Eukaryotic DNA mismatch repair

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Abstract

Eukaryotic mismatch repair (MMR) has been shown to require two different heterodimeric complexes of MutS-related proteins: MSH2–MSH3 and MSH2–MSH6. These two complexes have different mispair recognition properties and different abilities to support MMR. Alternative models have been proposed for how these MSH complexes function in MMR. Two different heterodimeric complexes of MutL-related proteins, MLH1–PMS1 (human PMS2) and MLH1–MLH3 (human PMS1) also function in MMR and appear to interact with other MMR proteins including the MSH complexes and replication factors. A number of other proteins have been implicated in MMR, including DNA polymerase δ, RPA (replication protein A), PCNA (proliferating cell nuclear antigen), RFC (replication factor C), Exonuclease 1, FEN1 (RAD27) and the DNA polymerase δ and ϵ associated exonucleases. MMR proteins have also been shown to function in other types of repair and recombination that appear distinct from MMR. MMR proteins function in these processes in conjunction with components of nucleotide excision repair (NER) and, possibly, recombination.

Introduction

Since the discovery that hereditary nonpolyposis colorectal carcinoma (HNPCC) is caused by inherited mutations in some of the genes encoding components of a DNA mismatch repair (MMR) pathway [1], there has been extensive progress in identifying and understanding the proteins that function in MMR in eukaryotes. It is the purpose of this article to review some of the recent advances in our understanding of MMR made using Saccharomyces cerevisiae, human and mouse systems. As this work has been so highly influenced by previous studies of MMR in bacteria, the reader is referred to reviews covering MMR there 2, 3 as well as other general reviews on this process 4, 5, 6, 7, 8. Similarly, although some aspects of the human genetics of MMR will be discussed here, the reader is referred to other reviews for a more comprehensive treatment of this subject 1, 4. (S. cerevisiae gene and protein names are used in this article with human names, when they differ, indicated in paranethses.)

Section snippets

MutS homologue proteins involved in mismatch repair

Genetic and protein–protein interaction experiments led to the proposal of a model for eukaryotic MMR in which mispaired bases in DNA are recognized by heterodimeric complexes of MutS-related proteins, the MSH2–MSH6 (MutSα) and MSH2–MSH3 (MutSβ) complexes 4, 9 (Figure 1). Studies of the mutator phenotypes caused by mutations in the Saccharomyces cerevisiae genes encoding these proteins suggested that the MSH2–MSH6 complex was responsible for the repair of base:base mispairs [9], that the

Other MutS homologue proteins

Analysis of the S. cerevisiae genome indicated the presence of six genes, MSH1–6, encoding proteins related to MutS. MSH2, 3 and 6 have been discussed above. To date, no higher eukaryotic homologue has been reported for MSH1, which has been shown in S. cerevisiae to function in mitochondrial genome stability 34, 35 but higher eukaryotic homologues of MSH4 and MSH5 have been reported 36, 37, 38. In S. cerevisiae, MSH4 and MSH5 do not function in MMR but rather are required for crossing over

MutL homologue proteins involved in mismatch repair

Genetic and protein–protein interaction experiments led to the proposal of a model for eukaryotic MMR in which a heterodimeric complex of MutL-related proteins, the MLH1–PMS1 (PMS2 in humans) complex interacts with MSH2-containing complexes bound to mispaired bases 43, 44 (See Figure 1). Recently, regions of interaction between PMS1 and MLH1 have been mapped [45] and several studies have demonstrated interactions between MutS and MutL homologues. An interaction of S. cerevisiae MLH1–PMS1 with

Other proteins implicated in mismatch repair

One of the important issues in MMR is the identification of the other proteins required for this process. Considerable progress has been made in this area recently, particularly with regard to the identification of exonucleases (Exonuclease 1, FEN1 (RAD27), and DNA polymerases δ and ϵ) and DNA replication factors (DNA polymerase δ, RPA [replication protein A], PCNA [proliferating cell nuclear antigen] and RFC [replication factor C]) that might function in MMR.

Exonuclease 1 was originally

Other functions for mismatch repair proteins

A number of studies have indicated that MMR proteins function in processes other than MMR — one being the repair of branched DNA structures. MSH2 and MSH3 are known to be required along with the RAD1–RAD10 endonuclease for the processing of non-homologous ends during certain types of recombination [73]. Similarly, repair of a 26 base insertion/deletion mispair formed during meiotic recombination required both MSH2 and RAD1–RAD10 [18]. It has been shown that MSH2 and MSH2–MSH6 can bind to

Implications for cancer genetics

HNPCC is caused by inherited mutations in MMR genes. Mutations in HNPCC families found to date are in the MSH2 and MLH1 genes with mutations in other genes such as MSH3, MSH6, PMS2 (S. cerevisiae PMS1) and PMS1 (S. cerevisiae MLH3) being either rare or non-existent [1]. The observed redundancy between MSH3 and MSH6 has provided an explanation for why mutations in these genes were not initially found in HNPCC families 4, 9. More recently, the observation that mutations in MSH6 cause only very

Conclusions

Considerable progress has been made in identifying and understanding the proteins that function in eukaryotic MMR but this proces has not yet been reconstituted with purified proteins nor have all of the proteins required for it been identified. Although several novel models relating to the mechanism of MMR have been proposed, there is only a limited understanding of its mechanism in eukaryotes and in particular how it is targeted to the daughter strand. Evidence has accumulated demonstrating

Note added in proof

The work referred to as GT Marsischky et al., unpublished data, is now in press [84].

Acknowledgements

The authors would like to thank Rick Fishel, Tom Petes, Paul Modrich as well as the members of our laboratory for helpful discussions. Clark Chen helped design Figure 1 and Neelam Amin and Clark Chen provided helpful comments about the manuscript. Work performed in the author’s laboratory was supported by National Institutes of Health Grants GM26017 and GM50006 as well as by the Ludwig Institute for Cancer Research. G Marsischky was a recipient of a Charles A King Trust Postdoctoral Fellowship

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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