Academic Journal
Genetic enhancers of partial PLK1 inhibition reveal hypersensitivity to kinetochore perturbations
| العنوان: | Genetic enhancers of partial PLK1 inhibition reveal hypersensitivity to kinetochore perturbations |
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| المؤلفون: | Normandin, Karine, Coulombe-Huntington, Jasmin, St-Denis, Corinne, Bernard, Alexandre, Bourouh, Mohammed, Bertomeu, Thierry, Tyers, Mike, Archambault, Vincent |
| المساهمون: | Snyder, Michael, Canadian Institutes of Health Research, Cancer Research Society of Canada, Natural Sciences and Engineering Research Council of Canada |
| المصدر: | PLOS Genetics ; volume 19, issue 8, page e1010903 ; ISSN 1553-7404 |
| بيانات النشر: | Public Library of Science (PLoS) |
| سنة النشر: | 2023 |
| المجموعة: | PLOS Publications (via CrossRef) |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1371/journal.pgen.1010903 |
| الاتاحة: | http://dx.doi.org/10.1371/journal.pgen.1010903 https://dx.plos.org/10.1371/journal.pgen.1010903 |
| Rights: | http://creativecommons.org/licenses/by/4.0/ |
| رقم الانضمام: | edsbas.8FA1DB7A |
| قاعدة البيانات: | BASE |
| DOI: | 10.1371/journal.pgen.1010903 |
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