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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 (gammaH2AX), into telomere-dysfunction-induced foci. Telomere uncapping occurs transiently in every cell cycle in G2, following DNA replication, but little is known about how protective structures are reassembled or whether this process is controlled by the cell-cycle surveillance machinery. 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- and p21-dependent manner. Uncapped telomeres that persist in mitotic p53-deficient cells are shorter than average and religate to generate end-to-end fusions. These results suggest that a p53-dependent pathway monitors telomere capping after DNA replication and delays G2/M progression in the presence of unprotected telomeres. This mechanism maintains a cell-cycle stage conducive for capping reactions and prevents progression into stages during which uncapped telomeres are prone to deleterious end fusions.

Original publication




Journal article


Curr Biol

Publication Date





521 - 526


Animals, Ataxia Telangiectasia Mutated Proteins, Base Sequence, Cell Cycle Proteins, Cell Line, Cells, Cultured, Cyclin-Dependent Kinase Inhibitor p21, DNA Damage, DNA-Binding Proteins, HeLa Cells, Histones, Humans, Mice, Mice, Knockout, Mitosis, Protein-Serine-Threonine Kinases, RNA, Small Interfering, Telomere, Tumor Suppressor Protein p53, Tumor Suppressor Proteins