Mutagenic agents increase the rate of mutations

In the early part of the 20th century, the existence of mutations was appreciated, but attempts to gain a fuller understanding of them were hampered by the fact that they occurred so rarely. In the 1920s, however, it was shown that the mutation rate in both barley plants and the fruit fly Drosophila was greatly increased as a result of exposure to X-rays. In the following decades, a number of chemical and physical agents were shown also to cause mutations. Mutagens such as these raise the general level of mutations in a population, rather than the incidence of mutation in at particular location in the genome. They are extremely useful tools for the microbial geneticist, but need to be treated with great care because they are also mutagenic (and in most cases carcinogenic) towards humans.

Chemical mutagens can be divided into five classes:

Base analogues

A base analogue is able to 'mimic' one of the four normal DNA bases by having a chemical structure sufficiently similar for it to be incorporated into a DNA molecule instead of that base during replication. One such base is 5-bromouracil (5-BU); in its usual keto form, it acts like thymine (which it closely resembles - see Figure 11.20), and therefore pairs with adenine, and is not mutagenic. However 5-BU is capable of tau-tomerising to the enol form, which, remember, pairs with G, not A. Whereas for thymine the enol form is a rarity, for 5-BU it is more common, hence mispairing with guanine occurs more frequently. So, we get the same outcome as with spontaneous mutation -the TA has been replaced by a CG - but its frequency is much increased. Several other base analogues, such as 2-aminopurine, which mimics adenine, have similar effects to 5-BU. Mutations brought about by base analogues all result in a purine being replaced by another purine, or a pyrimidine being replaced by another pyrimidine; this type of mutation is called a transition.

Alkylating agents

As the name suggests, this group of mutagens act by adding an alkyl group (e.g. methyl, ethyl) at various positions on DNA bases. Ethylethanesulphonate (EES) and ethyl-methanesulphonate (EMS) are alkylating agents, used as laboratory mutagens. They act by alkylating guanine or thymine at the oxygen atom involved in hydrogen bonding. This leads to an impairment of the normal base-pairing properties, and causes guanine for example to mispair with thymine.

Substitutions brought about by alkylating agents can be either transitions or transversions.

Deaminating agents

Nitrous acid is a potent mutagen, which alters the base-pairing affinities of cytosine and adenine by replacing an amino group with an oxygen atom. Transitions occur in both directions, AT ^ GC and GC ^ AT. Note that although guanine is deaminated, its base pairing properties are not affected.

Intercalating agents

These mutagens exert their effect by inserting themselves between adjacent nucleotides in a single strand of DNA. They distort the strand at this site and cause either the addition or, less commonly, deletion of a nucleotide. This leads to frameshift mutations, and often

Chemical or physical agents capable of inducing mutations are termed mutagens.

Figure 11.20 Base analogues mimic DNA base structure. In its keto form, the base analogue 5-bromouracil (5-BU) forms base pairs with adenine, but in the enol form it mispairs with guanine. 5-BU differs from thymine only in the substitution of a bromine atom in place of a methyl group. This makes the occurrence of a tautomeric shift more likely

Figure 11.20 Base analogues mimic DNA base structure. In its keto form, the base analogue 5-bromouracil (5-BU) forms base pairs with adenine, but in the enol form it mispairs with guanine. 5-BU differs from thymine only in the substitution of a bromine atom in place of a methyl group. This makes the occurrence of a tautomeric shift more likely during replication the bound mutagen interferes with new strand synthesis, leading to a gross deletion of nucleotides. Ethidium bromide, commonly used for the visualisation of small amounts of DNA in the molecular biology laboratory, is an intercalating agent; it has a planar structure with roughly the same dimensions as a purine-pyrimidine pairing.

Hydroxylating agents

Hydroxylamine has a specific mutagenic effect, hydroxylating the amino group of cy-tosine to cause the transition of GC ^ AT.

Base analogues and certain intercalating agents can only exert their mutagenic effects if they are incorporated into DNA while it is replicating. Others, which depend on altering base pairing by modifying the structure of DNA bases, are effective on both replicating and non-replicating DNA.

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Figure 11.21 Thymine dimer formation. Absorption of UV light results in the formation of dimers between adjacent thymine residues in the same strand. This can lead to errors being introduced into the DNA sequence. From Gardner, EJ, Simmons MJ and Snustad, DP: Principles of Genetics, 8th edn, John Wiley & Sons Inc., 1991. Reproduced by permission of the publishers.

Figure 11.21 Thymine dimer formation. Absorption of UV light results in the formation of dimers between adjacent thymine residues in the same strand. This can lead to errors being introduced into the DNA sequence. From Gardner, EJ, Simmons MJ and Snustad, DP: Principles of Genetics, 8th edn, John Wiley & Sons Inc., 1991. Reproduced by permission of the publishers.

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