MMDA

MLH3

MLH3 (MutL Homolog 3) is a gene that encodes a protein involved in the DNA mismatch repair (MMR) system, which is crucial for maintaining genomic stability by correcting DNA replication errors. MLH3 is part of the MutL family of proteins, which are homologs of the bacterial MutL protein, and plays a significant role in meiotic recombination and DNA repair processes.

Function

MLH3 is primarily known for its role in the DNA mismatch repair pathway. It forms a heterodimer with PMS2 or MLH1, which are other key proteins in the MMR system. This complex is responsible for recognizing and repairing mismatches that occur during DNA replication. The MLH1-MLH3 complex is particularly important in the repair of insertion-deletion loops and in the resolution of Holliday junctions during meiotic recombination.

In addition to its role in MMR, MLH3 is also involved in the process of meiosis, where it helps ensure the proper segregation of homologous chromosomes. This is achieved through its involvement in the formation and resolution of crossovers, which are essential for genetic diversity and accurate chromosome segregation.

Clinical Significance

Mutations in the MLH3 gene have been associated with various forms of cancer, particularly those related to Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC). Although MLH3 mutations are less common than mutations in other MMR genes such as MLH1, MSH2, and MSH6, they can contribute to the development of colorectal and endometrial cancers.

Research has also suggested a potential link between MLH3 mutations and infertility, due to its role in meiotic recombination. Defects in MLH3 can lead to improper chromosomal segregation, resulting in aneuploidy and reduced fertility.

Structure

The MLH3 protein consists of several domains that are critical for its function. These include the ATPase domain, which is involved in the energy-dependent steps of mismatch repair, and the interaction domains that allow it to form complexes with other MMR proteins. The structure of MLH3 is similar to other MutL homologs, with conserved regions that are essential for its activity.

Research and Developments

Ongoing research is focused on understanding the precise mechanisms by which MLH3 contributes to DNA repair and meiotic recombination. Studies are also exploring the potential of targeting MLH3 and other MMR proteins for cancer therapy, particularly in tumors that exhibit microsatellite instability (MSI) due to MMR defects.

Also see

• DNA mismatch repair
• MLH1
• PMS2
• MSH2
• Lynch syndrome
• Meiosis