Atalay Pınar Buket, Çavuşoğlu Elif Ergin, Aşci Öykü, Aygüneş Duygu
Department of Medical Biology and Genetics, Faculty of Medicine, Maltepe University, İstanbul, Turkey.
Department of Clinical Embryology, Maltepe University Graduate School of Health Sciences, Maltepe University, İstanbul, Turkey.
Turk J Biol. 2019 Jun 13;43(3):189-197. doi: 10.3906/biy-1812-46. eCollection 2019.
Microtubule-targeting agents represent one of the most successful groups of anticancer drugs used in cancer therapy today. These drugs induce a prolonged mitotic arrest through chronic spindle assembly checkpoint (SAC) activation. Apoptosis, an outcome of the prolonged mitotic arrest, is the main mechanism by which these anticancer drugs kill cancer cells. However, not much is known about the mechanism that directs chronic SAC activation to apoptosis among other possible outcomes. The aim of this study is to investigate whether Slx5, a sumo-targeted ubiquitin E3 ligase, is involved in directing chronic SAC activation to apoptosis. We show that chronic SAC activation triggered by a 10-h nocodazole incubation leads to a prolonged mitotic arrest in the Δ strain similar to wild type (WT). However, the proportion of cells displaying apoptotic features such as nuclear fragmentation, DNA fragmentation, and reactive oxygen species (ROS) production were increased more in the WT strain during the chronic SAC activation compared to , indicating that Slx5 may be involved in the chronic SAC-activation-apoptosis relation. We also showed that the possible role of Slx5 in the chronic SAC activation-apoptosis association was not through ubiquitin dependent degradation of 3 apoptosis-related and sumoylated candidate proteins.
微管靶向剂是当今癌症治疗中使用的最成功的抗癌药物类别之一。这些药物通过长期激活纺锤体组装检查点（SAC）诱导有丝分裂长期停滞。凋亡是有丝分裂长期停滞的结果，是这些抗癌药物杀死癌细胞的主要机制。然而，对于将长期SAC激活导向凋亡而非其他可能结果的机制，我们了解得并不多。本研究的目的是调查一种靶向SUMO的泛素E3连接酶Slx5是否参与将长期SAC激活导向凋亡。我们发现，10小时诺考达唑孵育引发的长期SAC激活在Δ菌株中导致与野生型（WT）相似的有丝分裂长期停滞。然而，在长期SAC激活期间，与Δ菌株相比，WT菌株中显示出核碎片化、DNA碎片化和活性氧（ROS）产生等凋亡特征的细胞比例增加得更多，这表明Slx5可能参与了长期SAC激活与凋亡之间的关系。我们还表明，Slx5在长期SAC激活与凋亡关联中的可能作用并非通过泛素依赖性降解3种与凋亡相关的SUMO化候选蛋白来实现。
