Defective sister chromatid cohesion is synthetically lethal with impaired APC/C function
Defective sister chromatid cohesion is synthetically lethal with impaired APC/C function
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DOI：
10.1038/ncomms9399
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发表时间：
2015-10-01
影响因子：
16.6
通讯作者：
Wolthuis, Rob M. F.
中科院分区：
文献类型：
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作者：
de Lange, Job;Faramarz, Atiq;Wolthuis, Rob M. F.
华沙断裂综合征(WABS)是由DDX11缺陷引起的，DDX11是一种对染色单体凝聚力至关重要的DNA解旋酶。这里，在患者来源的细胞系中的成对全基因组siRNA筛选显示，WABS细胞不耐受单个APC/C亚基或纺锤体检查点抑制物p31(彗星)的部分耗尽。凝聚力降低和APC/C功能受损的组合也会导致二倍体RPE1细胞的致命有丝分裂停止。此外，WABS细胞系和几种具有凝聚力缺陷的癌细胞系对一种新的细胞渗透性APC/C抑制剂APCIN表现出高度增强的反应，但对纺锤体毒药紫杉醇没有反应。APC/C抑制和内聚缺陷的合成杀伤力严格依赖于有丝分裂纺锤体的功能检查点以及完整的微管牵引力。这表明其潜在的机制涉及对有丝分裂延迟的凝聚力疲劳，导致纺锤体检查点重新激活和致命性有丝分裂停止。我们的结果指出，APC/C抑制剂是针对凝聚力缺陷癌症的有前途的治疗药物。
Warsaw breakage syndrome (WABS) is caused by defective DDX11, a DNA helicase that is essential for chromatid cohesion. Here, a paired genome-wide siRNA screen in patient-derived cell lines reveals that WABS cells do not tolerate partial depletion of individual APC/C subunits or the spindle checkpoint inhibitor p31(comet). A combination of reduced cohesion and impaired APC/C function also leads to fatal mitotic arrest in diploid RPE1 cells. Moreover, WABS cell lines, and several cancer cell lines with cohesion defects, display a highly increased response to a new cell-permeable APC/C inhibitor, apcin, but not to the spindle poison paclitaxel. Synthetic lethality of APC/C inhibition and cohesion defects strictly depends on a functional mitotic spindle checkpoint as well as on intact microtubule pulling forces. This indicates that the underlying mechanism involves cohesion fatigue in response to mitotic delay, leading to spindle checkpoint re-activation and lethal mitotic arrest. Our results point to APC/C inhibitors as promising therapeutic agents targeting cohesion-defective cancers.