DNA Damage

Abstract

Deoxyribonucleic acid (DNA) is composed of bases that code for all functions of life. Biochemical and physical events that alter DNA include base damage and single‐ and double‐strand break (DSB) induction. Cellular DNA damage is induced through exposure to environmental chemicals and radiation, as well as from endogenous sources including normal cellular metabolism. Notably, DNA damage can occur in both the nuclear and mitochondrial genomes. Damaged DNA can lead to deleterious biological outcomes including cancer development and other diseases. Whether biological consequences arise from DNA damage largely depends on the DNA repair capacity of the cell and the interactions of the DNA damage and DNA replication machinery. Detection and measurement of cellular DNA damage is accomplished through methods that vary in sensitivity and DNA damage context.

Key Concepts:

  • Estimated rates of induction of various deoxyribonucleic acid (DNA) lesions, including spontaneous hydrolysis and oxidative DNA damage, have been determined.

  • Potential biological outcomes of DNA damage include physiological conditions such as cancer, neurodegenerative diseases, heart disease and ageing.

  • Various exogenous and endogenous sources induce DNA base lesions and strand breaks that can be detected by various molecular and biochemical methods.

  • Incorporation of damaged deoxyribonucleotides during DNA synthesis can occur owing to errors committed by DNA polymerases and/or disruptions of nucleotide pool balance.

  • Many of the features resulting from DNA packing into chromatin, including DNA–protein interactions and sequence context, greatly affect the manner in which damage is distributed within the genome.

  • Cancer mutational signatures arise from context‐dependent DNA damage, and certain signatures can be attributed to specific types of DNA damage.

  • DNA is often the target of chemotherapeutic drugs used to treat cancer, resulting in tumour cell death.

  • Mitochondrial DNA damage can increase reactive oxygen species, leading to cell death, and in certain instances give rise to mutations that contribute to cancer phenotypes.

Keywords: DNA damage; DNA repair; mutation; cancer; mitochondria; nucleus

Figure 1.

Sites of chemical modification on DNA. The base (A, T, G, or C), deoxyribose and phosphate building block components of DNA are vulnerable to attack by numerous exogenous and endogenous agents. Important examples of DNA modifications at various positions caused by spontaneous hydrolysis (open arrows), particularly at the N‐glycosidic bond of G (I) to generate an abasic site or at the exocyclic amino group of U to form U (II). Other examples include radical attack by reactive oxygen species (ROS) at several positions (closed arrows) on the deoxyribose and bases such as C‐8 of G to produce 8‐oxoguanine (III). DNA contains many nucleophilic centres (stars) that are attractive sites for chemical reactions with exogenous and endogenous electrophilic chemicals such as alkylating agents. One example of an important mutagenic base modification is alkylation at the O6 position of G (IV).

Figure 2.

Representative DNA damage products. (a) The major endogenous DNA damages are depicted with alterations highlighted in red. Important examples shown here are uracil (from cytosine deamination), cyclobutane pyrimidine dimer (produced by UV light exposure), 8‐oxoguanine (produced by reactive oxygen species) and O6‐methylguanine (produced by alkyating agents). Reproduced with permission from Krwawicz et al., . © Acta Biochimica Polonica. (b) DNA lesions including abasic site (primarily produced by spontaneous depurination and depyrimidination), pyrimidine dimers (generated by UV exposure) and cisplatin‐induced intrastrand and interstrand cross‐links.

Figure 3.

Kataegis and hypermutation of base substitutions in breast cancer. (a) Rainfall plot of a sample PD4107a. Mutations are arranged starting with the short arm of chromosome 1 to the long arm of chromosome X. Each mutation type is colour coded according to the inset. The vertical axis describes the distance between mutations on a log scale. A ‘mutational storm’ is seen in red as represented by a dense cluster of mutations with short intermutational distance at one genomic location. (b) Rainfall plot of a sample PD4103a shows regions of kataegis at multiple locations throughout the genome, termed ‘mutational showers’. Reproduced with permission from Nik‐Zainal et al., . © Cell Press (Elsevier).

close

References

Aboussekhra A and Thoma F (1999) TATA‐binding protein promotes the selective formation of UV‐induced (6‐4)‐photoproducts and modulates DNA repair in the TATA box. EMBO Journal 18: 433–443.

Agar NS, Halliday GM, Barnetson RS et al. (2004) The basal layer in human squamous tumors harbors more UVA than UVB fingerprint mutations: a role for UVA in human skin carcinogenesis. Proceedings of the National Academy of Sciences USA 101: 4954–4959.

