both TPP1 and RAP1 are important to recruit telomerase to telomeres and to maintain telomere length. In addition, we demonstrate that RAP1 is important for silencing of genes located near the telomeres, demonstrating a conserved role of RAP1 in subtelomeric gene silencing from yeast to mammals. Citation Format: Maria Blasco. Role of shelterin in cancer and aging: Generation of conditional knockout mice for TRF1, TPP1, and RAP1 [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY33-04