Mechanisms of oncogene-induced genomic instability
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Updated: Mar 9, 2026
Visualizing and Quantifying Endonuclease-Based Site-Specific DNA Damage
Published on: August 21, 2021
Simona Graziano1, Susana Gonzalo1
1Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
Abstract:
Activating mutations in oncogenes promote uncontrolled proliferation and malignant transformation. Approximately 30% of human cancers carry mutations in the RAS oncogene. Paradoxically, expression of mutant constitutively active Ras protein in primary human cells results in a premature proliferation arrest known as oncogene-induced senescence (OIS). This is more commonly observed in human pre-neoplasia than in neoplastic lesions, and is considered a tumor suppressor mechanism. Senescent cells are still metabolically active but in a status of cell cycle arrest characterized by specific morphological and physiological features that distinguish them from both proliferating cells, and cells growth-arrested by other means. Although the molecular mechanisms by which OIS is established are not totally understood, the current view is that OIS in human cells is tightly linked to persistent activation of the DNA damage response (DDR) pathway, as a consequence of replication stress. Here we will highlight recent advances in our understanding of molecular mechanisms leading to hyper-replication stress in response to oncogene activation, and of the crosstalk between replication stress and persistent activation of the DDR. We will also discuss new evidence for DNA repair deficiencies during OIS, which might increase the genomic instability that drives senescence bypass and malignant transformation.
Insights
Activating oncogenes cause uncontrolled cell growth, but mutant Ras triggers oncogene-induced senescence (OIS), a tumor suppressor mechanism. OIS involves cell cycle arrest and DNA damage response, potentially leading to genomic instability.
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- Activating oncogene mutations drive uncontrolled cell proliferation and cancer.
- Mutant RAS oncogene mutations are found in ~30% of human cancers.
- Oncogene-induced senescence (OIS) is a tumor suppressor mechanism where cells arrest proliferation in response to oncogene activation.
Purpose of the Study:
- To review recent advances in understanding OIS mechanisms.
- To explore the link between oncogene activation, replication stress, and DNA damage response (DDR).
- To discuss DNA repair deficiencies in OIS and their role in malignant transformation.
Main Methods:
- Review of recent scientific literature on oncogene-induced senescence.
- Analysis of molecular mechanisms linking oncogene activation to replication stress.
- Examination of the interplay between replication stress and DNA damage response pathways.
Main Results:
- OIS is a complex cellular response to oncogene activation, characterized by cell cycle arrest and specific features.
- Persistent activation of the DNA damage response (DDR) pathway, triggered by replication stress, is crucial for OIS establishment.
- Evidence suggests DNA repair deficiencies during OIS may contribute to genomic instability and cancer progression.
Conclusions:
- Oncogene activation can paradoxically induce senescence, acting as a tumor suppressor mechanism.
- Replication stress and sustained DDR activation are key events in OIS.
- Defective DNA repair in senescent cells may promote malignant transformation by increasing genomic instability.
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