The DNA-damage response in human biology and disease
Open accessAbstract
The prime objective for every life form is to deliver its genetic material, intact and unchanged, to the next generation. This must be achieved despite constant assaults by endogenous and environmental agents on the DNA. To counter this threat, life has evolved several systems to detect DNA damage, signal its presence and mediate its repair. Such responses, which have an impact on a wide range of cellular events, are biologically significant because they prevent diverse human diseases. Our improving understanding of DNA-damage responses is providing new avenues for disease management.
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These DNA damage response foci mark individual damage sites and help enforce checkpoint arrest until damage is repaired.
“These foci mark individual sites of DNA damage and contribute to checkpoint enforcement and cell cycle arrest, until damage has been repaired”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [21]
In “DNA-damage signaling and cell-cycle checkpoints” (page unavailable), the paper describes DDR factors recruited at double-strand-break sites and signaling that slows or arrests the cell cycle to allow repair. It also says normal cell functioning resumes after effective repair. Our copy does not establish that the foci themselves mark individual damage sites or enforce the checkpoint. (LLM, conf=0.83)
Experimental — accuracy not yet measuredSome DNA damage response factors accumulate at damage sites and form nuclear foci containing H2AX phosphorylation and associated proteins such as MDC1, 53BP1 and activated ATM.
“Some DDR factors accumulate at sites of DNA damage and form cytologically detectable nuclear foci composed of extended chromatin modification events, such as the phosphorylation of histone H2AX, and the proteins associated with them, including MDC1, 53BP1 and the activated form of the kinase ataxia telangiectasia mutated (ATM)21”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [21]
The DNA-damage signaling and cell-cycle checkpoints section (page unavailable) describes H2AX phosphorylation on chromatin flanking double-strand breaks, recruitment of DDR factors, and ATM recruitment and activation at breaks. It does not identify MDC1 or 53BP1 among those factors or state that they form cytologically detectable nuclear foci with activated ATM. (LLM, conf=0.85)
Experimental — accuracy not yet measuredTwo variants of canonical NHEJ exist, Ku-independent MMEJ and AEJ, and their activity is connected with sequence deletions.
“Two variants of canonical NHEJ pathway exist—Ku-independent NHEJ pathway microhomology-mediated end-joining (MMEJ) and alternative end-joining (AEJ)—but their activity is connected with sequence deletions [4].”
From Focus on UV-Induced DNA Damage and Repair—Disease Relevance and Protective Strategies (2020) · cites this paper as [4]
The DNA damage response pathway is important for keeping the genome stable and preventing cancer.
“The DNA damage response (DDR) pathway plays a critical role in maintaining genomic stability and preventing carcinogenesis [1].”
From NER initiation factors, DDB2 and XPC, regulate UV radiation response by recruiting ATR and ATM kinases to DNA damage sites (2013) · cites this paper as [1]
Defects in DSB repair can cause cell cycle arrest, apoptosis or genomic aberrations and have been linked to disease progression and premature aging phenotypes.
“Defects in DSB repair can result in cell cycle arrest, apoptosis or genomic aberrations and have been linked to both disease progression and a premature onset of aging phenotypes (2,3).”
From Controlled DNA double-strand break induction in mice reveals post-damage transcriptome stability (2016) · cites this paper as [2]
DNA damage response pathways are conserved surveillance mechanisms that coordinate DNA repair, cell cycle progression, transcription, apoptosis, and senescence.
“To maintain genome stability, the DDR pathways are conserved surveillance mechanisms coordinating DNA repair, cell cycle progression, transcription, apoptosis, and senescence [19, 39–41].”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [39]
Activation of the DDR in response to DNA damage is essential for the maintenance of genome integrity.
“Activation of the DDR in response to DNA damage is essential for the maintenance of genome integrity [67].”
From Early onset senescence and cognitive impairment in a murine model of repeated mTBI (2021) · cites this paper as [67]
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- Authors
- Jackson, S. P., & Bartek, J.
- Affiliations
- University of Cambridge (GB)
- Corresponding author
- Jackson, Stephen P.
- ORCID
- Jackson, Stephen P.
- Venue
- Nature
- Published
- 2009-10-22
- Volume
- 461
- Issue
- 7267
- Pages
- 1071-1078
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2906700
- OpenAlex
- W2145200068
- Cited by
- 6,092
- References
- 106
- Citations by year
- 2026: 344 · 2025: 369 · 2024: 417 · 2023: 469 · 2022: 489 · 2021: 511 · 2020: 448 · 2019: 416 · 2018: 344 · 2017: 402 · 2016: 381 · 2015: 338 · 2014: 310 · 2013: 279 · 2012: 241
- FWCI
- 14.66
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- National Foundation for Cancer Research
- Wellcome Trust
- Cancer Research UK (A5290)
- European Commission
- Danmarks Grundforskningsfond
- Dansk Kræftforsknings Fond
- Biotechnology and Biological Sciences Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- DNA damage response, DNA repair, DNA damage detection, ionizing radiation, environmental chemicals, endogenous DNA damage, signal transduction, disease prevention, genotoxicity
- MeSH terms
- Cell Cycle, Disease, DNA Damage, DNA Repair, Humans, Signal Transduction, Genome, Human
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