Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2009 Oct 22;461(7267):1071-8.
doi: 10.1038/nature08467.

The DNA-damage response in human biology and disease

Stephen P Jackson  1 , Jiri Bartek
Affiliations
Review

The DNA-damage response in human biology and disease

Stephen P Jackson et al. Nature. .

Abstract

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.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Model for the DDR
The presence of a lesion in the DNA, which can lead to replication stalling, is recognized by various sensor proteins. These sensors initiate signaling pathways that impact a wide variety of cellular processes. See text for details.
Figure 2
Figure 2. Exploitation of the DDR pathways to enhance therapeutic responses
a, Normal cells have two DDR pathways, A and B. If one pathway (B) is eliminated, genome instability results, which can foster the evolution of a cancer cell. Addition of a inhibitor targeting the second pathway (A) leads to cell death. Normal cells that still retain an active B pathway, however, survive. b, Treatment with a PARP inhibitor selectively kills HR/BRCA-deficient cells. PARP inhibition impairs the repair of SSBs, which are converted to DSBs in S-phase. Such DSBs are effectively repaired by HR in non-cancerous cells but not in BRCA-deficient cells.
Figure 2
Figure 2. Exploitation of the DDR pathways to enhance therapeutic responses
a, Normal cells have two DDR pathways, A and B. If one pathway (B) is eliminated, genome instability results, which can foster the evolution of a cancer cell. Addition of a inhibitor targeting the second pathway (A) leads to cell death. Normal cells that still retain an active B pathway, however, survive. b, Treatment with a PARP inhibitor selectively kills HR/BRCA-deficient cells. PARP inhibition impairs the repair of SSBs, which are converted to DSBs in S-phase. Such DSBs are effectively repaired by HR in non-cancerous cells but not in BRCA-deficient cells.
See this image and copyright information in PMC

References

    1. Lindahl T, Barnes DE. Repair of endogenous DNA damage. Cold Spring Harb Symp Quant Biol. 2000;65:127–133. An excellent overview of the extent of endogenous DNA damage, the types of DNA lesions arising from cell autonomous sources, and the pathways that repair such lesions. - PubMed
    1. Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact. 2006;160:1–40. - PubMed
    1. Kawanishi S, Hiraku Y, Pinlaor S, Ma N. Oxidative and nitrative DNA damage in animals and patients with inflammatory diseases in relation to inflammation-related carcinogenesis. Biol Chem. 2006;387:365–372. - PubMed
    1. Khanna KK, Jackson SP. DNA double-trand breaks: signaling, repair and the cancer connection. Nat. Genet. 2001;27:247–254. - PubMed
    1. Ward JF. DNA damage produced by ionizing radiation in mammalian cells: identities, mechanisms of formation, and reparability. Prog Nucleic Acid Res Mol Biol. 1988;35:95–125. - PubMed

Publication types