6.7 DNA Mutation and Genome Repair
Every organism is constantly subjected to a barrage of mutagenic agents, including ionising radiation and
chemical mutagens (Chapter 8). Therefore, highly efficient mechanisms of DNA repair are needed to
maintain the genome integrity.^51 A number of complex machineries have evolved for recognising and cor-
recting the many different types of damage caused to DNA.
6.7.1 Types of DNA Mutation
Figure 6.32 shows some major types of DNA damage. DNA damage may result in an altered nucleotide,
which is read by the DNA replication machinery as a different base, resulting in a change of DNA sequence
(point mutation). If the mutation is within a coding sequence, it may give rise also to a change in the protein
sequence. If the mutation is within a non-coding sequence, it may affect control functions. Other mutation
types include (i) the addition of extra bases in a ‘microsatellite’sequence by polymerase slippageduring DNA
replication, (ii) removal of the base from the ribose backbone (almost always a purine base, depurination,
Section 8.1) leading to loss of the ribose and a break in the DNA strand, (iii) modification of the base or the
ribose by alkylating agents (Section 8.10) leading either to base mispairing, and consequent point mutation,
or inhibition of DNA replication, (iv) cross-linking of bases (particularly adjacent thymines; Figure 6.32 (see
also Figure 8.30) leading to major errors during DNA replication, and (v) single or double stranded breaks.
6.7.2 Mechanisms of DNA Repair
6.7.2. 1Direct Repair. Most DNA damage can only be repaired by the removal of the complete
nucleotide and often some surrounding sequence, followed by insertion of the correct nucleotides
(Figure 6.33). However, some lesions can be corrected in situ. Simple nicks in one of the phosphodiester
backbones are corrected by the enzyme DNA ligase. Also, certain alkyl groups can be removed at specific
positions from particular bases, for example O-6 methyl groups can be removed from guanosine bases by
O-6-methylguanine-DNA methyltransferase (Section 8.11.1).
6.7.2.2 Excision Repair. Excision repairis a very important mechanism in most organisms (Section
8.11.2).52,53One form of excision repair, used in situations where only a single base is slightly damaged,
involves a two-step process, whereby the damaged base is excised first by a DNA glycosylase. An endonu-
cleasethen cleaves the sugar phosphate backbone, leaving a single base gap, which is repaired by DNA
polymerase. In more extensively damaged DNA, the entire nucleotide(s) and a short region around them
are removed by an endonuclease complex. Once again, the gap created is filled in by DNA polymerase and
the remaining nick sealed by DNA ligase.
236 Chapter 6
Figure 6.31 Reverse transcriptase activity of telomerase preserves telomeres. Telomeric DNA is shown in black and
the template RNA, which is copied by the telomerase enzyme, in red