Mismatch repair enzymes

MSH2, MLH1, PM SI, DNA mismatch repair enzymes Hereditary nonpolyposis colorectal cancer... 

During the process of DNA replication, the normal rate of error is remarkably low, but errors still occur. Consequently, the cell has a system for repairing errors (Fig. 6.46) occurring during cell division when chromosomal DNA sequences are replicated by one of a series of polymerases. This is carried out by mismatch repair enzymes, which monitor and detect miscopied new DNA sequences. However, these repair processes are generally for normal bases put in the wrong place or the wrong number of bases in a repeat sequence. 

Du J, Campau E, Soragni E, Ku S, Puckett JW, Dervan PB, Gottesfeld JM (2012) Role of mismatch repair enzymes in GAA-TTC triplet-repeat expansion in Friedreich ataxia induced pluripotent stem cells. J Biol Chem 287(35 ) 29861-29872... 

FIGURE 14.22 High and low magnification of an invasive cecal adenocarcinoma from a 46-year-old patient with hereditary nonpolyposis colon cancer syndrome (Lynch syndrome). Neoplastic cell nuclei are completely devoid of MLH2 immunoreactivity, whereas cell nuclei of the surrounding stromal cells stain strongly. Only the complete absence of nuclear staining should be interpreted as a marker of a mismatch repair enzyme defect. 

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. 

The mismatch repair enzyme complex acts during replication when an incorrect, bnt normal base (i.e., A, G, C, or T) is incorporated into the growing chain (Fig. 13.16). In bacteria, parental DNA strands contain methyl groups on adenine bases in specific sequences. During replication, the newly synthesized strands are not immediately methylated. Before methylation occurs, the proteins involved in mismatch repair can distinguish parental from newly synthesized strands. A region of the new, unmethylated strand, containing the mismatched base, is removed and replaced. 

Schrader, C. E., Edelmann, W., Kucherlapati, R., and Stavnezer, J. (1999). Reduced isotype switching in splenic B cells from mice deficient in mismatch repair enzymes. J. Exp. Med. 190, 323-330. 

Mismatched bases produced during DNA replication are those not conforming to or A=T base pairing. They are identified and corrected in the new strand by the mismatch-repair enzyme complex . The mismatched nucleotides are identified and excised, and the gap filled by DNA polymerase. Mutations in this complex result in failure to correct mismatched base pairs and cause hereditary non-polyposis colorectal cancer (HNPCC). 

Mismatch Repair. Mispairs that break the normal base-pairing rules can arise spontaneously due to DNA biosynthetic errors, events associated with genetic recombination and the deamination of methylated cytosine (Modrich, 1987). With the latter, when cytosine deaminates to uracil, an endonuclease enzyme, /V-uracil-DNA glycosylase (Lindahl, 1979), excises the uracil residue before it can pair with adenine at the next replication. However, 5-methyl cytosine deaminates to form thymine and will not be excised by a glycosylase. As a result, thymine exits on one strand paired with guanine on the sister strand, that is, a mismatch. This will result in a spontaneous point mutation if left unrepaired. For this reason, methylated cytosines form spontaneous mutation hot-spots (Miller, 1985). The cell is able to repair mismatches by being able to distinguish between the DNA strand that exists before replication and a newly synthesized strand. 

Utilising a reversion assay in Salmonella enterica, Prieto et al reported an increased frequency of point mutations following bile-salt exposure. Mutations were predominantly nucleotide substitutions (GC to AT transitions) and -1 frameshift mutations.The frameshifts were dependent on SOS induction and linked to the activity of DinB polymerase (Pol IV). The authors proposed that the GC to AT transitions stimulated by bile, could have arisen from oxidative processes giving rise to oxidised cytosine residues. Consistent with this hypothesis, the authors demonstrated that strains of S. enterica-lacking enzymes required for base-excision repair (endonuclease III and exonuclease IV) and the removal of oxidised bases, demonstrated increased bile-acid sensitivity compared with competent strains. In another study using E. coli, resistance to the DNA-damaging effects of bile was associated with Dam-directed mismatch repair, a pathway also involved with the repair of oxidative DNA lesions. ... 

When base selection and proofreading are combined, DNA polymerase leaves behind one net error for every 106 to 108 bases added. Yet the measured accuracy of replication in E. coli is higher still. The additional accuracy is provided by a separate enzyme system that repairs the mismatched base pairs remaining after replication. We describe this mismatch repair, along with other DNA repair processes, in Section 25.2. 

If the two DNAs have the same sequence, they can form a Holliday junction, but no detectable genetic recombination takes place because no information change has occurred. If the two DNAs are very different, no recombination will take place because formation of a Holliday junction requires homologous information. If the two DNAs of the Holliday junction are similar to each other but not identical (that is, they contain mismatches), then repair enzymes, which remove the base and/or nucleotide from one of the mismatched strands, will repair the DNA. The fact that some enzymes participate both in repair and in recombination accounts for the fact that many recombination-deficient mutant bacteria are also highly sensitive to ultraviolet light. 

---