title: Prolonged mitotic arrest induces a caspase-dependent DNA damage response at telomeres that determines cell survival.
abstract: A delay in the completion of metaphase induces a stress response that inhibits further cell proliferation or induces apoptosis. This response is thought to protect against genomic instability and is important for the effects of anti-mitotic cancer drugs. Here, we show that mitotic arrest induces a caspase-dependent DNA damage response (DDR) at telomeres in non-apoptotic cells. This pathway is under the control of Mcl-1 and other Bcl-2 family proteins and requires caspase-9, caspase-3/7 and the endonuclease CAD/DFF40. The gradual caspase-dependent loss of the shelterin complex protein TRF2 from telomeres promotes a DDR that involves DNA-dependent protein kinase (DNA-PK). Suppression of mitotic telomere damage by enhanced expression of TRF2, or the inhibition of either caspase-3/7 or DNA-PK during mitotic arrest, promotes subsequent cell survival. Thus, we demonstrate that mitotic stress is characterised by the sub-apoptotic activation of a classical caspase pathway, which promotes telomere deprotection, activates DNA damage signalling, and determines cell fate in response to a prolonged delay in mitosis.
authors.affiliation: Division of Cancer Research, School of Medicine, University of Dundee, Jacqui Wood Cancer Centre, Ninewells Hospital, Dundee DD1 9SY, Scotland, UK.
authors.forename: Karolina O
authors.initials: KO
authors.lastname: Hain
authors.affiliation: Division of Cancer Research, School of Medicine, University of Dundee, Jacqui Wood Cancer Centre, Ninewells Hospital, Dundee DD1 9SY, Scotland, UK.
authors.forename: Didier J
authors.initials: DJ
authors.lastname: Colin
authors.affiliation: Division of Cancer Research, School of Medicine, University of Dundee, Jacqui Wood Cancer Centre, Ninewells Hospital, Dundee DD1 9SY, Scotland, UK.
authors.forename: Shubhra
authors.initials: S
authors.lastname: Rastogi
authors.affiliation: Division of Cancer Research, School of Medicine, University of Dundee, Jacqui Wood Cancer Centre, Ninewells Hospital, Dundee DD1 9SY, Scotland, UK.
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Allan
authors.affiliation: Division of Cancer Research, School of Medicine, University of Dundee, Jacqui Wood Cancer Centre, Ninewells Hospital, Dundee DD1 9SY, Scotland, UK.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Clarke
mesh_terms: D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival; D004249:DNA Damage; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological; D016615:Telomere / Q000378:metabolism*
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D053148:Caspase 3; D053179:Caspase 7; D053453:Caspase 9; D020169:Caspases