MSH4

MSH4, also known as MutS homolog 4, is a gene encoding a meiosis-specific member of the MutS family of DNA mismatch repair proteins. In most eukaryotes, MSH4 functions together with MSH5 to promote crossing over during meiosis and is not a primary component of canonical mismatch repair.

During meiosis, MSH4 and MSH5 form a heterodimer that binds to recombination intermediates such as Holliday junctions and other joint molecules. The MSH4–MSH5 complex stabilizes these structures and promotes class I crossovers, often in conjunction with the MLH1–MLH3 (MutL gamma) endonuclease complex to resolve crossover events. This activity helps ensure proper homologous chromosome segregation and genome stability in gametes.

Expression of MSH4 is largely restricted to germ cells undergoing meiosis. Deficiency or reduced activity of MSH4 in model organisms leads to reduced crossover formation, chromosome mis-segregation, and infertility, with increased rates of aneuploid gametes. In humans, variants or altered expression have been associated with reproductive anomalies, though the clinical implications are still being studied.

MSH4 is a member of the MutS family and shares the characteristic domain organization of MutS proteins, including regions required for DNA binding and ATPase activity, though its meiotic function is specialized for recombination rather than routine mismatch repair. The protein is evolutionarily conserved among eukaryotes, with orthologs identified in yeast, plants, and animals.

See also: MSH5, MLH1, MLH3, meiotic recombination.