DNA replication stress in CHK1-depleted tumour cells triggers premature (S-phase) mitosis through inappropriate activation of Aurora kinase B
| Autor: | Rene Rodriguez, Mark Meuth, Mary E. Gagou, Patrick A. Eyers, Pedro Zuazua-Villar |
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| Rok vydání: | 2014 |
| Předmět: |
Cancer Research
Time Factors CHK1 Immunology Aurora B kinase Aurora inhibitor Mitosis Apoptosis Biology premature mitosis Transfection S Phase Histones Cellular and Molecular Neuroscience Control of chromosome duplication Serine Aurora Kinase B Humans CHEK1 Phosphorylation Protein Kinase Inhibitors Aurora Kinase A S-phase checkpoints Cell Biology Chromatin Assembly and Disassembly HCT116 Cells DNA replication stress Cell biology Enzyme Activation enzymes and coenzymes (carbohydrates) Checkpoint Kinase 2 Premature chromosome condensation Checkpoint Kinase 1 Colonic Neoplasms Cancer research RNA Interference Original Article biological phenomena cell phenomena and immunity Tumor Suppressor Protein p53 Protein Kinases Signal Transduction |
| Zdroj: | Cell Death & Disease |
| ISSN: | 2041-4889 |
| Popis: | The disruption of DNA replication in cells triggers checkpoint responses that slow-down S-phase progression and protect replication fork integrity. These checkpoints are also determinants of cell fate and can help maintain cell viability or trigger cell death pathways. CHK1 has a pivotal role in such S-phase responses. It helps maintain fork integrity during replication stress and protects cells from several catastrophic fates including premature mitosis, premature chromosome condensation and apoptosis. Here we investigated the role of CHK1 in protecting cancer cells from premature mitosis and apoptosis. We show that premature mitosis (characterized by the induction of histone H3 phosphorylation, aberrant chromatin condensation, and persistent RPA foci in arrested S-phase cells) is induced in p53-deficient tumour cells depleted of CHK1 when DNA synthesis is disrupted. These events are accompanied by an activation of Aurora kinase B in S-phase cells that is essential for histone H3 Ser10 phosphorylation. Histone H3 phosphorylation precedes the induction of apoptosis in p53−/− tumour cell lines but does not appear to be required for this fate as an Aurora kinase inhibitor suppresses phosphorylation of both Aurora B and histone H3 but has little effect on cell death. In contrast, only a small fraction of p53+/+ tumour cells shows this premature mitotic response, although they undergo a more rapid and robust apoptotic response. Taken together, our results suggest a novel role for CHK1 in the control of Aurora B activation during DNA replication stress and support the idea that premature mitosis is a distinct cell fate triggered by the disruption of DNA replication when CHK1 function is suppressed. |
| Databáze: | OpenAIRE |
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