DNA Damage

Abstract

Deoxyribonucleic acid (DNA) encodes the information necessary for all functions of life. Despite the critical importance of DNA, its chemical structure is susceptible to chemical and physical alterations including base damage and single‐ and double‐strand break (DSB) induction. Cellular DNA damage results from both environmental exposures and endogenous sources from normal cellular metabolism. DNA damage in both the nuclear and mitochondrial genomes is associated with several human diseases including the development of cancer. The biological consequences of DNA damage are largely determined by a cell's DNA repair capabilities and the interaction of damaged DNA with the replication and transcription machinery. Technologies exist for the detection and measurement of cellular DNA damage in varying contexts.

Key Concepts

  • Estimated rates of induction of various deoxyribonucleic acid (DNA) lesions, including spontaneous hydrolysis and oxidative DNA damage, have been determined.
  • Potential biological consequences 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 molecular and biochemical methods.
  • Incorporation of damaged deoxyribonucleotides during DNA synthesis can occur due 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 impact how damage is distributed within the genome.
  • Mutational signatures of cancers arise from context‐dependent DNA damage and 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,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 alkylating agents). Source: Adapted from Krwawicz J, Arczewska KD, Speina E, Maciejewska A, Grzesiuk E. 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 Biochim Pol. 2007; 54 (3): 413–434. (b) DNA lesions including abasic sites (primarily produced by spontaneous depurination and depyrimidination), pyrimidine dimers (generated by UV exposure) and cisplatin‐induced intra‐ and interstrand cross‐links.
Figure 3. The number of mutations contributed by each mutational signature to the tumours in the Pan‐Cancer Analysis of Whole Genomes Consortium. The three classes of signatures are single‐base substitution, doublet‐base substitutions and indel (insertion/deletion) signatures. The size of each dot represents the proportion of samples of each tumour type that displays the mutational signature. The colour of each dot represents the median mutation burden of the signature in samples that show the signature. The proposed aetiology of each mutational signature is also displayed. Source: From Alexandrov, L. B., et al. (2020). The repertoire of mutational signatures in human cancer. Nature 578 (7793): 94–101. CC BY 4.0. Public Domain.
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Placentra, Victoria, Limpose, Kristin, Corbett, Anita, and Doetsch, Paul(Jul 2020) DNA Damage. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000557.pub4]