Mismatch Repair

Despite DNA polymerase proofreading, copying errors occur approximately every 1 million base pairs. One common error is nucleotide mismatch, such as pairing adenine with cytosine or thymine with guanine. These mismatches persist after initial proofreading and require additional repair mechanisms to maintain genetic accuracy.

The method depends on the organism. In E. coli, specific DNA sequences are methylated after replication, and mismatch repair proteins detect unmethylated sequences to identify the new strand. In eukaryotes, the newly synthesized strand is more likely to have DNA nicks, small breaks that mismatch repair proteins recognize and target for repair.

MutS, a mismatch repair protein, identifies and binds to mispaired bases by detecting their abnormal structure. MutL then identifies which strand is the newly synthesized copy. Together, these proteins from the Mutator protein family coordinate the recognition and targeting of errors for repair while preserving the template strand.

Exonuclease enzymes cut out the region containing the error and remove the incorrect nucleotides. DNA polymerase then fills in the correct nucleotides in their place. Finally, DNA ligase seals the sugar-phosphate backbone gaps, completing the mismatch repair process and restoring DNA integrity.

The human homolog of MutS is MSH2. When MSH2 function is compromised, point mutations and frameshift mutations throughout the genome are not properly repaired. Humans carrying a single defective MSH2 copy have significantly higher likelihood of developing cancer due to accumulated unrepaired mutations.

A permissive mismatch repair system allows some mutations to escape correction, increasing genetic variation. This can lead to mutations conferring antibiotic resistance, improving bacterial survival when exposed to antibiotics. However, this contributes to the emergence of multidrug-resistant bacteria, posing serious challenges for human infectious disease treatment.

While accurate mismatch repair prevents most errors, some mutations escape correction and contribute to genetic variation. This variation is essential for adaptation and evolution. However, in pathogens like Staphylococcus aureus, permissive repair systems enable rapid acquisition of antibiotic resistance, creating public health concerns through multidrug-resistant infections.