Chemical and Radiation Damage to DNA Can Lead to Mutations

DNA is continually subjected to a barrage of damaging chemical reactions; estimates of the number of DNA damage events in a single human cell range from 104 to 106 per day! Even if DNA were not exposed to damaging chemicals, certain aspects of DNA structure are inherently unstable. For example, the bond connecting a purine base to deoxyribose is prone to hydrolysis at a low rate under physiological conditions, leaving a sugar without an attached base. Thus coding information is lost, and this loss can lead to a mutation during DNA replication. Normal cellular reactions, including the movement of electrons along the electron-transport chain in mitochondria and lipid oxidation in peroxisomes (see Chapter 12), produce several chemicals that react with and damage DNA, including hydroxyl radicals and superoxide (O2). These chemicals can also cause mutations, including mutations that lead to cancers.

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Many spontaneous mutations are point mutations, which involve a change in a single base pair in the DNA sequence. A point mutation can introduce a stop codon, causing a nonsense mutation as discussed earlier, or a change in the amino acid sequence of an encoded protein, called a missense mutation. Silent mutations do not change the amino acid sequence (e.g., GAG to GAA; both encode glutamine). Point mutations can also occur in non-protein-coding DNA sequences that function in the regulation of a gene’s transcription, as discussed in Chapter 9. One of the most frequent causes of point mutations is deamination of a cytosine (C) base, which converts it into a uracil (U) base. Another is deamination of the common modified base 5-methyl cytosine, which forms thymine when it is deaminated. If these alterations are not corrected before the DNA is replicated, the cell will use the strand containing U or T as a template to form a U·A or T·A base pair, thus creating a permanent change in the DNA sequence (Figure 5-34).

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FIGURE 5-34 Deamination leads to point mutations. A spontaneous point mutation can be caused by deamination of 5-methylcytosine (C) to form thymine (T). If the resulting T·G base pair is not restored to the normal C·G base pair by base excision-repair mechanisms 1, it will lead to a permanent change in sequence (i.e., a mutation) following DNA replication 2. After one round of replication, one daughter DNA molecule will have the mutant T·A base pair and the other will have the wild-type C·G base pair.