TY - JOUR
T1 - A telomere-dependent DNA damage checkpoint induced by prolonged mitotic arrest
AU - Hayashi, Makoto T.
AU - Cesare, Anthony J.
AU - Fitzpatrick, James A.J.
AU - Lazzerini-Denchi, Eros
AU - Karlseder, Jan
N1 - Funding Information:
We thank J.M. Peters (Institute for Molecular Pathology), T. de Lange (The Rockefeller University) and P. Baumann (Stowers Institute for Medical Research) for antibodies; D. Gibbs (The Salk Institute) for production of lentivirus; and the Karlseder Laboratory for comments. M.T.H. is supported by a Human Frontier Science Program Long Term Fellowship and a Japan Society for the Promotion of Science Postdoctoral Fellowship for Research Abroad. A.J.C. is supported by a training grant from the US National Institutes of Health (NIH) (5T32CA009370-29). This work was supported by the Salk Institute Cancer Center Core Grant P30 CA014195-38 and grants from the NIH to J.K. (AG025837, GM087476).
PY - 2012/4
Y1 - 2012/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84861308305&partnerID=8YFLogxK
U2 - 10.1038/nsmb.2245
DO - 10.1038/nsmb.2245
M3 - Article
C2 - 22407014
AN - SCOPUS:84861308305
VL - 19
SP - 387
EP - 394
JO - Nature Structural and Molecular Biology
JF - Nature Structural and Molecular Biology
SN - 1545-9993
IS - 4
ER -