Mismatch Repair:
Mismatch repair (MMR) is a highly conserved DNA repair mechanism that corrects errors that occur during DNA replication, such as mismatches and small insertion-deletion loops (IDLs).
The fidelity of DNA replication is crucial for maintaining genomic stability, and MMR plays a central role in ensuring accurate DNA replication.Process of Mismatch Repair
Recognition of Mismatches:
MMR begins with the recognition of mismatches by specialized proteins, primarily MutS homologs.
MutS proteins scan the newly synthesized DNA for base pair mismatches or IDLs.
Recruitment of Repair Machinery:
Upon recognizing a mismatch, MutS forms a complex with MutL proteins and other accessory factors.
This complex recruits additional proteins, including exonucleases and DNA polymerases, to the site of the mismatch.
Excision of Mismatch:
The MutS-MutL complex helps to distinguish the newly synthesized (daughter) strand from the template (parental) strand.
An exonuclease, such as MutH in bacteria, cleaves the daughter strand near the mismatch.
This creates a nick in the DNA, allowing exonucleases to remove the mismatched segment.
Resynthesis and Ligation:
DNA polymerases are recruited to the nick and fill in the gap using the intact template strand as a guide.
Once the gap is filled, DNA ligase seals the nick, completing the repair process.
Importance of Mismatch Repair
Maintaining Genomic Stability:
MMR ensures the fidelity of DNA replication by correcting errors introduced during DNA synthesis.
By repairing mismatches and IDLs, MMR prevents the accumulation of mutations in the genome.
Preventing Microsatellite Instability:
Defects in MMR can lead to microsatellite instability (MSI), characterized by the expansion or contraction of repetitive DNA sequences (microsatellites).
MSI is associated with various human diseases, including hereditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome.
Ensuring Proper DNA Function:
Correcting mismatches is essential for maintaining the integrity and function of DNA sequences, including coding regions and regulatory elements.
Regulation of Mismatch Repair
Post-Replicative and Strand Discrimination:
MMR primarily occurs after DNA replication during the post-replicative phase.
The newly synthesized (daughter) strand is identified by specific signals, such as methylation in bacteria or transient nicks in eukaryotes.
MutS-MutL Complexes:
The formation and activity of MutS-MutL complexes are tightly regulated to ensure accurate repair.
ATP binding and hydrolysis by MutS and MutL proteins modulate their interactions with DNA and other repair factors.
Coordination with Other Repair Pathways:
MMR interacts with other DNA repair pathways, including base excision repair (BER) and nucleotide excision repair (NER), to ensure efficient and comprehensive DNA repair.
Defects in Mismatch Repair
Mutations in MMR Genes:
Inherited or acquired mutations in MMR genes can lead to defects in MMR function.
Deficient MMR is associated with increased mutation rates, genomic instability, and predisposition to cancer.
Lynch Syndrome (HNPCC):
Lynch syndrome, also known as hereditary non-polyposis colorectal cancer (HNPCC), is a hereditary cancer syndrome caused by germline mutations in MMR genes.
Individuals with Lynch syndrome have a significantly increased risk of developing colorectal cancer and other cancers, often at a young age.