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Living cells have evolved a series of enzymatic systems that repair DNA damage in a variety of ways. The low rate of spontaneous mutation is indicative of the efficiency of these repair systems. We can think of the spontaneous mutation rate as being at a balance point be- tween the rate at which permutational damage arises and the rate at which repair systems recognize this damage and restore the normal base sequence. Failure of these systems can lead to a higher mutation rate, as we shall see later. Let’s now examine some of the repair pathways, be- ginning with the error-free repair. For this pathway one of two things can happen:

• The repair pathway chemically repairs the damage to the DNA base.

• The repair pathway deletes the damaged DNA and uses an existing complementary sequence as a template to restore the normal sequence.

The most straightforward way to repair a lesion is to reverse it directly, thereby regenerating the normal base (Figure 14-25a). Although some types of damage are essentially irreversible, in a few cases lesions can be re-paired by direct reversal. One case is a mutagenic photo- dimer caused by UV light. The cyclobutane pyrimidine photodimer can be repaired by an enzyme called a photolyase. The enzyme binds to the photodimer and splits it, in the presence of certain wavelengths of visible light, to regenerate the original bases (Figure 14-26). This re- pair mechanism is called light repair or photorepair. The photolyase enzyme cannot operate in the dark, and so other repair pathways are required to remove UV damage in the absence of visible light. Alkyltransferases also are enzymes that directly re- verse lesions. 

They remove certain alkyl groups that have been added to the O-6 positions of guanine (see Figure 14-9) by such mutagens as nitrosoguanidine and ethyl- methanesulfonate. The methyltransferase from E. coli has been well studied. This enzyme transfers the methyl a group from O-6-methylguanine to a cysteine residue on the protein. However, the transfer inactivates the enzyme, so this repair system can be saturated if the level of alkylation is high enough.

Homology-dependent repair systems One of the overarching principles guiding cellular genetic systems is the power of nucleotide sequence complementarity. (You will recall that genetic analysis also depends heavily on this principle.) Important repair systems exploit the properties of antiparallel complementarity to restore damaged DNA segments back to their initial, undamaged state. In these systems, a segment of a DNA chain is removed and replaced with a newly synthesized nucleotide segment complementary to the opposite template strand.

Because these systems depend on the complementarity, or homology, of the template strand to the strand being repaired, they are called homology-dependent repair systems. Because re- pair takes place through a template, the rules of DNA replication ensure that repair is accomplished with high fidelity—that is, it is error-free. There are two major homology-dependent error-free repair systems. One system (excision repair) repairs damage that has been detected before replication. 

The other (postreplication repair) repairs damage that is detected in the course of the replication process or afterwards. EXCISION-REPAIR PATHWAYS Unlike the examples of reversal of damage described above, excision repair entails the removal and replacement of an entire base.

Base excision repair Base excision repair (see Figure 14-25b) is carried out by DNA glycosylases that cleave base–sugar bonds, thereby liberating the altered bases and generating apurinic or apyrimidinic sites. An enzyme called AP endonuclease then cuts the sugar-phosphate backbone around the site lacking a base. A third enzyme, deoxyribophosphodiesterase, cleans up the backbone by removing a stretch of neighbouring sugar-phosphate residues so that a DNA polymerase can fill the gap with nucleotides complementary to the other strand. DNA ligase then seals the new nucleotide into the backbone (Figure 14-27).