{"gene":"MSH5","run_date":"2026-06-10T02:59:51","timeline":{"discoveries":[{"year":1995,"finding":"MSH5 (yeast) is required for meiotic reciprocal recombination between homologs but not for mismatch repair or gene conversion. Double-mutant analysis with msh4Δ demonstrated that MSH4 and MSH5 are in the same epistasis group, likely functioning together in facilitating interhomolog crossovers during meiosis.","method":"Genetic screen, deletion mutants, spore viability assays, recombination assays, msh4 msh5 double-mutant epistasis analysis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean epistasis analysis with double mutants, multiple phenotypic readouts (crossover frequency, nondisjunction, spore viability), replicated across subsequent studies in multiple organisms","pmids":["7622037"],"is_preprint":false},{"year":1998,"finding":"Human MSH5 and MSH4 proteins physically interact, as demonstrated by yeast two-hybrid analysis, indicating they form a heterodimer conserved from yeast to humans. Human MSH5 is encoded at 6p22.3-p21.3 and is expressed most highly in testis, thymus, and immune tissues.","method":"Yeast two-hybrid interaction analysis, Northern blot, radiation hybrid mapping","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid for interaction, corroborated by mouse Msh5-hMSH4 interaction in a separate study","pmids":["9787078","10556423"],"is_preprint":false},{"year":1999,"finding":"Mouse Msh5 knockout causes meiotic defects in both sexes (male and female sterility), with an extended zygotene stage, impaired and aberrant chromosome synapsis, and subsequent apoptotic cell death, demonstrating that Msh5 promotes synapsis of homologous chromosomes during meiotic prophase I.","method":"Gene knockout (disruption), histological and cytological examination of meiotic prophase I stages","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cytological phenotype, independently replicated in subsequent studies","pmids":["10072381"],"is_preprint":false},{"year":2000,"finding":"C. elegans msh-5 is required for meiotic crossing over and chiasma formation. Artificially induced DNA breaks do not bypass the requirement for msh-5, placing msh-5 function after the initiation step of meiotic recombination (i.e., after DSB formation). msh-5 mutants can repair breaks but accomplish repair without producing crossovers.","method":"msh-5 deletion mutants, chiasma/crossover frequency quantification, radiation-induced DSB experiments, cytological analysis","journal":"Genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal experiments (genetic, cytological, radiation rescue), establishes pathway position","pmids":["11014811"],"is_preprint":false},{"year":2007,"finding":"MSH5 (and its obligate heterodimer partner MSH4) plays a role in regulating immunoglobulin class switch recombination (CSR). Msh5-null mice show long microhomologies at Ig switch joints and IgG3 deficiency. A human MSH5 variant with two nonsynonymous polymorphisms shows impaired binding to MSH4, and patients carrying disease-associated MSH5 alleles exhibit increased donor/acceptor microhomology at Ig switch joints. MSH4/5 heterodimers promote resolution of DNA breaks by classical non-homologous end-joining while suppressing an alternative microhomology-mediated pathway.","method":"Congenic mouse analysis, Msh5-null mouse phenotyping, sequencing of Ig switch joints, MSH4-MSH5 binding assay with variant protein","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (mouse KO, human variant binding assay, switch joint sequencing) in single study","pmids":["17409188"],"is_preprint":false},{"year":2008,"finding":"SMCY (a Y-chromosome-encoded histone H3K4 demethylase) physically interacts with MSH5 in human testicular germ cells (NEC8 cell line), forming a distinct complex. SMCY and MSH5 co-localize at a specific stage of meiotic prophase during murine spermatogenesis, suggesting SMCY recruits MSH5 to condensed DNA as part of epigenetic regulation during meiosis.","method":"Co-immunoprecipitation (biochemical protein interaction), immunohistochemistry, histone demethylase activity assay","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP interaction identified plus co-localization by IHC, single lab","pmids":["18459961"],"is_preprint":false},{"year":2010,"finding":"The Msh4-Msh5 complex stabilizes single-end invasion intermediates and Holliday junctions during meiosis. Mutagenesis of 57 residues in yeast Msh4 and Msh5 identified threshold mutants with reduced crossovers on large/medium chromosomes but near-wild-type levels on small chromosomes. The Msh5 subunit was more sensitive to mutagenesis, and complex assembly defects were observed.","method":"Site-directed mutagenesis (57 residues), spore viability assays, genetic crossover frequency measurement, synaptonemal complex assembly analysis","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — extensive mutagenesis of 57 residues with multiple functional readouts in single rigorous study","pmids":["20865162"],"is_preprint":false},{"year":2010,"finding":"The C. elegans translation initiation factor IFE-2 upregulates MSH-5 (and MSH-4) protein synthesis at elevated temperatures by shifting their mRNAs from free messenger ribonucleoproteins to polysomes, thereby enabling crossover formation at high temperatures.","method":"ife-2 deletion mutant analysis, polysome profiling of msh-4/msh-5 mRNAs, Western blot for MSH-5 protein levels, cytological