USP9X limits mitotic checkpoint complex turnover to strengthen the spindle assembly checkpoint and guard against chromosomal instability

Agnieszka Skowyra, Lindsey Allan, Adrian Saurin (Lead / Corresponding author), Paul R. Clarke (Lead / Corresponding author)

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    9 Citations (Scopus)
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    Abstract

    Faithful chromosome segregation during mitosis depends on the spindle assembly checkpoint (SAC), which delays progression through mitosis until every chromosome has stably attached to spindle microtubules via the kinetochore. We show here that the deubiquitinase USP9X strengthens the SAC by antagonising the turnover of the mitotic checkpoint complex produced at unattached kinetochores. USP9X thereby opposes activation of anaphase-promoting complex/cyclosome (APC/C) and specifically inhibits the mitotic degradation of SAC-controlled APC/C substrates. We demonstrate that depletion or loss of USP9X reduces the effectiveness of the SAC, elevates chromosome segregation defects and enhances chromosomal instability (CIN). These findings provide a rationale to explain why loss of USP9X could be either pro- or anti-tumourigenic depending on the existing level of CIN.
    Original languageEnglish
    Pages (from-to)852-865
    Number of pages14
    JournalCell Reports
    Volume23
    Issue number3
    Early online date17 Apr 2018
    DOIs
    Publication statusPublished - 17 Apr 2018

    Keywords

    • APC/C
    • Cdc20
    • Mcl-1
    • USP9X
    • cancer
    • chromosomal instability
    • cyclin
    • deubiquitinase
    • mitosis
    • spindle assembly checkpoint

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