DNA Mismatch Repair Proteins and Human Defects and Disorders

The exchange of genetic information between chromosome homologs, a process called crossing over, is critical in meiosis for the proper segregation of chromosomes. Crossing over is therefore a key step in the development of healthy eggs and sperm. DNA mismatch repair (MMR) proteins facilitate crossing over, and researchers suspect that malfunctions in MMR mechanisms lead to some cases of aneuploidy, the wrong number of chromosomes in a cell. In humans aneuploidy syndromes occur in at least 10 percent of pregnancies and lead to miscarriage, Down syndrome, or other birth defects. Furthermore, mutations in MMR genes have been found in approximately 50 percent of hereditary nonpolyposis colorectal cancer patients and are thought to be linked to infertility. This underscores the importance of obtaining new mechanistic understandings and molecular tools to establish how these genes are linked to disease.

Eric Alani, Molecular Biology and Genetics, is working to elucidate how MMR genes mechanistically function and malfunction. In baker’s yeast, Alani’s model system, most meiotic crossovers are formed in a pathway in which the branched nucleic acid structure called double Holliday junctions (dHJs) are acted upon by the DNA mismatch repair MutLγ (Mlh1-Mlh3) endonuclease, among other factors. Alani is concentrating on creating a model to explain how MutLγ, in a mechanism that is currently unknown, acts to resolve dHJs. This work will help to understand the molecular defects that underlie human infertility and hereditary forms of colorectal cancer. NIH Award Number: 2R01GM053085-22

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