Disruption of the mevalonate pathway induces dNTP depletion and DNA damage
| Autor: | Javier Martínez-Botas, Covadonga Martín Sánchez, Jong-Sik Jin, Gema de la Peña, Miguel A. Lasunción, M.J. Hazen, Yajaira Suárez, Wei Zhang, José Manuel Pérez Martín, Sara Rodríguez-Acebes, Alberto Dávalos, Diego Gómez-Coronado, Yung-Chi Cheng, Rebeca Busto |
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| Rok vydání: | 2014 |
| Předmět: |
DNA Replication
Cell cycle checkpoint Cell division Halogenation DNA damage Carboxy-Lyases Cell Mevalonic Acid Deoxyribonucleosides HL-60 Cells Biology Histones Adenosine Triphosphate Hemiterpenes Organophosphorus Compounds Cell Line Tumor medicine Humans Lymphocytes RNA Small Interfering Molecular Biology Mitosis Cell Proliferation Cell growth DNA replication Cell Biology Cell Cycle Checkpoints medicine.anatomical_structure Biochemistry Gene Expression Regulation Checkpoint Kinase 1 Mevalonate pathway Protein Kinases DNA Damage Signal Transduction |
| Zdroj: | Biochimica et biophysica acta. 1851(9) |
| ISSN: | 0006-3002 |
| Popis: | The mevalonate pathway is tightly linked to cell division. Mevalonate derived non-sterol isoprenoids and cholesterol are essential for cell cycle progression and mitosis completion respectively. In the present work, we studied the effects of fluoromevalonate, a competitive inhibitor of mevalonate diphosphate decarboxylase, on cell proliferation and cell cycle progression in both HL-60 and MOLT-4 cells. This enzyme catalyzes the synthesis of isopentenyl diphosphate, the first isoprenoid in the cholesterol biosynthesis pathway, consuming ATP at the same time. Inhibition of mevalonate diphosphate decarboxylase was followed by a rapid accumulation of mevalonate diphosphate and the reduction of ATP concentrations, while the cell content of cholesterol was barely affected. Strikingly, mevalonate diphosphate decarboxylase inhibition also resulted in the depletion of dNTP pools, which has never been reported before. These effects were accompanied by inhibition of cell proliferation and cell cycle arrest at S phase, together with the appearance of γ-H2AX foci and Chk1 activation. Inhibition of Chk1 in cells treated with fluoromevalonate resulted in premature entry into mitosis and massive cell death, indicating that the inhibition of mevalonate diphosphate decarboxylase triggered a DNA damage response. Notably, the supply of exogenously deoxyribonucleosides abolished γ-H2AX formation and prevented the effects of mevalonate diphosphate decarboxylase inhibition on DNA replication and cell growth. The results indicate that dNTP pool depletion caused by mevalonate diphosphate decarboxylase inhibition hampered DNA replication with subsequent DNA damage, which may have important consequences for replication stress and genomic instability. |
| Databáze: | OpenAIRE |
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