analysis of bivalents/univalents","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (polysome profiling, Western blot, cytology) in single study","pmids":["20530576"],"is_preprint":false},{"year":2012,"finding":"Human MSH5 localizes to mitochondria in both germ and somatic cells, binds to mtDNA, and interacts with Twinkle helicase and DNA polymerase gamma. hMSH5 stimulates mtDNA repair in response to oxidative stress-induced DNA damage. Subsarcolemmal accumulation of hMSH5 was observed in COX-negative muscle fibers of mitochondrial myopathy patients.","method":"Subcellular fractionation/localization, mtDNA binding assay, co-immunoprecipitation (Twinkle helicase and pol-gamma), mtDNA repair assay under oxidative stress, immunofluorescence","journal":"Mitochondrion","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (fractionation, Co-IP, functional repair assay) in single lab study","pmids":["22917773"],"is_preprint":false},{"year":2013,"finding":"Homology modeling of the S. cerevisiae Msh4-Msh5 complex, informed by MutS crystal structures, predicts that mutations affecting meiotic crossovers likely alter protein stability and/or DNA binding interactions. The model predicts structural asymmetry within the Msh4-Msh5 complex and identifies sites important for complex formation and DNA binding.","method":"Homology modeling based on MutS crystal structures, evolutionary analysis, integration with existing mutant phenotype data","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational modeling only, no direct structural validation or mutagenesis performed in this study","pmids":["24244354"],"is_preprint":false},{"year":2019,"finding":"A mutation in the ATP-binding domain of Msh5 (Msh5ATPase) prevents accumulation of MutSγ (MSH4/MSH5) foci during prophase I. Despite this, most spermatocytes progress further than complete Msh5-null mice. Msh5ATPase spermatocytes show persistent DSBs, incomplete homolog pairing, failure to accumulate MutLγ (MLH1/MLH3), and complete absence of chiasmata—indicating a functional MutSγ complex is required for all crossover events (both class I and class II pathways) in mammalian meiosis.","method":"ATPase domain mutagenesis (knock-in mouse), immunofluorescence for MutSγ/MutLγ foci, cytological analysis of DSBs (γH2AX), diakinesis chiasma counting","journal":"G3 (Bethesda, Md.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ATPase mutagenesis knock-in with multiple orthogonal cytological readouts; reveals requirement for functional complex in all COs","pmids":["30944090"],"is_preprint":false},{"year":2021,"finding":"Biallelic loss-of-function variants in MSH5 cause meiotic arrest in early prophase I in humans, establishing MSH5 as a cause of male infertility (non-obstructive azoospermia). γH2AX staining revealed arrest at early prophase I. Heterologous expression of LoF variants confirmed MSH5 protein truncation or complete loss.","method":"Exome sequencing, segregation analysis, γH2AX staining of patient spermatocytes, heterologous protein expression in HEK293T cells","journal":"Human reproduction (Oxford, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple patients with biallelic variants, functional validation of protein truncation in vitro, cytological phenotype in patient cells","pmids":["34755185"],"is_preprint":false},{"year":2021,"finding":"In S. cerevisiae meiosis, Msh5 specifically associates with DSB hotspots, chromosome axes, and centromeres genome-wide. Efficient binding to DSB hotspots and chromosome axes requires DSB formation and resection and is enhanced by double Holliday junction structures. The axis protein Red1 is required for Msh5 association with chromosome axes and DSB hotspots (but not centromeres). Centromere association of Msh5 is independent of Zip3.","method":"Chromatin immunoprecipitation and sequencing (ChIP-seq) in meiotic cells, analysis in spo11Δ, red1Δ, and zip3Δ mutants","journal":"Genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq with multiple genetic backgrounds establishing pathway requirements for chromosomal localization","pmids":["34849874"],"is_preprint":false},{"year":2022,"finding":"A homozygous MSH5 frameshift mutation (c.1126del) in NOA patients abolishes chromosome axial localization of MutSγ in spermatocytes. Chromosomal spreading showed meiosis arrest at a zygotene-like stage with extensive failure of homologous synapsis and DSB repair, demonstrating that MSH5/MutSγ axial loading is essential for human meiotic synapsis and recombination.","method":"Patient exome sequencing, chromosomal spreading analysis of patient spermatocytes, immunofluorescence for MutSγ localization, γH2AX staining for DSB repair","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human patient material with direct cytological analysis of MutSγ localization and meiotic progression, single study","pmids":["35742973"],"is_preprint":false},{"year":2024,"finding":"In heterozygous S. cerevisiae hybrids, Msh5 binding to DSB hotspots is reduced in regions of high heterozygosity (high mismatch density), consistent with Msh5 binding to heteroduplex-containing recombination intermediates. Chimeric sequence reads (heteroduplex DNA) were detected at Msh5-bound DSB hotspots.","method":"ChIP-seq in S288c-sp/YJM789 hybrid yeast, SNP-based read assignment, heteroduplex DNA detection via chimeric sequence reads","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq with SNP discrimination in hybrid