Oncogenes induce genotoxic stress by mitotic processing of unusual replication intermediates
Open accessAbstract
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.
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Mitotic defects can derive from exogenous xenobiotics and endogenous replication/mitotic stress.
“Mitotic defects can derive from: (1) exogenous sources, including a large panel of xenobiotics that alter DNA replication, cell cycle checkpoints, chromosome segregation, and/or microtubular dynamics [976]; or (2) endogenous sources, such as high levels of DNA replication stress or mitotic stress caused by an aberrant ploidy or by deregulated expression/activity of factors involved in DNA”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [977]
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- Authors
- Neelsen, K. J., Zanini, I. M. Y., Herrador, R., & Lopes, M.
- Affiliations
- University of Zurich (CH)
- Corresponding author
- Lopes, Massimo
- Venue
- Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2013-03-11
- Volume
- 200
- Issue
- 6
- Pages
- 699-708
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC3601361
- OpenAlex
- W2031666034
- Cited by
- 188
- References
- 40
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 4 · 2023: 9 · 2022: 8 · 2021: 12 · 2020: 15 · 2019: 14 · 2018: 20 · 2017: 24 · 2016: 16 · 2015: 27 · 2014: 15 · 2013: 12
- FWCI
- 10.45
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Cell Biology (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (114922)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- DNA damage response, genotoxic stress, replication fork reversal, replication fork stalling, cyclin E, CDC25A, MUS81, G2/M cell cycle arrest, CDK1 activation, DNA damage checkpoint, genomic instability, mitosis
- MeSH terms
- DNA Replication, DNA-Binding Proteins, Endonucleases, Humans, Mitosis, Oncogenes, G2 Phase, CDC2 Protein Kinase, Chromosome Breakage, Cyclin E, cdc25 Phosphatases, Cell Line, Tumor
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