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USP9X Limits Mitotic Checkpoint Complex Turnover to Strengthen the Spindle Assembly Checkpoint and Guard against Chromosomal Instability

Skowyra, Agnieszka ; Allan, Lindsey A. ; Saurin, Adrian T. ; Clarke, Paul R.

Cell reports (Cambridge), 2018-04, Vol.23 (3), p.852-865 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
USP9X Limits Mitotic Checkpoint Complex Turnover to Strengthen the Spindle Assembly Checkpoint and Guard against Chromosomal Instability
Autor: Skowyra, Agnieszka ; Allan, Lindsey A. ; Saurin, Adrian T. ; Clarke, Paul R.
Assuntos: Anaphase-Promoting Complex-Cyclosome - metabolism ; APC/C ; Apc11 Subunit, Anaphase-Promoting Complex-Cyclosome - antagonists & inhibitors ; Apc11 Subunit, Anaphase-Promoting Complex-Cyclosome - genetics ; Apc11 Subunit, Anaphase-Promoting Complex-Cyclosome - metabolism ; cancer ; Cdc20 ; Cdc20 Proteins - metabolism ; Chromosomal Instability ; Chromosome Segregation ; cyclin ; Cyclin B - metabolism ; deubiquitinase ; HeLa Cells ; Humans ; Karyotype ; Kinesins - metabolism ; Kinetochores - metabolism ; Mcl-1 ; mitosis ; Mitosis - drug effects ; NIMA-Related Kinases - metabolism ; Nocodazole - pharmacology ; RNA Interference ; RNA, Small Interfering - metabolism ; Spindle Apparatus - metabolism ; spindle assembly checkpoint ; Ubiquitin Thiolesterase - antagonists & inhibitors ; Ubiquitin Thiolesterase - genetics ; Ubiquitin Thiolesterase - metabolism ; USP9X
É parte de: Cell reports (Cambridge), 2018-04, Vol.23 (3), p.852-865
Notas: Lead Contact
Descrição: 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 antagonizing 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-tumorigenic depending on the existing level of CIN. [Display omitted] •The deubiquitinase USP9X reinforces the spindle assembly checkpoint•USP9X controls the mitotic checkpoint complex (MCC) downstream of kinetochores•USP9X inhibits the ubiquitination and degradation of Cdc20, a component of MCC•USP9X loss elevates chromosomal instability (CIN) Skowyra et al. show the deubiquitinase USP9X limits activation of the ubiquitin ligase APC/C during mitosis. Loss of USP9X causes chromosomal instability (CIN), which can promote cancer. This work also provides a rationale for targeting USP9X when it is expressed in cancer cells with high levels of CIN.
Editor: United States: Elsevier Inc
Idioma: Inglês

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USP9X Limits Mitotic Checkpoint Complex Turnover to Strengthen the Spindle Assembly Checkpoint and Guard against Chromosomal Instability

Skowyra, Agnieszka ; Allan, Lindsey A. ; Saurin, Adrian T. ; Clarke, Paul R.

United States: Elsevier Inc

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