Mutagen

There are many hundreds of known chemical mutagens. Some resemble the bases found in normal DNA; others alter the structures of existing bases; others insert themselves in the helix between bases; while others work indirectly, creating reactive compounds that directly damage the DNA structure.

"Base analogs" are molecules whose chemical structure is similar to one of the four DNA bases (adenine, thymine, cytosine, and guanine). Because of this similarity, they can be incorporated into the helix during DNA replication. A key feature of mutagenic base analogs is that they form base pairs with more than one other base. This can cause mutations during the next round of replication, when the replication machinery tries to pair a new base with the incorporated mutagen. For instance, 5-bromo-deoxyuridine (5BU) exists in two different forms. One mimics thymine and therefore pairs with adenine during replication, while the other mimics cytosine and therefore pairs with guanine. In its thymine-mimicking form, 5BU can be incorporated across from an adenine. If it then converts to its cytosine-like form, during the next round of replication, it will cause a gua-nine to enter the opposite strand, rather than the correct adenine.

The mutagen 5 bromodeoxyuridine exists in two forms, one of which pairs with adenine, and the other of which pairs with guanine. Adapted from <http://fig.cox.miami.edu/Faculty/Dana/baseanalog.jpg>.

"Base-altering mutagens" cause chemical changes in bases that are part of the DNA. For example, nitrite preservatives in food convert to the mutagen nitrous acid. Nitrous acid causes deamination, or loss of an-NH₂ group, of cytosine. When this occurs, cytosine becomes uracil, a base that is not normally incorporated in DNA but that is very similar to thymine. Unless repaired, this uracil will cause an adenine to enter the opposite strand instead of a guanine. Many base-altering mutagens are complex organic molecules. These are formed in large quantities in smoke, making up the "tar" of cigarette smoke, for example. They act as alkylating agents, combining with DNA to form bulky groups that interrupt replication.

"Intercalating agents" are flat molecules that insert themselves between adjacent bases in the double helix, distorting the shape at the point of insertion. Where this occurs, DNA polymerase may add an additional base opposite the intercalating agent. If this occurs in a gene, it induces a frameshift mutation (that is, it alters the reading of the gene transcript, changing which amino acids are added to the encoded protein). Ethidium bromide is one such agent, widely used in DNA research because its dark color allows DNA to be easily visualized. This is useful in gel electrophoresis, for instance, to find the DNA bands that have been separated in a gel.

Other damaging agents include chemicals that create "free radicals" inside a cell. Free radicals are compounds in which an atom, usually an oxygen, has an unbonded electron. Free radicals are highly reactive and can cause several types of damage to DNA.