DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis
Abstract
During the evolution of cancer, the incipient tumour experiences 'oncogenic stress', which evokes a counter-response to eliminate such hazardous cells. However, the nature of this stress remains elusive, as does the inducible anti-cancer barrier that elicits growth arrest or cell death. Here we show that in clinical specimens from different stages of human tumours of the urinary bladder, breast, lung and colon, the early precursor lesions (but not normal tissues) commonly express markers of an activated DNA damage response. These include phosphorylated kinases ATM and Chk2, and phosphorylated histone H2AX and p53. Similar checkpoint responses were induced in cultured cells upon expression of different oncogenes that deregulate DNA replication. Together with genetic analyses, including a genome-wide assessment of allelic imbalances, our data indicate that early in tumorigenesis (before genomic instability and malignant conversion), human cells activate an ATR/ATM-regulated DNA damage response network that delays or prevents cancer. Mutations compromising this checkpoint, including defects in the ATM-Chk2-p53 pathway, might allow cell proliferation, survival, increased genomic instability and tumour progression.
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Human cells that bypass oncogene-induced senescence, as well as cells in some human premalignant lesions, show signs of a persistently activated DDR.
“Moreover, human cells that bypass oncogene-induced senescence [ 58 ], as well as cells in some human premalignant lesions [ 73 , 74 ], show signs of a persistently activated DDR.”
From Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor (2008) · cites this paper as [73]
DNA damage in the nucleus of normal cells expressing oncogenes has already been characterized and could arise by either replication stress or oxidative damage.
“DNA damage in the nucleus of normal cell-expressing oncogenes already has been characterized using techniques that detect DNA breaks, and they could arise by either replication stress or oxidative damage (2, 15, 28).”
From Mitochondrial Dysfunction Contributes to Oncogene-Induced Senescence (2009) · cites this paper as [2]
Oncogene-induced senescence involves the DNA damage response.
“OIS also involves the DNA damage response (2, 15, 28), but the mechanism of DNA damage and the contribution of mitochondria to it are unclear.”
From Mitochondrial Dysfunction Contributes to Oncogene-Induced Senescence (2009) · cites this paper as [2]
DDR activation and senescence, presumably owing to unscheduled DNA replication, are frequently observed in early stages of cancer lesions.
“DDR activation and senescence, presumably owing to unscheduled DNA replication, are frequently observed in the early stages of cancer lesions, [69,70,356,357].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [356]
Activated DNA damage response markers occur in many pre-cancerous lesions, and checkpoint-compromising mutations are suggested to be required for tumor progression.
“Indeed, the markers of activated DDR are found in many pre-cancerous lesions, and mutations compromising DNA damage checkpoint (for example, defects in ATM/p53 pathway) are suggested to be a prerequisite for tumor progression.13,14”
From Senescence from G2 arrest, revisited (2015) · cites this paper as [13]
Both telomere dysfunction and the DDR are activated at the earliest stages in many human carcinomas.
“Recent observations indicate that both telomere dysfunction73, 74 and the DDR75, 76 are activated at the earliest stages in many human carcinomas.”
From Telomere dysfunction and tumour suppression: the senescence connection (2008) · cites this paper as [75]
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References 52 · Cited by 2,688
- Authors
- Bartkova, J., Hořejší, Z., Koed, K., Krämer, A., Tort, F., Zieger, K., Guldberg, P., Sehested, M., Nesland, J. M., Lukas, C., Ørntoft, T., Lukas, J., & Bartek, J.
- Affiliations
- Aarhus University Hospital (DK)
- Danish Cancer Society (DK)
- Copenhagen University Hospital (DK)
- University of Oslo (NO)
- Venue
- Nature
- Published
- 2005-04
- Volume
- 434
- Issue
- 7035
- Pages
- 864-870
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2059971436
- Cited by
- 2,688
- References
- 52
- Citations by year
- 2026: 29 · 2025: 46 · 2024: 56 · 2023: 85 · 2022: 76 · 2021: 109 · 2020: 100 · 2019: 88 · 2018: 121 · 2017: 131 · 2016: 133 · 2015: 147 · 2014: 153 · 2013: 154 · 2012: 167
- FWCI
- 69.90
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- 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 › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- DNA damage response, carcinogenesis, oncogenic stress, tumor suppression, ATM, Chk2, p53, histone H2AX, p53-dependent cell death, precancerous lesions, chromosomal instability, 53BP1 foci, lung hyperplasia, bladder cancer, breast cancer, colorectal cancer, lung cancer, allelic imbalance
- MeSH terms
- Urinary Bladder Neoplasms, Cell Cycle, Cell Transformation, Neoplastic, DNA Damage, DNA-Binding Proteins, Enzyme Activation, Humans, Mutation, Neoplasms, Oncogenes, Phosphorylation, Transcription Factors, Signal Transduction, Genes, p53, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Cyclin E, Polymorphism, Single Nucleotide, cdc25 Phosphatases, Allelic Imbalance, Genomic Instability, Cell Line, Tumor, E2F Transcription Factors, Checkpoint Kinase 2
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