Genetic enhancers of partial PLK1 inhibition reveal hypersensitivity to kinetochore perturbations

• DOI: 10.1371/journal.pgen.1010903
• Publication Date: 2023-08-28T17:33:03Z
• Authors: Karine Normandin; Jasmin Coulombe-H...; Corinne St-Denis; Alexandre Bernard; Mohammed Bourouh; Thierry Bertomeu; Mike Tyers; Vincent Archambault
• Keywords: PLK1

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