Biochemistry and genetics of eukaryotic mismatch repair.

Abstract

The process of mismatch repair was first postulated to explain the results of experiments on genetic recombination and bacterial mutagenesis. Mismatch repair has long been known to play a major role in two cellular processes: (1) the repair of errors made during DNA replication or as the result of some types of chemical damage to DNA and DNA precursors; and (2) the processing of recombination intermediates to yield new configurations of genetic markers. More recent studies have suggested that mismatch repair may also be crucial for (1) the regulation of recombination events between divergent DNA sequences that could result in different types of genetic instability (Rayssiguier et al. 1989; Selva et al. 1995; Datta et al. 1996), (2) some types of nucleotide excision repair responsible for repair of physicallchemical damage to DNA (Karran and Marinus 1982; Fram et al. 1985; Feng et al. 1991; Mellon and Champe 1996), and (3) participating in a cell-cycle checkpoint control system by recognizing certain types of DNA damage and triggering cell-cycle arrest or other responses to DNA damage (Hawn et al. 1995; Anthoney et al. 1996). The most extensively characterized general mismatch repair system is the Escherichia coli MutHLS system, which repairs a broad spectrum of mispaired bases and has been reconstituted with purified enzymes. Eukaryotes are known to contain a mismatch repair system that has at least some components that are highly related to key components of the bacterial MutHLS mismatch repair system. The observation that defects in mismatch repair genes are linked to both inherited cancer susceptibility and some sporadic cancers has generated considerable interest in the gene products that function in eukaryotic mismatch repair. The goal of this review is to discuss recent studies on the mechanisms of MutHLSlike mismatch repair in the yeast Saccharomyces cerevisiae and in humans and to relate insights derived from these studies to human cancer genetics. Given space constraints, i t is difficult to cover everything known about mismatch repair or to reference all of the relevant work that has been done in this area. However, a brief overview of the E. coli MutHLS pathway is presented below to allow comparison of the E. coli and eukaryotic mismatch repair pathways and proteins. For more detailed information, particularly related to bacterial mismatch repair, base-specific mismatch repair systems, and cancer genetics, see other recent reviews (Modrich 1991; Eshleman and Markowitz 1995; Fishel and Kolodner 1995; Friedberg et al. 1995; Kolodner 1995; Marra and Boland 1995; Modrich and Lahue 1996).