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Chromosomal directionality of DNA mismatch repair in Escherichia coli

Significance DNA mismatch repair (MMR) is critical to avoid mutations that can lead to genetic disease, cancer, and death. The MMR system is evolutionarily conserved from bacteria to humans and is an example of a remarkable molecular machine. Here we show that this machine operates unidirectionally with respect to the chromosome of Escherichia coli. The most likely explanation for this directionality is that the MMR machinery is associated with the complex responsible for DNA replication. We suggest that this association facilitates the mechanism of strand discrimination in MMR. Defects in DNA mismatch repair (MMR) result in elevated mutagenesis and in cancer predisposition. This disease burden arises because MMR is required to correct errors made in the copying of DNA. MMR is bidirectional at the level of DNA strand polarity as it operates equally well in the 5′ to 3′ and the 3′ to 5′ directions. However, the directionality of MMR with respect to the chromosome, which comprises parental DNA strands of opposite polarity, has been unknown. Here, we show that MMR in Escherichia coli is unidirectional with respect to the chromosome. Our data demonstrate that, following the recognition of a 3-bp insertion-deletion loop mismatch, the MMR machinery searches for the first hemimethylated GATC site located on its origin-distal side, toward the replication fork, and that resection then proceeds back toward the mismatch and away from the replication fork. This study provides support for a tight coupling between MMR and DNA replication.