Peter Karran, Imperial Cancer Research Fund, South Mimms, Hertfordshire, UK
Published online: April 2001
DOI: 10.1038/npg.els.0000572
Mismatch repair edits DNA replication and reduces spontaneous mutation rates. Individuals with inherited mutations in a mismatch repair gene are susceptible to cancer, and the absence of mismatch repair renders their tumours resistant to some anticancer drugs.
Keywords: hereditary nonpolyposis colorectal cancer; mutator phenotype; microsatellite instability; DNA damage tolerance; alkylating agents; cisplatin
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Figure 1. Likely steps in human mismatch correction. Errors committed during replication (A/C mispair, slipped/mispaired G, GT, GTC, or GTCA which form extrahelical loops) are recognized and bound by either hMutS or hMutS as indicated. The hMutL heterodimer is then recruited. This may possibly follow movement of the mismatched DNA through the bound heterodimer in a translocation process that is dependent on ATP hydrolysis. The mismatched segment is removed by hEXO1 or a similar activity with the reverse polarity. By analogy to mismatch repair in prokaryotes and to other repair pathways in human cells, a DNA helicase is likely to be involved in displacing the mispaired strand. The excised region is resynthesized by either DNA polymerase or both of which require PCNA as a processivity factor. Repair is completed by ligation of the newly synthesized patch to the original DNA strand. There is evidence to suggest that PCNA is actually recruited to the repair complex at an early stage as indicated.
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