The sites on each nucleotide modified by spontaneous oxidative damage (red arrows), hydrolytic attack (blue arrows), and methylation (green arrows) are shown, with the width of each arrow indicating the relative frequency of each event (see  Table 5–3). (After T. Lindahl, Nature 362:709–715, 1993. With permission from Macmillan Publishers Ltd.) human cell loses about 18,000 purine bases (adenine and guanine) every day because their N-glycosyl linkages to deoxyribose hydrolyze, a spontaneous reaction called depurination. Similarly, a spontaneous deamination of cytosine to uracil in DNA occurs at a rate of about 100 bases per cell per day (Figure 5–38). DNA bases are also occasionally damaged by an encounter with reactive metabolites produced in the cell, including reactive forms of oxygen and the high-energy methyl donor S-adenosylmethionine, or by exposure to chemicals in the environment. Likewise, ultraviolet radiation from the sun can produce a covalent linkage between two adjacent pyrimidine bases in DNA to form, for example, thymine dimers (Figure 5–39). If left uncorrected when the DNA is replicated, most of these changes would be expected to lead either to the deletion of one or more base pairs or to a base-pair substitution in the daughter DNA chain (Figure 5–40). The mutations would then be propagated throughout subsequent cell generations. Such a high rate of random changes in the DNA sequence would have disastrous consequences.
The DNA Double Helix Is Readily Repaired
The double-helical structure of DNA is ideally suited for repair because it carries two separate copies of all the genetic information—one in each of its two strands. Thus, when one strand is damaged, the complementary strand retains an intact copy of the same information, and this copy is generally used to restore the correct nucleotide sequences to the damaged strand.
An indication of the importance of a double-strand helix to the safe storage of genetic information is that all cells use it; only a few small viruses use single-strand DNA or RNA as their genetic material. The types of repair processes described in this section cannot operate on such nucleic acids, and once damaged, the chance of a permanent nucleotide change occurring in these single-strand genomes of viruses is thus very high. It seems that only organisms with tiny genomes (and therefore tiny targets for DNA damage) can afford to encode their genetic information in any molecule other than a DNA double helix.
Figure 5–38 Depurination and deamination. These reactions are two of the most frequent spontaneous chemical reactions that create serious DNA damage in cells. Depurination can release guanine (shown here), as well as adenine, from DNA. The major type of deamination reaction converts cytosine to an altered DNA base, uracil (shown here), but deamination occurs on other bases as well. These reactions normally take place in double-helical DNA; for convenience, only one strand is shown.
Figure 5–39 The most common type of thymine dimer. This type of damage occurs in the DNA of cells exposed to ultraviolet irradiation (as in sunlight). A similar dimer will form between any two neighboring pyrimidine bases (C or T residues) in DNA.
Cells have multiple pathways to repair their DNA using different enzymes that act upon different kinds of lesions. Figure 5–41 shows two of the most common pathways. In both, the damage is excised, the original DNA sequence is restored by a DNA polymerase that uses the undamaged strand as its template, and a remaining break in the double helix is sealed by DNA ligase (see Figure 5–12).