Polo样激酶1（PLK1）是一种在有丝分裂和细胞质分裂中必需的丝氨酸/苏氨酸激酶。由于癌细胞对部分PLK1失活往往过敏，因此已经开发了化学PLK1抑制剂，并在临床试验中进行了测试。然而，这些小分子抑制剂单独并不完全有效。PLK1在细胞分裂周期中促进了许多分子和细胞事件的发生，目前尚不清楚其中哪些事件最重要地依赖于PLK1的活性。我们使用CRISPR基因组范围筛选策略，鉴定了在部分化学抑制PLK1时增强了细胞增殖缺陷的基因。鉴定到的基因编码与PLK1在多个方面功能相关的蛋白质，尤其是促进着丝粒体和着丝粒体纺锤体功能的因子。在PLK1受损细胞中失去了动力蛋白KIF18A或外部着丝粒体蛋白SKA1会导致有丝分裂缺陷、纺锤体装配检查点的激活和核重组缺陷。我们还表明，部分PLK1抑制对着丝粒体中CENP-A的加载非常敏感。我们的结果表明，部分抑制PLK1会损害着丝粒体/着丝粒体纺锤体复合物的完整性和功能，使细胞对不同类型的着丝粒体干扰产生过敏反应。我们提出KIF18A是与PLK1抑制剂联合治疗的有希望的靶点。版权：© 2023 Normandin等。本文是一篇开放获取文章，按照创作共享许可证，允许在任何媒介中进行无限制的使用、分发和复制，只要保留原始作者和出处来源的署名。

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.Copyright: © 2023 Normandin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.