Repair proteins mutated mismatched

Cellular sensitivity to different platinum compounds and the recognition of the platinum DNA adducts by mismatch repair protein complexes appear to be linked [103]. It may also be significant that hMSH2 is expressed to higher levels in testicular and ovarian tissue than in other organs such as heart, liver and colon [109], Whether or not mismatch repair plays a general role in the anticancer activity of cisplatin still remains debatable, however. Mismatch repair proteins bind to cisplatin-DNA adducts in vitro with weak specificity [109][113]. Although specificity is enhanced when aplat-inum lesion is combined with a mutation [113], it is still less than the affinity of these proteins for the unplatinated mutation [63] [108]. 

Metallointercalators that selectively and efficiently target single base mismatches have found several applications both as biologic probes and as potential chemotherapeutic agents. For instance, [Rh(bpy)2phzi] + was used to probe the relative frequency of mismatched sites in cell lines deficient versus proficient in their mismatch repair machinery (18). The relative cleavage observed with the phzi complex in healthy cell lines was low compared with that in cancer cell lines that carried mutations in essential repair proteins. These results support previous studies on the association of mismatch repair deficiency and cancer. 

A subset of colorectal cancers arises via the MSI pathway owing to mutations or alterations in specific mismatch repair proteins. This pathway is discussed further later. 

Medullary carcinomas of the pancreas, like their colorectal counterparts, often show microsatellite instability, which is usually caused by somatic hypermethyl-ation of the MLHl promoter in sporadic cases " and by an inherited mutation in MLHl or MSH2 HNPCC syndrome.Immunolabeling for MLHl and MSH2 reveals loss of expression of one of these DNA mismatch repair proteins in many cases. 

Loss of these systems correlates with Increased risk for cancer. For example, humans who inherit mutations in genes that encode a crucial mismatch-repair or excision-repair protein have an enormously Increased probability of developing certain cancers (Table 23-1). Without proper DNA repair, people with xeroderma pigmentosum or hereditary nonpolyposis colorectal cancer have a propensity to accumulate mutations in many other genes, including those that are critical in controlling cell growth and proliferation. 

Mismatch repair is required to remove incorrect nucleotides from mismatched base pairs in newly synthesized DNA. It is critical that the repair proteins be able to distinguish between the template and nascent DNA strands to avoid "correcting" the wrong nucleotide. In E. coli, the nascent DNA strand is transiently unmethylated at adenines in the sequence GATC. Mutations in the human homologues (hMSH2 and hMLHl) of bacterial-mismatch repair enzymes have been associated with hereditary nonpolyposis colon cancer. 

A second group of inherited colon cancers are termed hereditary nonpolyposis colorectal cancer (HNPCC). HNPCC may account for 5% of all colon cancer cases and can be caused by mutations in any of five different genes. All of these genes encode proteins involved in DNA mismatch repair (Fig II-5-3). As with inherited breast cancer, fiiulty DNA repair leads to mutated cells capable of producing tumors. 

Dean N, McKay R, Miraglia L, Howard R, Cooper S, Giddings ], Nicklin P, Meister L, Ziel R, Geiger T, Muller M, Fabbro D (19 ) Iidiibition of growth of human tumor cell lines in nude mice by an antisense oligonucleotide inhibitor of protein kinase C-a expression. Cancer Res 56 3499-3507 Defranco AL (1991) Immunosuppressants at work. Nature 352 754-755 De las Alas MM, Aebi S, Fink D, Howell SB, Los G (1997) Loss of DNA mismatch repair effects on the rate of mutation to drug resistance. J Natl Cancer Inst 89 1537-1541... 

Even high-fidelity DNA polymerases sometimes incorporate an incorrect nucleotide. All cells contain a specialized mismatch repair system that catches these errors and corrects them. Mismatch repair involves excision of DNA past the mismatch, and eventually, it allows Pol III to try again (reviewed in References 71 and 72). The process of mismatch repair requires proteins MutS and MutL, among others. Mutations in the human homo-logues of these proteins lead to a predisposition to development of tumors (73). 

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