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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Oct 02, 2023 |
| Title |
Genetic enhancers of partial PLK1 inhibition reveal hypersensitivity to kinetochore perturbations |
| Organism |
Homo sapiens |
| Experiment type |
Other
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| Summary |
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 molecules alone were not completely effective. PLK1 promotes numerous molecular and cellular events in the cell division cycle. To date, 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. Among them, factors that promote centromere and kinetochore function were clearly enriched. In particular, inactivation of the kinesin KIF18A or SKA1 in PLK1-compromised cells results in mitotic defects, activation of the spindle assembly checkpoint and nuclear reassembly defects. Our results suggest that functions of PLK1 at kinetochores are most sensitive to its inhibition, and point at KIF18A as a possible target for combinatorial therapies using existing PLK1 inhibitors.
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| Overall design |
Genome-wide CRISPR/Cas9 screens to test for gene deletions that affect fitness in human cells treated with PLK1 inhibitors BI2536, BI6727 and GSK461364A.
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| Contributor(s) |
Normandin K, Coulombe-Huntington J, St-Denis C, Bernard A, Bourouh M, Bertomeu T, Tyers M, Archambault V |
| Citation(s) |
37639469 |
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| Submission date |
Mar 24, 2023 |
| Last update date |
Oct 02, 2023 |
| Contact name |
Micheal D Tyers |
| E-mail(s) |
mike.tyers@sickkids.ca
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| Organization name |
Université de Montréal
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| Department |
IRIC
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| Street address |
2950 Chemin de Polytechnique
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| City |
Montréal |
| State/province |
Québec |
| ZIP/Postal code |
H3T 1J4 |
| Country |
Canada |
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| Platforms (1) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
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| Samples (9)
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| GSM7115648 |
Treated with 4.2 nM BI2536 for 8 days |
| GSM7115649 |
Treated with 12.5 nM BI6727 for 8 days |
| GSM7115650 |
Treated with 100 nM GSK461364A for 8 days |
| GSM7115651 |
Control, treated with DMSO 0.3% for 8 days |
| GSM7115652 |
Control, untreated for 8 days |
| GSM7115653 |
Control, Cas9 induced with Doxycicline 7 days |
| GSM7115654 |
Control, treated with DMSO 0.1% for 2 days |
| GSM7115655 |
Control, treated with DMSO 0.1% for 4 days |
| GSM7115656 |
Control, treated with DMSO 0.1% for 6 days |
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| Relations |
| BioProject |
PRJNA948403 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE228155_sgRNA_read_counts.tsv.gz |
3.2 Mb |
(ftp)(http) |
TSV |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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