A24
p53 prevents entry into mitosis with uncapped telomeres
Maria Thanasoula, Jose Miguel Escandell Planells, Purificacon Muoz, Sophie Badie, Maria Blasco, Madalena Tarsounas
University of Oxford, UK
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.
References
[1] Telomere and Genome Stability Group, The CR-UK/MRC Gray Institute for Radiation Oncology and Biology, Old Campus Road, Oxford OX3 7D, U.K
[2] Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Center (CNIO), Madrid E-28029, Spain
[3] Present address: Epigenetics and Cancer Biology Program (PEBC), Catalan Institute of Oncology (ICO), Gran Via s/n, 08907 LHospitalet de Llobregat, Barcelona, Spain
