Mismatch repair removes inserted bases
No mismatch repai r leads to replication of inserted bases
Original sequence with four New sequence with five copies of tA restored copies of TA results manifested as the expansion or contraction of sequences in the human genome called microsatellite repeats, the short runs of repeated simple sequences such as di nucleotides and tri nucleotides (e.g., CACACACACA-CACA) that are scattered throughout the genome (see Chapter 19 for a review). Although the number of repeats at each site was constant in normal cells of these individuals, cells in the tumor showed huge expansions of the repeat (e.g., CACACACACACACACACACACA CACACACACACACACA) or contractions of the repeat (such as CACACACACA). Indeed, investigators, quickly found that HNPCC resulted from repair-deficient mutations in genes (MSH2 and MUTL) that encoded enzymes involved in a DNA repair process called mismatch repair.
Indeed, the colon cancer-causing mutations on chromosomes 2 and 5 were, in fact, mutations in one copy of the MSH2 gene or the MUTL gene. In the tumors themselves, the normal allele of these genes often appear to be deleted. This is another example of the "two-hit" model. Individuals inheriting a cancer-causing allele of one of these genes are at high risk for HNPCC. The "second hit" is the mutational "knockout" of the normal copy of the MSH2 or MUTL gene in one or more of these cells, which creates a cell with no functional copies of these genes, a cell that can no longer accomplish mismatch repair. That cell is now going to experience a high frequency of new mutations every time it replicates its DNA.
Why should a defect in DNA repair cause cancer? If you have an error-prone system for replicating DNA, one that cannot repair the occasional errors made during replication or spontaneous damage to DNA, every round of replication is a potentially mutagenic event. Every round of replication gives you a chance to lose another tumor suppressor gene by mutation. Every round of replication makes the loss of control of cell division more inevitable. If DNA repair defects really make a cell susceptible to cancer, shouldn't defects in other repair systems also make cells more cancer prone? Yes! Indeed, there are a number of human diseases in which individuals who are demonstrably repair defective are highly cancer prone, including xeroderma pigmentosa, Bloom syndrome, ataxia telangiectasia, and Fanconi anemia. Each of these disorders results from homozygosity (or compound heterozygosity) for inherited recessive mutations in genes required for various aspects of DNA repair. For example, patients with xeroderma pigmentosa are defective in various aspects of a process called excision repair, whereas children with ataxia telangiectasia are deficient in a process that forces cells with unrepaired DNA damage to stop dividing until they can repair their DNA. In each of the disorders, mutations in genes whose protein products are required for DNA repair predispose their bearers to develop tumors. How? The best guess is that these repair-deficient disorders effectively raise the mutation rate and, in doing so, increase the probability of mutating the tumor-suppressor genes.
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