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Updated: Dec 7, 2025
Studying Cell Cycle-regulated Gene Expression by Two Complementary Cell Synchronization Protocols
Published on: June 6, 2017
The Greatwall kinase safeguards the genome integrity by affecting the kinome activity in mitosis
Xavier Bisteau1,2, Joann Lee3, Vinayaka Srinivas4
1Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore, 138673, Republic of Singapore. xbisteau@ulb.ac.be.
Abstract:
Progression through mitosis is balanced by the timely regulation of phosphorylation and dephosphorylation events ensuring the correct segregation of chromosomes before cytokinesis. This balance is regulated by the opposing actions of CDK1 and PP2A, as well as the Greatwall kinase/MASTL. MASTL is commonly overexpressed in cancer, which makes it a potential therapeutic anticancer target. Loss of Mastl induces multiple chromosomal errors that lead to the accumulation of micronuclei and multilobulated cells in mitosis. Our analyses revealed that loss of Mastl leads to chromosome breaks and abnormalities impairing correct segregation. Phospho-proteomic data for Mastl knockout cells revealed alterations in proteins implicated in multiple processes during mitosis including double-strand DNA damage repair. In silico prediction of the kinases with affected activity unveiled NEK2 to be regulated in the absence of Mastl. We uncovered that, RAD51AP1, involved in regulation of homologous recombination, is phosphorylated by NEK2 and CDK1 but also efficiently dephosphorylated by PP2A/B55. Our results suggest that MastlKO disturbs the equilibrium of the mitotic phosphoproteome that leads to the disruption of DNA damage repair and triggers an accumulation of chromosome breaks even in noncancerous cells.
Insights
Loss of the Greatwall kinase/MASTL (Mastl) causes chromosome segregation errors and DNA damage by disrupting mitotic phosphoregulation. This highlights Mastl as a potential target for cancer therapy by restoring proper cell division.
Area of Science:
- Cell Biology
- Molecular Oncology
Background:
- Mitotic progression relies on precise phosphorylation/dephosphorylation balance, regulated by CDK1, PP2A, and Greatwall kinase/MASTL.
- MASTL overexpression in cancer presents a therapeutic target, as its loss induces chromosomal instability.
Purpose of the Study:
- To investigate the consequences of Mastl loss on mitotic fidelity and DNA repair.
- To identify kinases and substrates affected by Mastl deficiency during mitosis.
Main Methods:
- Analysis of Mastl knockout cells for chromosomal abnormalities and DNA damage markers.
- Phosphoproteomic profiling of Mastl knockout cells.
- In silico kinase activity prediction and validation of substrate phosphorylation.
Main Results:
- Loss of Mastl leads to chromosome breaks, missegregation, micronuclei, and multilobulated cells.
- Phosphoproteomic analysis revealed altered proteins involved in mitosis and DNA repair, including NEK2 kinase activity.
- RAD51AP1 phosphorylation by NEK2/CDK1 and dephosphorylation by PP2A/B55 is dysregulated in Mastl-deficient cells.
Conclusions:
- Mastl deficiency disrupts the mitotic phosphoproteome, impairing DNA damage repair and causing chromosome instability.
- These findings underscore the critical role of Mastl in maintaining genomic integrity and suggest its potential as an anticancer target.
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