Mismatch Repair Proteins: Their Function and Role in Disease

Mismatch repair (MMR) proteins function as a biological maintenance crew for DNA, responsible for a process called mismatch repair. This system corrects errors that can occur when DNA is copied, acting as a proofreading mechanism that scans the genetic code for mistakes. The primary purpose is to maintain the stability of genetic information from one generation of cells to the next. By identifying and fixing errors shortly after they arise, the MMR system helps protect the integrity of the cell’s genetic blueprint and supports normal cellular function and survival.

Guarding the Genome: The Primary Function of Mismatch Repair Proteins

The DNA within each cell contains the complete set of instructions for an organism, but its replication is not always perfect. The machinery that copies DNA can sometimes insert the wrong base—for instance, pairing a guanine (G) with a thymine (T) where a cytosine (C) belongs. This type of error is a base-base mismatch.

Another common mistake involves the accidental insertion or deletion of one or more bases, creating small loops in the DNA known as insertion/deletion loops (indels). If left uncorrected, both mismatches and indels can alter the genetic code, leading to non-functional proteins that disrupt cell processes. The mismatch repair system serves as a post-replicative quality control checkpoint, scanning the newly created DNA strand to find and fix errors the primary replication machinery missed. This secondary check significantly increases the overall accuracy of DNA replication.

The Mismatch Repair Toolkit: Major Proteins and Their Roles

The mismatch repair system is composed of a core set of proteins that are highly conserved across species. In humans, these proteins are categorized into MutS and MutL homologs. The MutS homologs act as the initial error detection unit. These proteins include MSH2, MSH3, and MSH6, which form pairs called heterodimers.

The specific pairing determines the type of error that can be recognized; a complex of MSH2 and MSH6 (MutSα) is specialized in identifying single base-base mismatches and small indels. Another complex, formed by MSH2 and MSH3 (MutSβ), recognizes larger insertion/deletion loops.

Once an error is flagged by a MutS complex, the MutL homologs are called to the site. This family includes proteins such as MLH1 and PMS2, which also work in pairs (forming MutLα). These proteins act as intermediaries, connecting the initial error recognition step to the subsequent repair activities.

How Mismatch Repair Corrects DNA Errors

The process of mismatch repair is a multi-step sequence that begins with error recognition. The MSH2-MSH6 (MutSα) or MSH2-MSH3 (MutSβ) protein complex identifies and binds to the physical distortion in the DNA helix caused by a mismatch or an indel. This binding event is the initial trigger for the entire repair cascade.

Following the attachment of the MSH complex, a corresponding MLH complex, typically MLH1-PMS2 (MutLα), is recruited to the site. The arrival of the MLH proteins stabilizes the MSH-DNA interaction and initiates the next phase of the process.

The repair system must distinguish the new, error-containing strand from the original, correct template strand. In human cells, this is achieved by recognizing signals on the new strand, such as transient single-strand breaks or nicks. The replication factor PCNA also helps direct the MMR proteins to the correct strand.

Once the new strand is identified, the MLH complex activates an endonuclease, which cuts the DNA backbone near the mismatch. An exonuclease, such as EXO1, is then recruited to remove a portion of the new DNA strand, including the error itself. This excision process creates a single-stranded gap. DNA polymerase is then tasked with filling this gap, using the undamaged template strand as a guide. The final step is performed by DNA ligase, which seals the remaining nick in the DNA backbone, completing the repair.

Consequences of Defective Mismatch Repair: The Link to Human Diseases

When the MMR system is faulty due to mutations in its genes, it can no longer effectively correct replication errors. This deficiency leads to a dramatic increase in the rate of spontaneous mutations across the genome. A direct consequence is microsatellite instability (MSI), where short, repetitive DNA sequences that are especially susceptible to errors become unstable in length.

The most well-known condition caused by inherited defects in MMR genes is Lynch syndrome. This syndrome results from a germline mutation—one that is inherited and present in all cells of the body—in one of the primary MMR genes, most commonly MLH1, MSH2, MSH6, or PMS2. Individuals with Lynch syndrome have an elevated lifetime risk for certain cancers, including:

• Colorectal cancer
• Endometrial cancer
• Ovarian cancer
• Stomach cancer

The cancers in these individuals are characterized by high levels of microsatellite instability (MSI-H). MMR deficiency is not limited to inherited syndromes; it can also be acquired in sporadic tumors.

Mismatch Repair Proteins in Diagnostics and Therapeutics

The status of mismatch repair proteins in tumors is a factor in clinical decision-making. Pathologists can test tumor tissue to determine if it is mismatch repair-deficient (dMMR). One common method is immunohistochemistry (IHC), which uses antibodies to detect the presence or absence of the four main MMR proteins: MLH1, MSH2, MSH6, and PMS2. Another approach is a molecular test to check for microsatellite instability (MSI).

For individuals suspected of having an inherited condition, genetic testing is used to screen for germline mutations in the MMR genes. This testing is important for confirming a diagnosis of Lynch syndrome and allows for predictive testing of at-risk family members, enabling them to undertake enhanced surveillance.

The tumor’s MMR status is also a predictive biomarker for cancer therapy. Tumors that are dMMR or MSI-High (MSI-H) respond well to immune checkpoint inhibitors. These tumors accumulate a high number of mutations, which results in the production of many abnormal proteins, or neoantigens. These neoantigens make the cancer cells more visible to the immune system, and checkpoint inhibitors work by releasing the natural brakes on immune cells, allowing them to attack the tumor.