Association between MSH4 (MutS homologue 4) and the DNA strand-exchange RAD51 and DMC1 proteins during mammalian meiosis

Abstract

During meiotic prophase, chromosomes must undergo highly regulated recombination events, some of which lead to reciprocal exchanges. In yeast, MSH4, a meiosis-specific homologue of the bacterial MutS protein, is required for meiotic recombination. In mice, disruption of the Msh4 gene results in male and female infertility due to meiotic failure. To date, the implication of MSH4 mutations has not been established in human sterility. However, it is noteworthy that mutant mice exhibit a defect in the chromosome synapsis, strikingly similar to the clinical observations found in human infertility. As a step towards understanding the molecular mechanisms underlying the role of MSH4 in human gametogenesis, we decided to determine whether this protein interacts with recombination machinery enzymes. Our results provide biochemical evidence indicating that the human MSH4 protein physically interacts with both RAD51 and DMC1, two RecA homologues known to initiate DNA strand-exchange between homologous chromosomes. Immunolocalization analyses show that some MSH4 foci, located on mouse meiotic chromosomes, colocalize with DMC1/RAD51 complexes. Our data support the view that MSH4 is associated with the early meiotic recombination machinery in mammals. We consider the possibility that MSH4 is involved in the regulation of recombination events by exerting a function closely after DNA strand-exchange has been initiated.