Oncogenes induce genotoxic stress by mitotic processing of unusual replication intermediates
| Autor: | Kai J. Neelsen, Massimo Lopes, Raquel Herrador, Isabella M.Y. Zanini |
|---|---|
| Přispěvatelé: | University of Zurich, Lopes, Massimo |
| Rok vydání: | 2013 |
| Předmět: |
DNA re-replication
DNA Replication G2 Phase DNA repair Mitosis Eukaryotic DNA replication Biology 1307 Cell Biology 03 medical and health sciences 0302 clinical medicine Control of chromosome duplication Cell Line Tumor Report CDC2 Protein Kinase Cyclin E Humans cdc25 Phosphatases S phase Research Articles 030304 developmental biology 0303 health sciences 10061 Institute of Molecular Cancer Research DNA replication Chromosome Breakage Cell Biology Oncogenes Endonucleases DNA-Binding Proteins 030220 oncology & carcinogenesis Cancer research Origin recognition complex 570 Life sciences biology Chromosome breakage |
| Zdroj: | The Journal of cell biology The Journal of Cell Biology |
| DOI: | 10.1083/jcb.201212058 |
| Popis: | Processing of unusual replication intermediates such as reversed forks by MUS81 contributes to oncogene-induced double-strand breaks and depends on mitotic entry. Oncogene-induced DNA replication stress activates the DNA damage response (DDR), a crucial anticancer barrier. DDR inactivation in these conditions promotes genome instability and tumor progression, but the underlying molecular mechanisms are elusive. We found that overexpression of both Cyclin E and Cdc25A rapidly slowed down replication forks and induced fork reversal, suggestive of increased topological stress. Surprisingly, these phenotypes, per se, are neither associated with chromosomal breakage nor with significant DDR activation. Oncogene-induced DNA breakage and DDR activation instead occurred upon persistent G2/M arrest or, in a checkpoint-defective context, upon premature CDK1 activation. Depletion of MUS81, a cell cycle–regulated nuclease, markedly limited chromosomal breakage and led to further accumulation of reversed forks. We propose that nucleolytic processing of unusual replication intermediates mediates oncogene-induced genotoxicity and that limiting such processing to mitosis is a central anti-tumorigenic function of the DNA damage checkpoints. |
| Databáze: | OpenAIRE |
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