Repair Of Dna Damage

As we have seen, damage to DNA can have two consequences. Some kinds of damage, such as thymine dimers or nicks and breaks in the DNA backbone, create impediments to replication or transcription. Other kinds of damage create altered bases that have no immediate structural consequence on replication but cause mispairing; these can result in a permanent alteration to the UNA sequence after replication. For example, the conversion of cytosine to uracil by deami nation creates a U:G mismatch, which, after a round of replication, becomes a C:ti to T:A transition mutation on one daughter chromosome. These considerations explain why cells have evolved elaborate mechanisms to identify and repair damage before it blocks replication or causes a mutation. Cells would not endure long without such mechanisms.

In this section, we consider the systems that repair damage to DNA (Table 0-1). In the most direct of these systems (representing tree repair), a repair enzyme simply reverses (undoes) the damage. One more elaborate step involves excision repair systems, in which the damaged nucleotide is not repaired but removed from the DNA. In excision repair systems, the other, undamaged, strand serves as a template for reincorporation of the correct nucleotide by DNA polymerase. As we shall see, two kinds of excision repair exisl, one involving the removal ol only the damaged nucleotide and the other, the removal of a short stretch of single-stranded DNA that contains the lesion.

Yet more elaborate is recombinaUonal repair, which is employed when both strands are damaged as when the DNA is broken, hi such situations, one strand cannot serve as a template for the repair of the other. Hence in recombinational repair (known as double-strand break repair), sequence information is retrieved from a second undamaged copy of the chromosome. Finally, when progression of a replicating DNA polymerase is blocked by damaged bases, s special translesion polymerase copies across the site of the damag« in a manner that do«s not depend on base pairing between the template and newly synthesized DNA strands. This mechanism is a system of last resort because translesion synthesis is inevitably highly error-prone (mutagenic).

Direct Reversal of DNA Damage

An example of repair by simple reversal of damage is photoreactivation. Photoreactivation directly reverses the formation of pyrimidine dimers that result from ultraviolet irradiation. In photoreactivation, the enzyme DNA photolyase captures energy from light and uses it to break the covalent bonds linking adjacent pyrimidines (Figure 9-11). In other words, the damaged bases are mended directly.

Another example of direct reversal is the removal of the methyl group from the methylated base Or,-methylguanine (see above). In this case,

TABLE 9-1 DNA Repair Systems

Type Damage Enzyme

Mismatch repair Replication errors MutS, Mut!, and Mutt I in f coli

MSH, ML 11, and PMS in humans Photoreactivalion Pyrimidine dinners DNA photolyase

Base excision repair Damaged base DNA glycosylate

Nucleotide excision repair Pyrimidine dimer UvrA, UvrB UvrC, and (JvrD in £ coli

Bulky adduct on base XPC, XPA. XPD, ERCCl XPr and

XPG in humans

DouDie strand break repair DouOle-strand breaks RecA and ReoBCD in E. coli

Translesion DNA synthesis Pyrimidine dimer or apurmic site Y-family DNA polymerases, such as

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