Alexandrov LB, Nik‐Zainal S, Wedge DC et al. 2013 Signatures of mutational processes in human cancer. Nature 500: 415–421.

Anders M and Dekant W (1994) Conjugation‐dependent carcinogenicity and toxicity of foreign compounds. Advances in Pharmacology 27: 1–519.

Babior BM (1984) The respiratory burst of phagocytes. Journal of Clinical Investigation 73: 599–601.

Beckman KB and Ames BN (1997) Oxidative decay of DNA. Journal of Biological Chemistry 272: 19633–19636.

Boiteux S and Guillet M (2004) Abasic sites in DNA: repair and biological consequences in Saccharomyces cerevisiae. DNA Repair (Amst) 3: 1–12.

Boiteux S, Huisman O and Laval J (1984) 3‐Methyladenine residues in DNA induce the SOS function sfiA in Escherichia coli. EMBO Journal 3: 2569–2573.

Brand MD (1990) The proton leak across the mitochondrial inner membrane. Biochimica et Biophysica Acta 1018: 128–133.

Chiou CC, Chang PY, Chan EC et al. (2003) Urinary 8‐hydroxydeoxyguanosine and its analogs as DNA marker of oxidative stress: development of an ELISA and measurement in both bladder and prostate cancers. Clinica Chimica Acta 334: 87–94.

Cooke MS, Evans MD, Dizdaroglu M and Lunec J (2003a) Oxidative DNA damage: mechanisms, mutation, and disease. FASEB Journal 17: 1195–1214.

Cooke MS, Podmore ID, Mistry N et al. (2003b). Immunochemical detection of UV‐induced DNA damage and repair. Journal of Immunological Methods 280: 125–133.

Cosman M, De Los Santos C, Fiala R et al. (1992) Solution conformation of the major adduct between the carcinogen (+)‐anti‐benzo[a]pyrene diol epoxide and DNA. Proceedings of the National Academy of Sciences USA 89: 1914–1918.

Crutzen PJ and Andreae MO (1990) Biomass burning in the tropics: impact on atmospheric chemistry and biogeochemical cycles. Science 250: 1669–1678.

Davies NP, Hardman LC and Murray V (2000) The effect of chromatin structure on cisplatin damage in intact human cells. Nucleic Acids Research 28: 2954–2958.

Di Tomaso MV, Martinez‐Lopez W, Folle GA and Palitti F (2006) Modulation of chromosome damage localization by DNA replication timing. International Journal of Radiation Biology 82: 877–886.

Enright HU, Miller WJ and Hebbel RP (1992) Nucleosomal histone protein protects DNA from iron‐mediated damage. Nucleic Acids Research 20: 3341–3346.

Fahl WE, Lalwani ND, Watanabe T, Goel SK and Reddy JK (1984) DNA damage related to increased hydrogen peroxide generation by hypolipidemic drug‐induced liver peroxisomes. Proceedings of the National Academy of Sciences of the USA 81: 7827–7830.

Friedberg EC, Walker GC, Siede W et al. (2006) DNA Repair and Mutagenesis. Wasgington, DC: ASM Press.

Galea AM and Murray V (2002) The interaction of cisplatin and analogues with DNA in reconstituted chromatin. Biochimica et Biophysica Acta 1579: 142–152.

Ghosh R, Paniker L and Mitchell DL (2001) Bound transcription factor suppresses photoproduct formation in the NF‐kappa B promoter. Photochemistry and Photobiology 73: 1–5.

de Gruijl FR and Forbes PD (1995) UV‐induced skin cancer in a hairless mouse model. BioEssays 17: 651–660.

Hartmann A, Agurell E, Beevers C et al. (2003) Recommendations for conducting the in vivo alkaline Comet assay. 4th International Comet Assay Workshop. Mutagenesis 18: 45–51.

Ise T, Nagatani G, Imamura T et al. (1999) Transcription factor Y‐box binding protein 1 binds preferentially to cisplatin‐modified DNA and interacts with proliferating cell nuclear antigen. Cancer Research 59: 342–346.

Ishikawa K, Takenaga K, Akimoto M et al. (2008) ROS‐generating mitochondrial DNA mutations can regulate tumor cell metastasis. Science 320: 661–664.

Kraemer KH (1994) Nucleotide excision repair genes involved in xeroderma pigmentosum. Japanese Journal of Cancer Research 85: inside front cover.

