Signaling mismatch repair: the mechanics of an adenosine-nucleotide molecular switch.

Abstract

DNA mismatch repair (MMR) is the cellular processby which mispaired nucleotides in DNA are corrected(Jiricny 1996; Kolodner 1996; Modrich and Lahue 1996;Fishel and Wilson 1997). Mispaired bases in DNA canoccur as a result of chemical or physical DNA damage,polymerase errors during DNA replication, or recombination between nonhomologous parental DNA sequences(Friedberg et al. 1995). The most widely studied systemfor MMR is the DNA adenine methylation (Dam)-instructed pathway of Escherichia coli (Modrich 1989,1997). The Dam-instructed pathway promotes a longpatch (~2 kb) excision repair reaction which is genetically dependent on the mutH, mutL, mutS, andmutU(uvrD) gene products. Discrimination of the newlyreplicated DNA strand from the original template DNAstrand is dependent on transient undermethylation of theadenine nucleotide within a GATC Dam sequence. TheMutHLS pathway appears to be the most active MMRpathway in E. coli and is known both to increase the fidelity of DNA replication (Rydberg 1978) and to act onrecombination intermediates containing mispaired bases(Wildenberg and Meselson 1975; Wagner and Meselson1976; Fishel and Kolodner 1983; Fishel et al. 1986). Thissystem has been largely reconstituted in vitro and requires the MutH, MutL, MutS, and UvrD (helicase II)proteins along with DNA polymerase III (pol III) holoenzyme, DNA ligase, single-stranded DNA-binding protein(SSB), and one of the single-stranded DNA exonucleases, ExoI, ExoVII, RecJ, or ExoX (Lu et al. 1983; Su andModrich 1986; Lahue et al. 1987, 1989; Welsh et al.1987; Grilley et al. 1989; Cooper et al. 1993)...