Division of Cancer Research, School of Medicine, University of Dundee, Jacqui Wood Cancer Centre, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
Division of Cancer Research, School of Medicine, University of Dundee, Jacqui Wood Cancer Centre, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
Cell Rep. 2018 Apr 17;23(3):852-865. doi: 10.1016/j.celrep.2018.03.100.
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.
在有丝分裂过程中，忠实的染色体分离取决于纺锤体组装检查点（SAC），该检查点延迟有丝分裂的进程，直到每个染色体都通过动粒稳定地附着到纺锤体微管上。在这里，我们发现去泛素化酶 USP9X 通过拮抗未附着动粒产生的有丝分裂检查点复合物的周转来增强 SAC。USP9X 从而反对后期促进复合物/周期素体（APC/C）的激活，并特异性抑制 SAC 控制的 APC/C 底物的有丝分裂降解。我们证明，USP9X 的耗竭或缺失会降低 SAC 的有效性，增加染色体分离缺陷，并增强染色体不稳定性（CIN）。这些发现为解释为什么 USP9X 的缺失可能具有促癌或抑癌作用提供了依据，具体取决于现有的 CIN 水平。