Krwawicz J, Arczewska KD, Speina E, Maciejewska A and Grzesiuk E (2007) Bacterial DNA repair genes and their eukaryotic homologues: 1. Mutations in genes involved in base excision repair (BER) and DNA‐end processors and their implication in mutagenesis and human disease. Acta Biochimica Polonica 54: 413–434.

Lambeth JD (2004) NOX enzymes and the biology of reactive oxygen. Nature Reviews Immunology 4: 181–189.

Lawley PD (1966) Effects of some chemical mutagens and carcinogens on nucleic acids. Progress in Nucleic Acid Research and Molecular Biology 5: 89–131.

Lee HC and Wei YH (2012) Mitochondria and aging. Advances in Experimental Medicine and Biology 942: 311–327.

Lindahl T (1979) DNA glycosylases, endonucleases for apurinic/apyrimidinic sites, and base excision‐repair. Progress in Nucleic Acid Research and Molecular Biology 22: 135–192.

Lindahl T (1993) Instability and decay of the primary structure of DNA. Nature 362: 709–715.

Lindahl T and Karlstrom O (1973) Heat‐induced depyrimidination of deoxyribonucleic acid in neutral solution. Biochemistry 12: 5151–5154.

Loeb LA and Preston BD (1986) Mutagenesis by apurinic/apyrimidinic sites. Annual Review of Genetics 20: 201–230.

Mak WB and Fix D (2008) DNA sequence context affects UV‐induced mutagenesis in Escherichia coli. Mutatation Research 638: 154–161.

Martinez‐Lopez W, Boccardo EM, Folle GA, Porro V and Obe G (1998) Intrachromosomal localization of aberration breakpoints induced by neutrons and gamma rays in Chinese hamster ovary cells. Radiation Research 150: 585–592.

Marullo R, Werner E, Degtyareva N et al. (2013) Cisplatin induces a mitochondrial‐ROS response that contributes to cytotoxicity depending on mitochondrial redox status and bioenergetic functions. PLoS One 8: e81162.

Mathews CK (2006) DNA precursor metabolism and genomic stability. FASEB Journal 20: 1300–1314.

Nicholls DG (1974) The influence of respiration and ATP hydrolysis on the proton‐electrochemical gradient across the inner membrane of rat‐liver mitochondria as determined by ion distribution. European Journal of Biochemistry 50: 305–315.

Nik‐Zainal S, Alexandrov LB, Wedge DC et al. (2012) Mutational processes molding the genomes of 21 breast cancers. Cell 149: 979–993.

Rogakou EP, Pilch DR, Orr AH, Ivanova VS and Bonner WM (1998) DNA double‐stranded breaks induce histone H2AX phosphorylation on serine 139. Journal of Biological Chemistry 273: 5858–5868.

Saxowsky TT and Doetsch PW (2006) RNA polymerase encounters with DNA damage: transcription‐coupled repair or transcriptional mutagenesis? Chemical Reviews 106: 474–488.

Shen JC, RideoutWM III and Jones PA (1994) The rate of hydrolytic deamination of 5‐methylcytosine in double‐stranded DNA. Nucleic Acids Research 22: 972–976.

Singh R and Farmer PB (2006) Liquid chromatography‐electrospray ionization‐mass spectrometry: the future of DNA adduct detection. Carcinogenesis 27: 178–196.

Snow ET, Foote RS and Mitra S (1984) Base‐pairing properties of O6‐methylguanine in template DNA during in vitro DNA replication. Journal of Biological Chemistry 259: 8095–8100.

Sutherland BM, Bennett PV and Sutherland JC (2005). Methods in Molecular Biology. Totowa: Humana Press Inc.

Valko M, Leibfritz D, Moncol J et al. (2007) Free radicals and antioxidants in normal physiological functions and human disease. International Journal of Biochemistry & Cell Biology 39: 44–84.

Wheeler LJ, Rajagopal I and Mathews CK (2005) Stimulation of mutagenesis by proportional deoxyribonucleoside triphosphate accumulation in Escherichia coli. DNA Repair (Amst) 4: 1450–1456.

Wheeler MD (2003) Endotoxin and Kupffer cell activation in alcoholic liver disease. Alcohol Research & Health 27: 300–306.

You YH, Li C and Pfeifer GP (1999) Involvement of 5‐methylcytosine in sunlight‐induced mutagenesis. Journal of Molecular Biology 293: 493–503.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Limpose, Kristin, Corbett, Anita H, and Doetsch, Paul W(Sep 2014) DNA Damage. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000557.pub3]