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Coupling distant sites in DNA during DNA mismatch repair

How can the activities of different proteins that act at two distant sites on DNA be coupled? In cis mechanisms, an intact DNA helix is required so that the protein molecules can slide (diffuse), translocate, polymerize, or otherwise communicate along the DNA helix with the second site. Examples include the nucleotide-dependent translocation of type I and III restriction endonucleases (1) and the polymerization of SeqA that blocks bacterial replication origins (2). In trans mechanisms, contacts occur between the two sites, and the intervening DNA is looped out; this also could occur between sites on different DNAs. Trans mechanisms are common in the regulation of gene expression (3). The DNA mismatch repair (MMR) system must recognize mispairs resulting from replication errors, distinguish between newly synthesized and parental DNA strands, and coordinate an excision repair reaction so that the misincorporated base is removed from the newly synthesized strand (4). In Escherichia coli, MutL mediates communication between the mispairs, which are recognized by MutS, and a distant hemimethylated GATC site, which is cleaved by MutH on the newly synthesized strand that is not yet modified by the Dam methylase (Fig. 1). The single-strand break created by MutH can direct excision either 3′ or 5′ to the mispaired base and is the key postinitiation intermediate in MMR that allows excision to proceed by means of the UvrD helicase and one of four single-stranded DNA exonucleases. Efficient MutH cleavage depends on MutS, MutL, and the mispair; however, the mechanism by which this coupling occurs and drives appropriate directionality of excision is poorly understood even though E. coli MMR was first reconstituted with purified proteins almost 20 years ago (4). In a recent issue of PNAS, Pluciennik and Modrich (5) provided welcome insight into the problem; their results support a cis mechanism for MMR.