DNA Mismatch Repair and Colon Cancer

Abstract

The Mismatch Repair (MMR) system is the major pathway responsible for repair of base-base mispairs and short insertion/deletion loops (IDLs) that arise during DNA replication and as intermediates of homologous recombination. Left unrepaired, these structures will give rise to basesubstitution and frameshift mutations, respectively. With the exception of archaea, the MMR system is highly conserved from bacteria to man, and in all these organisms makes a critical contribution towards the maintenance of genomic stability. In the last decade, our understanding of the biochemical and structural aspects of MMR has made great advances. However, the precise biological functions of the key factors of the human MMR system, the MutS homologues (MSH) hMSH2, hMSH3 and hMSH6, and the MutL homologues (MLH) hMLH1 and hPMS2 (where PMS stands for Post Meiotic Segregation) have yet to be elucidated. The roles of other MSH and MLH/PMS homologues, such as hMSH4, hMSH5, hPMS1 and hMLH3, remain largely uncharacterised, in spite of the availability of viable mouse knock-out models. The functional relationship between MMR proteins and the DNA replication factors PCNA, RF-C, RPA and DNA polymerase δ, as well as exonucleolytic enzymes such as EXO1, also requires further study. The recent advancements in the MMR field have been propelled by the discovery in 1993 of a causal link between inherited mutations in MMR genes and the common colon cancer predisposition syndrome Hereditary Non-polyposis Colon Cancer (HNPCC). In addition, many sporadic (i.e. non-familial) colon cancers have defective MMR that results from somatic transcriptional silencing of hMLH1. Finally, although MMR-deficient tumours appear to have a better prognosis than other colorectal cancers (CRCs), cells with a MMR defect were found to be resistant to certain drugs