DNA mismatch repair

DNA mismatch repair

Colorectal adenocarcinoma with MMR - MLH1 -- high mag

DNA mismatch repair (MMR) is a fundamental cellular process responsible for correcting errors that occur during DNA replication. These errors often involve misincorporation of bases, leading to mismatches that, if not corrected, can result in mutations, genetic instability, and contribute to the development of various cancers. The MMR system enhances the fidelity of DNA replication by a factor of 100 to 1000 times, making it a critical mechanism for maintaining genetic integrity.

Mechanism

The process of DNA mismatch repair begins immediately after DNA has been replicated. It involves several key steps and proteins, which can vary among organisms but generally include recognition of the mismatch, removal of the error-containing segment of the newly synthesized DNA strand, and resynthesis of the correct sequence using the original, template strand as a guide.

In Eukaryotes, the MMR system involves several proteins, including MSH2, MSH6, MLH1, and PMS2. These proteins form complexes, such as MSH2-MSH6 (MutSα) and MSH2-MSH3 (MutSβ), which recognize and bind to mismatches. Another complex, MLH1-PMS2 (MutLα), is recruited to the site of the mismatch and interacts with the exonuclease EXO1, which removes the erroneous DNA segment. DNA polymerase then fills in the gap, and DNA ligase seals the nick, completing the repair process.

Genetic and Clinical Significance

Mutations in the genes encoding the MMR proteins can lead to a failure in the repair process, resulting in an increased mutation rate and predisposition to cancer. One well-characterized condition associated with MMR defects is Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC). Individuals with Lynch syndrome have a significantly increased risk of developing colorectal cancer, among other types of cancer.

MMR deficiency is not only linked to hereditary syndromes but is also observed in sporadic tumors. The loss of MMR function in these cases can lead to microsatellite instability (MSI), a condition characterized by the accumulation of length variations in microsatellite regions of DNA. Testing for MSI is now a routine part of the diagnostic and prognostic assessment of certain types of cancer, including colorectal and endometrial cancers.

Research and Therapeutic Implications

Understanding the mechanisms of DNA mismatch repair has significant implications for cancer research and treatment. Agents that target the pathways involved in MMR or exploit the vulnerabilities of MMR-deficient cells are being explored as potential cancer therapies. Furthermore, the identification of MMR defects in tumors can inform treatment decisions, as these tumors may respond differently to certain chemotherapeutic agents.

Conclusion

DNA mismatch repair is a critical cellular mechanism for maintaining genomic stability and preventing cancer. The study of MMR continues to provide insights into the molecular basis of genetic diseases and offers potential avenues for the development of novel therapeutic strategies.