DNA Damage


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).



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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]