(A–D) Enzymology of the E. coli methyl-directed DNA mismatch repair pathway. See text for details. The pathway is shown to emphasize that it is bidirectional, i.e. can efficiently repair errors whether the nearest strand-discrimination signal (a hemi-methylated d(GATC) site) is located either 5’- or 3’-relative to the error, and that errors can still be corrected when the distance between the error and the nearest d(GATC) site is quite far (> 1000 bp). Figure adapted from Ref. (12) to highlight segments of the pathway where persistent questions regarding the mechanistic details remain (see Sections 3.1–3.4 for details): (1) the initial encounter with mis-matched base-pair, (2) the identification a hemi-methylated d(GATC) site, (3) the search for and nicking of a hemi-methylated d(GATC) site after the mismatch has been identified, and (4) the directional loading of the strand excision machinery toward the error.