High impact information on MSH5

• Absence of either of the meiosis-specific mutS homologs Msh4 or Msh5 results in a similar reduction in crossing-over [1].
• Diploids lacking the MSH5 gene display decreased levels of spore viability, increased levels of meiosis I chromosome nondisjuction, and decreased levels of reciprocal exchange between, but not within, homologs [2].
• Here we describe the identification of the human homologue of the Saccharomyces cerevisiae MSH5, which is known to participate in meiotic segregation fidelity and crossing-over [3].
• A mutation in the MSH5 gene results in alkylation tolerance [4].
• We further demonstrated that a mutated form of the MSH5 gene, msh5-14, not the msh5delta-null mutation, is responsible for the cellular tolerance to MNNG in XS-14 cells [4].

Biological context of MSH5

• In Saccharomyces cerevisiae the MSH5 gene encoding a MutS homolog was identified as a gene required for meiotic crossing over [5].
• Sequence and structural characterization demonstrated that MSH5 spans approximately 25 kb and contains 26 exons that range in length from 36 bp for exon 8 to 254 bp for exon 25 [6].
• A single amino acid substitution in MSH5 results in DNA alkylation tolerance [7].
• The cDNA appears, on the basis of amino acid sequence analysis, to be a member of the MutS family and shares 30% sequence identity with that of S. cerevisiae MSH5, a yeast gene that plays a critical role in facilitating crossover during meiosis [6].
• Here we present evidence that a single point mutation that results in a Y823H amino acid substitution, but not deletion, of the MSH5 gene is responsible for tolerance to killing by DNA alkylating agents [7].

Anatomical context of MSH5

• A large number of mgt1delta, MNNG-tolerant revertants were isolated, among which one cell line, XS-14, has been found to carry a mutated allele of the MSH5 gene [4].
• Northern blot analysis demonstrated the presence of a 2.9-kb human MSH5 mRNA species in all human tissues tested, but the highest expression was in human testis, an organ containing cells that undergo constant DNA synthesis and meiosis [6].

Regulatory relationships of MSH5

• These results combine with data from budding yeast to establish a conserved role for Msh5 proteins in promoting the crossover outcome of meiotic recombination events [8].

Other interactions of MSH5

• Mutation of conserved amino acids in the NTP binding and putative helix-turn-helix domains of Msh5p abolish function but are still capable of interaction with Msh4p, suggesting that NTP binding plays a role downstream of hetero-oligomer formation [9].
• In contrast, MMS4 functions independently of MSH5 in the production of viable spores [10].
• Exo1p functions in the same pathway as Msh5p for intergenic recombination [11].

Analytical, diagnostic and therapeutic context of MSH5

• MSH5 has been mapped to human chromosome band 6p21.3 by fluorescence in situ hybridization [6].

References