title: A telomere-dependent DNA damage checkpoint induced by prolonged mitotic arrest.
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.
authors.affiliation: The Salk Institute for Biological Studies, Molecular and Cellular Biology Department, La Jolla, California, USA.
authors.forename: Makoto T
authors.initials: MT
authors.lastname: Hayashi
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Cesare
authors.forename: James A J
authors.initials: JA
authors.lastname: Fitzpatrick
authors.forename: Eros
authors.initials: E
authors.lastname: Lazzerini-Denchi
authors.forename: Jan
authors.initials: J
authors.lastname: Karlseder
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D064107:Aurora Kinase B; D064127:Aurora Kinases; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016615:Telomere / Q000378:metabolism*; D035341:Telomeric Repeat Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D035341:Telomeric Repeat Binding Protein 2; D050257:Tubulin Modulators; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; C576921:AURKB protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases