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Figure 6 Diagram of possible chromosomal mutations. (a) Undamaged chromosome; (b) chromosome with break, (c) terminal deletion of positions 10-12; (d) translocation of a section containing positions 13-15 from another chromosome,

(e) insertion of section 13-15 in between positions 9 and 10;

(f) inversion of section from positions 4-10; (g) internal deletion of section 6-7, which contains the centromere.

breaks in two different chromosomes, they may exchange the ends distal to the breaks, a process known as translocation (Figure 6d). In some cases, a piece of a chromosome may be inserted in the interior of a different chromosome, a process known as insertion (Figure 6e). If there are two or more breaks in the same chromosome, a number of things can also happen. For example, an inversion may take place, where the piece of chromosome between the two breaks is 'flipped' (Figure 6f; this takes place between positions 4 and 10). Such double breaks may also result in an internal deletion. As illustrated in Figure 6g, if the breaks are on either side of the centromere, this may result in an acentromeric chromosome (a chromosome without a centromere). This could result in loss of an entire chromosome during cell division. The loss of an entire chromosome is called aneuploidy. Unfortunately, once formed, there is no way for a cell to repair chromosomal mutations.

Formation of Mutations Spontaneous mutations

Mutations can be formed either endogenously or as a consequence of exposure to mutagenic agents. One type of endogenous mutations is spontaneous mutations, which may occur as a result of errors during DNA replication, for example, when a G is paired with a T instead of a C. This results in a mismatch. There are several types of enzymes, called mismatch repair enzymes, which can correct such mistakes. However, sometimes this mistake is not repaired and this results in a mutation. Strand breaks and abasic sites can also form spontaneously, for example, due to thermal energy arising from the heat produced by cellular metabolism or due to the inherent instability in the chemical bonds. Other types of spontaneous DNA damage include loss of amino groups on the bases or rearrangements in the chemical structure within the bases. Finally, endogenous mutations may occur as a result of endogenous DNA damage caused by ROSs formed by routine oxidative metabolism. Spontaneous and endogenous DNA damage may lead to mutations in mechanisms similar to mutagen-induced DNA damage, as discussed below.

Chemically induced mutations

Although they occur naturally, the occurrence of spontaneous mutations may be accelerated by chemical exposure. For example, the more rapidly a cell divides the greater the chance of a spontaneous mutation. Some chemicals increase the rate of cell division in some tissues (this is called cell proliferation), and thus the probability that a spontaneous mutation will occur. In addition, inhibition of DNA repair by arsenic, cadmium, or other metals may lead to increased incidence of spontaneous mutations, because of the reduced rate of removal of mismatches and endogenous DNA damage. Also, exposure to genotoxic agents may lead to mutations in the mismatch repair or other repair genes, leading to decreased rates of repair.

Mutations can also be induced by exposure to muta-genic compounds, which certainly applies to point mutations. Point mutations can be induced when damaged DNA is repaired or undergoes replication. DNA repair can lead to mutations because most types of DNA repair require DNA synthesis as an essential step, and the DNA polymerases involved in DNA repair are more prone to make errors than the polymerases involved in replicative DNA synthesis (S phase synthesis). The polymerases involved in homologous recombination are also more error-prone than those involved in DNA replication. During replication, DNA polymerases may also make a mistake if there is a damaged base. Such damaged bases may 'miscode'; for example, an A may be inserted instead of a C opposite an oxidized G, and a T may be inserted opposite a methylated G during DNA synthesis. If the replication enzymes encounter an abasic site, there is no information to determine which nucleotide should be inserted, so A's are inserted preferentially opposite an abasic site. If the replication enzymes encounter a bulky lesion, replication may be arrested, and a new set of enzymes may be recruited to carry out translesion synthesis. In this type of synthesis, DNA is replicated past the lesion by so-called error-prone polymerases. These poly-merases may induce a mutation because (1) the damaged bases may miscode, for example, an A may be inserted instead of a C opposite an adducted G, or (2) these polymerases are inherently error-prone, so they may make a mistake even at a site where there is no damage. Similar events may occur to produce frameshift mutations.

Frameshift mutations may occur in one of two ways. The first method involves replication of damaged bases. Deletion of one or more damaged bases (Figure 7a) may occur if there is a sequence with two or more of the same bases side by side, in this case two G's, one of which is damaged. During synthesis, the damaged G may 'bulge out' of the DNA strand, and the C on the opposite strand may then bind with the next, undamaged, G (Figure 7a). When DNA replication resumes, the new strand has a one-base deletion. Alternatively, if a DNA strand with a damaged G is replicated, a C may be inserted opposite the damaged G, but then it may be displaced by an A (some chemically modified G's may bind with A just as well as, or even better than, C). In this case, the C may bulge out, resulting in the newly synthesized strand having an extra base inserted. A second method of frameshift mutations may occur as a result of intercolating agents. These are chemicals that can intercolate or 'slip'

between DNA bases, and may mimic a DNA base during DNA replication. represents a damaged guanine. Dotted line represents newly synthesized DNA.

Chromosomal mutations may occur as a result of DSBs. If such breaks are unrepaired, this may result in chromosomal deletions. Errors in repair of DSBs may lead to inversions, translocations, or insertions.

Finally, some organisms may undergo a phenomenon known as adaptive mutagenesis. In this process, environmental stressors cause an increase in endogenous or spontaneous mutations, presumably by endogenous inhibition of repair and mismatch detection. This is thought to be an adaptive mechanism whereby bacteria create de novo genetic variation, because some of the new variants may survive the stress better than others. It is not known if adaptive mutation occurs in eukaryotes, or genotoxic stressors can also induce adaptive mutations. However, a similar process occurs in cancer cells, which gradually accumulate more and more mutations after initiation of the tumor - a process called genomic instability. Latent genomic instability can also occur in radiation-exposed cells, which may spontaneously develop high numbers of mutations long after radiation exposure and initial repair of the damage to DNA.

Modulators of Mutagenesis

There are variety of endogenous and environmental factors that can modulate genotoxic responses and mutagenesis. For example, in some species, development

(a) Original damaged template (b) Original damaged template

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