Mechanism of bidirectional methyl-directed mismatch repair. Repair is initiated by activation of a latent MutH endonuclease in a reaction that is dependent on a mismatch, MutS, MutL, and ATP hydrolysis. The activated form of MutH cleaves the unmodified strand at a GATC site that can be located on either side of the mismatch. Excision subsequently removes DNA spanning the two sites, with ensuing repair synthesis initiating near the GATC site or the mismatch, depending on the polarity of the unmodified strand. MutS and MutL are shown as required for the excision stage of mismatch correction since they are necessary for repair of preincised heteroduplexes, perhaps for loading the appropriate excision activities. BLUE strand = parental (or template) strand, RED strand = newly synthesized strand, GREEN strand = repair synthesis. Methyl groups (CH3) indicate 6-methyladenines in the sequence d(GmATC).