Any chemical treatment that alters the hydrogen-bonding properties of a purine or pyrimidine base already in the DNA will increase the frequency of mutations as the DNA replicates.
One powerful mutagen that modifies purines and pyrimidines in DNA is nitrous acid (HNO2). This chemical primarily converts amino (—NH2) to keto (C=O) groups—for example, converting cytosine to uracil. Uracil then pairs with adenine rather than guanine when the DNA is replicated. ■ purines and pyrimidines, p. 32
The largest group of chemical mutagens consists of alkylating agents, highly reactive chemicals that add alkyl groups, short chains of carbon atoms, onto purines and pyrimidines, thereby altering their hydrogen-bonding properties. A common alkylating agent used in research laboratories is nitrosoguanidine. Many compounds formerly used in cancer therapy, such as nitrogen mustard, are in this group. These compounds kill rapidly dividing cancer cells, but they also damage DNA in normal cells. As a result, these agents have caused cancers to arise more than 10 years after they were used to treat the original cancer.
Base analogs are compounds that resemble the purine or pyrimidine bases closely enough that they are incorporated into DNA in place of the natural bases during DNA replication (figure 8.4). Base analogs such as 5-bromouracil and 2-amino purine, however, do not have the same hydrogen-bonding properties as the natural bases, thymine and adenine respectively. This difference increases the probability that, once incorporated into DNA, the base analog will pair with the wrong base as the complementary strand is being synthesized.
Certain base analogs are also useful in treating diseases because of their ability to inhibit DNA replication. For example, azidothymidine (AZT), an analog of thymidine, inhibits replication of the human immunodeficiency virus (HIV) and is used in treating HIV-infected people. The analog does not have an —OH on the third carbon of deoxyribose and therefore the elongation of the DNA chain cannot proceed. Note that the sugar deoxyribose and not the base thymine is modified in this base analog. ■ AZT, p. 750 ■ DNA replication, p. 170
A number of chemical mutagens, termed intercalating agents, are three-ringed planar molecules of about the same size as a pair of nucleotides in DNA. These molecules do not alter hydrogen-bonding properties of the bases; rather, they insert or intercalate between adjacent base pairs in the replication fork in DNA synthesis. This pushes the nucleotides apart, producing enough space between bases that an extra nucleotide often is added in the
strand being synthesized. The result is a frameshift mutation. Less frequently, the intercalation results in a newly synthesized strand that lacks a nucleotide. As in spontaneous frameshift mutants, the addition or subtraction of a nucleotide often results in a stop codon being generated prematurely, and a shortened protein being synthesized. An intercalating agent commonly used in the laboratory to isolate plasmids is ethidium bromide. The manufacturer now warns users that ethidium bromide should be used with great care because it likely is a carcinogen, a cancer-causing agent. ■ replication fork, p. 172 ■ stop codon, p. 177
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