Disease relevance of MSH4

• To date, the implication of MSH4 mutations has not been established in human sterility [1].

High impact information on MSH4

• We demonstrate that MSH4 is present in the nuclei of spermatocytes early in prophase I and that it forms discrete foci along meiotic chromosomes during the zygotene and pachytene stages of meiosis [2].
• Our results show that MSH4 localization on chromosomes during the early stages of meiosis is essential for normal chromosome synapsis in prophase I and that it acts in the same pathway as MSH5 [2].
• Here, we demonstrate that purified hMSH4-hMSH5 binds uniquely to Holliday Junctions [3].
• The DNA mismatch-repair MLH3 protein interacts with MSH4 in meiotic cells, supporting a role for this MutL homolog in mammalian meiotic recombination [4].
• As a step forward to the understanding of the molecular mechanisms underlying the roles of these two mammalian MutS homologues, here we have identified von Hippel-Lindau (VHL) tumor suppressor-binding protein 1 (VBP1) as an interacting protein partner for human MSH4 (hMSH4) [5].

Biological context of MSH4

• Immunolocalization analysis shows that MSH4 is present at sites along the synaptonemal complex as soon as homologous chromosomes synapse [6].
• These results suggest that MSH4 is first required for chromosome synapsis and that this MutS homologue is involved later with MLH1 in meiotic reciprocal recombination [6].
• MSH4 acts in conjunction with MLH1 during mammalian meiosis [6].
• The number of MSH4 foci decreases gradually as pachynema progresses [6].
• 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 [1].

Anatomical context of MSH4

• By Northern blot analysis, human MSH4 transcripts are only detectable in testis and in ovary with a lower level of expression [7].

Associations of MSH4 with chemical compounds

• Furthermore, it seems that the tyrosine phosphorylation of hMSH5 promotes the dissociation of hMSH4-hMSH5 heterocomplex [8].

Physical interactions of MSH4

• Human MutS homologue MSH4 physically interacts with von Hippel-Lindau tumor suppressor-binding protein 1 [5].
• Here we show that hMSH4 interacts with hMLH1 [6].

Co-localisations of MSH4

• During this transition, MLH1 foci begin to appear and colocalize with MSH4 [6].

Other interactions of MSH4

• Mammalian MSH4 and MSH5 proteins form a heterodimeric complex and play an important role in the meiotic processes [5].
• We further demonstrate that the meiosis-specific MSH4 protein, known to participate to meiotic recombination, is co-immunoprecipitated with MLH3 from mouse meiotic cell extracts [4].
• Immunolocalization analyses show that some MSH4 foci, located on mouse meiotic chromosomes, colocalize with DMC1/RAD51 complexes [1].
• Formation of hMSH4-hMSH5 heterocomplex is a prerequisite for subsequent GPS2 recruitment [9].

Analytical, diagnostic and therapeutic context of MSH4

• We have mapped MSH4 to human chromosome 1 at band p31 by fluorescence in situ hybridization [7].

References