Mismatch Excision Repairs Other Mismatches and Small Insertions and Deletions

Another process, also conserved in organisms from bacteria to humans, principally eliminates base-pair mismatches and insertions or deletions of one or a few nucleotides that are accidentally introduced by DNA polymerases during replication. As with base excision repair of a T in a T-G mismatch, the conceptual problem with mismatch excision repair is determining which is the normal and which is the mutant DNA strand. How this happens in human cells is not known with certainty. It is thought that the proteins that bind to the mismatched segment of DNA distinguish the template and daughter strands; then the mispaired segment of the daughter strand—the one with the replication error—is excised and repaired to produce an exact complement of the template strand (Figure 5-36). In contrast to base excision repair, mismatch excision repair occurs after DNA replication.

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FIGURE 5-36 Mismatch excision repair in human cells. The mismatch excision-repair pathway corrects errors introduced during replication. A complex of the MSH2 and MSH6 proteins (bacterial MutS homologs 1 and 6) binds to a mispaired segment of DNA in such a way as to distinguish between the template and the newly synthesized daughter strand (step 1). This binding triggers binding of MLH1 and PMS2 (both homologs of bacterial MutL). The resulting DNA-protein complex then binds an endonuclease that cuts the newly synthesized daughter strand. Next a DNA helicase unwinds the helix, and an exonuclease removes several nucleotides from the cut end of the daughter strand, including the mismatched base (step 2). Finally, as with base excision repair, the gap is filled in by a DNA polymerase (Pol δ, in this case) and sealed by DNA ligase (step 3).

Predisposition to a colon cancer known as hereditary nonpolyposis colorectal cancer results from an inherited loss-of-function mutation in one copy of either the MLH1 or the MSH2 gene. The MSH2 and MLH1 proteins are essential for DNA mismatch repair (see Figure 5-36). Cells with at least one functional copy of each of these genes exhibit normal mismatch repair. However, tumor cells frequently arise from individual cells that have experienced a random mutation in the second copy; when both copies of one gene are nonfunctional, the mismatch repair system is lost. Inactivating mutations in these genes are also common in noninherited forms of colon cancer.

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