Review
Mismatch repair defects in cancer

https://doi.org/10.1016/S0959-437X(00)00066-6Get rights and content

Abstract

Post-replicative mismatch repair in humans utilises the hMSH2, hMSH6, hMSH3, hMLH1 and hPMS2 genes and possibly the newly identified hMLH3 gene. Recently, a link has been established between hMSH6 mutations and ‘atypical’ hereditary non-polyposis colon cancer (HNPCC) with an increased incidence of endometrial cancers. To satisfy the need for a diagnostic test capable of differentiating between pathogenic mutations and polymorphisms, several functional assays that fulfil these criteria have been described. These should allow for better diagnosis of HNPCC.

Introduction

Until recently, correction of replication errors in human cells was thought to involve the five dedicated mismatch repair (MMR) proteins hMSH2, hMSH3, hMSH6, hMLH1 and hPMS2, as well as members of the replication machinery. It now appears that a sixth member of the MMR family, hMLH3, may also be involved [1]. What are the individual roles of these polypeptides in the correction process? And why do mutations in only some of them segregate with the most common cancer predisposition syndrome, hereditary non-polyposis colon cancer (HNPCC) [2]? Intensive biochemical and genetic studies of the MMR process during the past five years have significantly improved our understanding of the molecular mechanism of this important metabolic pathway and have helped us correlate mutations in individual genes with phenotypes of MMR deficient cancer cells.

We aim to address the principal developments in the MMR field over the past twelve months; however, as eukaryotic MMR has been reviewed in this journal very recently [3], we will focus on the link between human cancer and loss of mismatch correction, be it through inherited mutations of MMR genes or through transcriptional silencing by epigenetic processes. For a more detailed treatise, the reader is referred to other reviews dealing with the MMR process in bacterial, yeast and mammalian systems 4, 5, 6, 7, 8, 9, 10.

Section snippets

Biochemistry of MMR in human cells

The primary role of postreplicative MMR is to eliminate from the newly synthesised strand DNA polymerase errors such as base/base mismatches and insertion/deletion loops (IDLs) that arise during the slippage of the primer against the template strand (especially in repeated sequence motifs such as microsatellites). This process is postulated to consist of three principal steps, mismatch recognition and assembly of the repairosome, degradation of the error-containing strand and repair synthesis.

Mismatch repair gene mutations and cancer

Mismatch repair deficiency is linked predominantly to cancers of the colon, endometrium and ovary. But why is it that individuals heterozygous for a MMR mutation are predisposed to cancers in these particular tissues? And why is it that of the >240 HNPCC mutations described to date, ∼60% are in hMLH1 and ∼35% are in hMSH2 (http://www.nfdht.nl; see also [2])? We have no answer to the first question; the best we can do is speculate either that in these tissues the wild-type allele of the mutated

Conclusions

Thanks to the progress in the study of the molecular mechanisms of MMR, as well as to the development of several functional assays, we are now able to make the first genotype/phenotype correlations in HNPCC. As more studies are published, it ought to be possible to extend the phenotypic findings also to prognosis, thus making genetic counselling and surveillance of HNPCC kindreds more reliable. Understanding the involvement of MMR proteins in drug resistance and drug-induced apoptosis will

Acknowledgements

The authors would like to thank all their colleagues for their respective contributions to the study of mismatch repair mechanisms and to Gray Crouse for comments on the manuscript. Work performed in the authors’ laboratory was supported in part by grants from the Swiss National Science Foundation (to J Jiricny) and from the Sigrid Juselius Foundation (to M Nyström-Lahti).

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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