How MutS finds a needle in a haystack

Abstract

Despite the remarkable fidelity of replicative DNA polymerases (Pols), these enzymes still make mistakes (i.e., mismatches, insertions, deletions) that, if left uncorrected, result in mutations. It is the role of DNA mismatch repair (MMR) to identify and correct these mistakes (1). Lynch syndrome, a human hereditary disorder that increases cancer risk (2), is the result of impaired MMR, while bacterial antibiotic resistance results in part from the combination of error-prone replication and suppression of MMR (3, 4). Taken together, these examples illustrate the biological importance of MMR. Mechanistically, MMR involves three discrete steps: (i) error recognition by the MutS family of proteins; (ii) incision of the daughter DNA strand containing the error by the MutL family of proteins (or MutH in Escherichia coli), ultimately leading to formation of a single-stranded DNA (ssDNA) gap that can measure hundreds of bases in length; and (iii) resynthesis of the ssDNA gap followed by nick ligation. Although MutS proteins can locate mismatches in vitro using either 1D or 3D searching (5), the specific mechanisms used by MutS in vivo are poorly defined. In PNAS, Liao et al. (6) provide evidence that Bacillus subtilis MutS is recruited to the replication fork through specific interactions with several different replication fork proteins, irrespective of replication errors, possibly facilitating the ability of MutS to carry out a highly efficient 1D search for errors in newly replicated DNA.