p53 prevents entry into mitosis with uncapped telomeres


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Maria Thanasoula1, Jose Miguel Escandell Planells1, Purificacon Muoz2,3, Sophie Badie1, Mara A Blasco2 and Madalena Tarsounas1

1Gray Institute for Radiation Oncology and Biology, Oxford, UK, 2Spanish National Cancer Center (CNIO), Madrid, Spain, 3Present address: Catalan Institute of Oncology (ICO), Hospitalet de Llobregat, Barcelona, Spain

Abstract

Proffered paper presentation

Telomeres are protected by capping structures consisting of core protein complexes that bind with sequence specificity to telomeric DNA. In their absence, telomeres trigger a DNA damage response, materialized in accumulation at the telomere of damage response proteins, e.g. phosphorylated histone H2AX (gH2AX), into telomere-dysfunction induced foci (TIFs). Telomere uncapping occurs transiently in every cell cycle in G2, following DNA replication.

Here, we report that telomere capping is monitored at the G2/M transition by the p53/p21 damage response pathway. Unlike their wild type counterparts, human and mouse cells lacking p53 or p21 progress into mitosis prematurely with persisting uncapped telomeres. Furthermore, artificially uncapped telomeres delay mitotic entry in a p53-dependent manner. Uncapped telomeres that persist in mitotic p53-deficient cells are shorter than average and re-ligate to generate end-to-end fusions. Together, these results suggest that, at the G2/M transition, p53 acts as a sensor of telomere capping to delay mitotic progression in the presence of unprotected telomeres.