Mismatch Repair

What is it

a highly conserved repair pathway that plays an important role in the detection and correction of errors created during/after DNA replication (i.e., post-replication repair) and/or after natural genetic recombination events

What lesions it repairs:

The specificity of MMR is primarily for base-base mismatches and insertion/deletion mispairs generated during DNA replication and recombination. MMR also suppresses homeologous recombination and was recently shown to play a role in DNA damage signaling in eukaryotic cells. MMR also helps to maintain the stability of repetitive DNA sequences, known as microsatellites. While MMR primarily targets replication errors, it can also be involved in the recognition and repair of certain types of DNA damage that affect base pairing

How do these lesions appear:

• Mismatched Bases: MMR corrects base-pair mismatches that arise during DNA replication. For example, when an incorrect nucleotide is incorporated opposite its template base.

• Insertion-Deletion Loops (Indels): Small Indels: MMR is involved in the repair of small insertion-deletion loops that may occur during DNA replication. These loops can result from slippage of the DNA polymerase during synthesis.

How does it work? important proteins

The key proteins involved in mismatch repair include MutS, MutL, and MutH in bacteria, while in eukaryotes, the primary proteins are MutS homologs (MSH2, MSH3, MSH6) and MutL homologs (MLH1, PMS2). These proteins work together to recognize and repair mismatches by excising the incorrectly incorporated nucleotide and resynthesizing the correct DNA strand.

How does it work? Steps

First, a protein complex (group of proteins) recognizes and binds to the mispaired base. A second complex cuts the DNA near the mismatch, and more enzymes chop out the incorrect nucleotide and a surrounding patch of DNA. A DNA polymerase then replaces the missing section with correct nucleotides, and an enzyme called a DNA ligase seals the gap. 

How is the original strand identified?

In eukaryotes, the processes that allow the original strand to be identified in mismatch repair involve recognition of nicks (single-stranded breaks) that are found only in the newly synthesized DNA

Effect on humans

Mutations in the mismatch repair (MMR) pathway can have significant consequences for human health. The MMR pathway is crucial for maintaining the integrity of the genome by correcting errors that occur during DNA replication. Mutations in MMR genes can lead to a condition known as microsatellite instability (MSI) and are associated with various health implications, including an increased risk of cancer. For instance, individuals with mutations in MMR genes, particularly MLH1, MSH2, MSH6, and PMS2, are predisposed to hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome