Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions
Abstract
DNA damage checkpoint genes, such as p53, are frequently mutated in human cancer, but the selective pressure for their inactivation remains elusive. We analysed a panel of human lung hyperplasias, all of which retained wild-type p53 genes and had no signs of gross chromosomal instability, and found signs of a DNA damage response, including histone H2AX and Chk2 phosphorylation, p53 accumulation, focal staining of p53 binding protein 1 (53BP1) and apoptosis. Progression to carcinoma was associated with p53 or 53BP1 inactivation and decreased apoptosis. A DNA damage response was also observed in dysplastic nevi and in human skin xenografts, in which hyperplasia was induced by overexpression of growth factors. Both lung and experimentally-induced skin hyperplasias showed allelic imbalance at loci that are prone to DNA double-strand break formation when DNA replication is compromised (common fragile sites). We propose that, from its earliest stages, cancer development is associated with DNA replication stress, which leads to DNA double-strand breaks, genomic instability and selective pressure for p53 mutations.
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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 [74]
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 [15]
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 [15]
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 [357]
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 [14]
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 [76]
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Cellular senescence predicts treatment outcome in metastasised colorectal cancer
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Mitotic catastrophe and cancer drug resistance: A link that must to be broken
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Self-citationRb inactivation leads to E2F1-mediated DNA double-strand break accumulation
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Self-citationIntegrating genetic and gene expression evidence into genome-wide association analysis of gene sets
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“…anti-cancer barriers to limit proliferation in response to, and in the presence of, DNA damage (Norbury and Zhivotovsky, 2004; Bartkova et al., 2005; Gorgoulis et al., 2005; Bartkova et al., 2006; Di Micco et al., 2006; Vousden and Lane, 2007; Sherman et al., 2011; Roos and Kaina, 2013).”
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Self-citation
- Authors
- Gorgoulis, V. G., Vassiliou, L.-V. F., Karakaidos, P., Zacharatos, P., Kotsinas, A., Liloglou, T., Venere, M., DiTullio, R. A., Kastrinakis, N. G., Levy, B., Kletsas, D., Yoneta, A., Herlyn, M., Kittas, C., & Halazonetis, T. D.
- Affiliations
- National and Kapodistrian University of Athens (GR)
- University of Liverpool (GB)
- The Wistar Institute (US)
- Icahn School of Medicine at Mount Sinai (US)
- National Centre of Scientific Research "Demokritos" (GR)
- Corresponding author
- Halazonetis, Thanos D.
- ORCID
- Venue
- Nature
- Published
- 2005-04
- Volume
- 434
- Issue
- 7035
- Pages
- 907-913
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2082559623
- Semantic Scholar
- 862935011d05593c96f9feac523892069a51c87f
- Cited by
- 2,009
- References
- 5
- Citations by year
- 2026: 14 · 2025: 25 · 2024: 29 · 2023: 69 · 2022: 39 · 2021: 87 · 2020: 84 · 2019: 63 · 2018: 91 · 2017: 92 · 2016: 107 · 2015: 107 · 2014: 116 · 2013: 126 · 2012: 133
- FWCI
- 50.75
- 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)
- Edge Hill University Research Information Repository (Edge Hill University) (submittedVersion)
- Funders
- National Institutes of Health
- 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 › Cancer Research › Carcinogens and Genotoxicity Assessment
- Keywords
- DNA damage response, DNA damage checkpoint, genomic instability, precancerous lesions, p53, 53BP1, DNA double-strand breaks, common fragile sites, replication stress, apoptosis, lung hyperplasia, dysplastic nevi, skin xenografts, bladder cancer, breast cancer, colorectal cancer, tumor suppression, histone H2AX, Chk2 phosphorylation
- MeSH terms
- Tumor Suppressor p53-Binding Protein 1, Cell Transformation, Neoplastic, Chromosome Fragility, DNA Damage, DNA Replication, Enzyme Activation, Histones, Humans, Hyperplasia, Mutation, Phosphoproteins, Phosphorylation, Precancerous Conditions, Genes, p53, Tumor Suppressor Protein p53, Apoptosis, Protein Serine-Threonine Kinases, Disease Progression, Allelic Imbalance, Genomic Instability, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, Checkpoint Kinase 2
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