p53 Prevents entry into mitosis with uncapped telomeres

2014-08-29

"C:\Users\kurtw_000\Box Sync\DocDR\2014\02-03-2014d1015\p53 Prevents entry into mitosis with uncapped telomeres.pdf"

Abstract
Telomeres are protected by capping structures consisting of core protein complexes that bind with sequence specificity to telomeric DNA (reviewed in [1]). In their absence, telomeres trigger a DNA damage response, materialized in accumulation at the telomere of damage response proteins, e.g., phosphorylated histone H2AX (?H2AX), into telomere-dysfunction-induced foci [2 and 3]. Telomere uncapping occurs transiently in every cell cycle in G2 [4], 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.

-Mitotic TIFs Mark Short, Uncapped Telomeres
-The p53/p21 Pathway Prevents Mitotic Entry
with Uncapped Telomeres and Telomere Fusion
-Uncapped Telomeres Trigger ATM- and
p53/p21-Dependent G2/M Arrest
-immunofluorescence
-FISH
-Q-FISH

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