Polo-like kinase 1 (PLK1) is a serine/threonine kinase required for mitosis and cytokinesis. As cancer cells are often hypersensitive to partial PLK1 inactivation, chemical inhibitors of PLK1 have been developed and tested in clinical trials. However, these small molecule inhibitors alone are not completely effective. PLK1 promotes numerous molecular and cellular events in the cell division cycle and it is unclear which of these events most crucially depend on PLK1 activity. We used a CRISPR-based genome-wide screening strategy to identify genes whose inactivation enhances cell proliferation defects upon partial chemical inhibition of PLK1. Genes identified encode proteins that are functionally linked to PLK1 in multiple ways, most notably factors that promote centromere and kinetochore function. Loss of the kinesin KIF18A or the outer kinetochore protein SKA1 in PLK1-compromised cells resulted in mitotic defects, activation of the spindle assembly checkpoint and nuclear reassembly defects. We also show that PLK1-dependent CENP-A loading at centromeres is extremely sensitive to partial PLK1 inhibition. Our results suggest that partial inhibition of PLK1 compromises the integrity and function of the centromere/kinetochore complex, rendering cells hypersensitive to different kinetochore perturbations. We propose that KIF18A is a promising target for combinatorial therapies with PLK1 inhibitors.

中文翻译：

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部分 PLK1 抑制的遗传增强子揭示了对着丝粒扰动的超敏反应。

Polo 样激酶 1 (PLK1) 是有丝分裂和胞质分裂所需的丝氨酸/苏氨酸激酶。由于癌细胞通常对 PLK1 部分失活高度敏感，因此已开发出 PLK1 化学抑制剂并在临床试验中进行测试。然而，单独使用这些小分子抑制剂并不完全有效。PLK1 在细胞分裂周期中促进许多分子和细胞事件，目前尚不清楚这些事件中哪些最关键地依赖于 PLK1 活性。我们使用基于 CRISPR 的全基因组筛选策略来识别在部分化学抑制 PLK1 后失活会增强细胞增殖缺陷的基因。鉴定出的基因编码的蛋白质以多种方式与 PLK1 功能相关，最显着的是促进着丝粒和着丝粒功能的因子。PLK1受损细胞中驱动蛋白KIF18A或外着丝粒蛋白SKA1的丢失导致有丝分裂缺陷、纺锤体组装检查点的激活和核重组缺陷。我们还表明，着丝粒上的 PLK1 依赖性 CENP-A 负载对部分 PLK1 抑制极其敏感。我们的结果表明，部分抑制 PLK1 会损害着丝粒/着丝粒复合体的完整性和功能，使细胞对不同的着丝粒扰动过敏。我们认为 KIF18A 是 PLK1 抑制剂联合治疗的一个有前景的靶点。