Prolonged mitotic arrest induces a caspase-dependent DNA damage response at telomeres that determines cell survival

Karolina O. Hain, Didier J. Colin, Shubhra Rastogi, Lindsey A. Allan, Paul R. Clarke (Lead / Corresponding author)

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    23 Citations (Scopus)
    183 Downloads (Pure)

    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.
    Original languageEnglish
    Article number26766
    Number of pages11
    JournalScientific Reports
    Volume6
    DOIs
    Publication statusPublished - 27 May 2016

    Keywords

    • Apoptosis
    • Mitosis
    • Stress signalling

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