A telomere-dependent DNA damage checkpoint induced by prolonged mitotic arrest

Makoto T. Hayashi, Anthony J. Cesare, James A.J. Fitzpatrick, Eros Lazzerini-Denchi, Jan Karlseder

Research output: Contribution to journalArticlepeer-review

117 Scopus citations

Abstract

Telomere shortening and disruption of telomeric components are pathways that induce telomere deprotection. Here we describe another pathway, in which prolonged mitotic arrest induces damage signals at telomeres in human cells. Exposure to microtubule drugs, kinesin inhibitors, proteasome inhibitors or the disruption of proper chromosome cohesion resulted in the formation of damage foci at telomeres. Induction of mitotic telomere deprotection coincided with dissociation of TRF2 from telomeres, telomeric 3′-overhang degradation and ATM activation, and deprotection could be suppressed by TRF2 overexpression or inhibition of Aurora B kinase. Normal cells that escaped from prolonged mitotic arrest halted in the following G1 phase, whereas cells lacking p53 continued to cycle and became aneuploid. We propose a telomere-dependent mitotic-duration monitoring system that reacts to improper progression through mitosis.

Original languageEnglish
Pages (from-to)387-394
Number of pages8
JournalNature Structural and Molecular Biology
Volume19
Issue number4
DOIs
StatePublished - Apr 2012

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