DNA polymerases make mistakes in assembling polynucleotide strands—typically about 1 wrong base is inserted per 100,000 replicated. While this may seem insignificant considering that a human cell has around 3 billion base pairs, the mistakes add up: if polymerase mistakes were not repaired, there would be about 60,000 incorrect bases in new strands every time a human cell divided. It gets worse: errors in base pairs can arise spontaneously as well. Because the bases themselves are chemically instable, outside agents like radiation can damage them, causing *mutations that prevent them from pairing properly.

Fortunately, our cells correct DNA replication errors and repair damaged nucleotides. Cells have at least three DNA repair mechanisms at their disposal:

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Most DNA polymerases perform a proofreading function each time they introduce a new nucleotide into a growing DNA strand (Figure 13.18A). When a DNA polymerase recognizes a mispairing of bases, it removes the improperly introduced nucleotide and tries again. (Other proteins in the replication complex also play roles in proofreading.) The error rate for this process is only about 1 in 10,000 repaired base pairs, and it lowers the overall error rate for replication to about one error in every 10¹⁰ bases replicated.

After the DNA has been replicated, a second set of proteins surveys the newly replicated molecule and looks for mismatched base pairs that were missed in proofreading (Figure 13.18B). For example, this mismatch repair mechanism might detect an A-C base pair instead of an A-T pair. The repair system recognizes which of the two bases in the A-C pair is the wrong one and makes the repair. If the correct pair should be A-T, the repair system replaces C with T, restoring an A-T pair. Alternatively, if it recognizes that the correct pair should be C-G, it replaces A with G. When mismatch repair fails, DNA sequences are altered. One form of colon cancer arises in part from a failure of mismatch repair.

DNA molecules can also be damaged during the life of a cell (e.g., when it is in G1). High-energy radiation, chemicals from the environment, and spontaneous chemical changes can damage DNA. For example, when adjacent thymines on the same DNA strand absorb ultraviolet light (at about 260 nm), they form a covalent bond between the bases, making a thymine dimer. These dimers interfere with base pairing during replication, leading to random bases being inserted. This is the primary cause of skin cancer in humans. Excision repair mechanisms deal with these kinds of damage (Figure 13.18C).