Repair of Damaged DNA

Probably no function is more important to a cell than being able to repair damaged DNA. No molecule is more critical to the cell than its DNA. The amount of spontaneous and muta-

gen-induced damage to DNA that occurs in cells is enormous. Every 24 hours, the DNA in every cell in the human body is damaged spontaneously more than 10,000 times. This damage, if not repaired, can lead to cell death and, in animals, cancer. In humans, two breast cancer susceptibility genes code for enzymes that repair damaged DNA. Mutations in either one result in a high (80%) probability of breast cancer. A major reason why mutations are so rare is that they are repaired before they can alter the properties of cells. It is not surprising that, in the course of many millions of years of evolution, all cells, both prokaryotic and eukaryotic, have developed several different mechanisms for repairing any damage that their DNA might suffer. Except for the light repair of UV dimers, the mechanisms that we will discuss operate on all types of damaged DNA.

Repair of Errors in Base Incorporation

A major cause of spontaneous mutation occurs during DNA replication—the incorporation of the wrong base by DNA polymerase. This complex enzyme selects the proper base to hydrogen bond to the template strand and then forms a covalent bond between the nucleotide and the 3'OH group of deoxyri-bose on the strand of DNA being synthesized. On rare occasions, however, the wrong base is selected, so that proper hydrogen bonding to the base in the template strand does not occur. This leads to a distortion in the DNA helix and, if allowed to remain, results in a mutation. Cells have developed two ways of dealing with these errors. One major process is carried out by the DNA polymerase itself and is called proofreading. A second mechanism, called mismatch repair, involves an enzyme that cuts out these errors in base incorporation. ■ DNA replication, p. 170 ■ DNA polymerase, p. 171

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Proofreading by DNA Polymerase

DNA polymerase is a complex enzyme that not only is involved in the synthesis of DNA but also has a proofreading function. One part of this enzyme can back up and then excise the nucleotide if it is not correctly hydrogen bonded to the base in the template strand. Following excision, the DNA polymerase then selects the proper nucleotide and incorporates it into the growing DNA strand.

Mismatch Repair

The proofreading function of DNA polymerase is very efficient. Cells, however, have a backup repair system, mismatch repair, that recognizes incorrect bases missed by the proofreading of DNA polymerase. In this process, the mismatch repair enzyme, an endonuclease, recognizes the pair of improperly hydrogen-bonded bases and excises a short stretch of nucleotides from the newly synthesized strand (figure 8.6). The gap is then filled in with the proper nucleotides by DNA polymerase. DNA ligase joins the end of the repaired strand to the newly synthesized one. ■ DNA ligase, p. 172

Mismatch repair also occurs in humans. Defects in this repair system lead to an increased incidence of colorectal cancers.

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