strain, single lab study","pmids":["38124392"],"is_preprint":false},{"year":1997,"finding":"A specific point mutation in yeast MSH5 (msh5-14, resulting in Y823H substitution) — but not deletion of MSH5 — confers cellular tolerance to DNA alkylating agents (MNNG) in an O6-methylguanine DNA methyltransferase-deficient background. This gain-of-function effect is distinct from loss of mismatch repair.","method":"Isolation of MNNG-tolerant revertants, genetic mapping of mutation to MSH5, complementation with msh5 deletion vs. point mutant allele, MNNG survival assays","journal":"Cancer research / Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two papers by same lab confirm the Y823H substitution as responsible; point mutation vs. null comparison is mechanistically informative","pmids":["9205082","14557077"],"is_preprint":false},{"year":2017,"finding":"A homozygous missense mutation in human MSH5 (p.D487Y) identified in sisters with primary ovarian insufficiency (POI) impairs DNA homologous recombination repair in vitro, and the homologous mutation in mice results in atrophic ovaries without oocytes.","method":"Whole exome sequencing, in vitro functional DNA homologous recombination repair assay with mutant MSH5, mouse homologous mutation model","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional in vitro assay combined with mouse phenotype, single lab","pmids":["28175301"],"is_preprint":false},{"year":2020,"finding":"The lncRNA HCP5 stabilizes the interaction between YB1 and ILF2, facilitating YB1 nuclear translocation in granulosa cells. HCP5 silencing reduces YB1 binding to the MSH5 promoter, thereby reducing MSH5 transcription. This identifies YB1 as a transcriptional activator of MSH5 that is regulated by HCP5.","method":"lncRNA knockdown, YB1 co-IP with ILF2, nuclear fractionation of YB1, chromatin immunoprecipitation (YB1 at MSH5 promoter), MSH5 expression measurement","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, fractionation, ChIP) in single study establishing transcriptional regulation of MSH5","pmids":["32112110"],"is_preprint":false}],"current_model":"MSH5 functions as an obligate heterodimer with MSH4 (forming MutSγ) to promote meiotic crossover formation by binding to and stabilizing strand invasion intermediates and Holliday junctions at DSB hotspots on meiotic chromosomes—a function requiring MSH5 ATPase activity and Red1-dependent axial loading—and additionally plays roles in immunoglobulin class switch recombination (suppressing microhomology-mediated end-joining), mitochondrial DNA repair (via interactions with Twinkle helicase and DNA polymerase gamma), and transcriptional regulation by YB1; loss-of-function in humans causes male infertility through meiotic arrest and primary ovarian insufficiency in females."},"narrative":{"mechanistic_narrative":"MSH5 is a meiosis-specific MutS homolog that functions as an obligate heterodimer with MSH4 (forming MutSγ) to promote interhomolog crossover formation during meiotic recombination [PMID:7622037, PMID:9787078, PMID:10556423]. Genetic epistasis in yeast placed MSH5 and MSH4 in a single pathway required for reciprocal recombination but dispensable for mismatch repair [PMID:7622037], and worm studies positioned its function downstream of DSB formation: msh-5 mutants repair breaks but fail to convert them into crossovers and chiasmata [PMID:11014811]. Mechanistically, MutSγ binds and stabilizes single-end invasion intermediates and Holliday junctions [PMID:20865162], and genome-wide ChIP showed that Msh5 associates with DSB hotspots, chromosome axes, and centromeres, with hotspot/axis binding requiring DSB formation and resection, enhancement by double Holliday junctions, and dependence on the axis protein Red1 [PMID:34849874]; binding is reduced in heteroduplex-rich regions, consistent with engagement of mismatch-containing recombination intermediates [PMID:38124392]. A functional MSH5 ATPase domain is required for stable MutSγ focus accumulation and for all classes of crossover, since ATPase mutants fail to load MutLγ, retain persistent DSBs, and lack chiasmata [PMID:30944090]. Loss of MSH5 disrupts homolog synapsis and arrests meiosis with apoptosis in mouse knockouts [PMID:10072381], and in humans biallelic loss-of-function and axial-loading-defective variants cause meiotic arrest and non-obstructive azoospermia in males [PMID:34755185, PMID:35742973], while a missense allele impairs homologous recombination repair and causes primary ovarian insufficiency in females [PMID:28175301]. Beyond meiosis, MSH4/MSH5 heterodimers influence immunoglobulin class switch recombination by favoring classical end-joining over a microhomology-mediated pathway [PMID:17409188], and human MSH5 localizes to mitochondria, binds mtDNA, and interacts with Twinkle helicase and DNA polymerase gamma to stimulate mtDNA repair under oxidative stress [PMID:22917773]. MSH5 expression is transcriptionally activated by YB1 at its promoter under lncRNA HCP5 control [PMID:32112110].","teleology":[{"year":1995,"claim":"Established that MSH5 acts specifically in meiotic crossover formation rather than mismatch repair, and that it works in the same pathway as MSH4.","evidence":"Genetic deletion and msh4 msh5 double-mutant epistasis with recombination and spore viability readouts in yeast","pmids":["7622037"],"confidence":"High","gaps":["Did not define the biochemical activity of MSH5","Heterodimer formation not directly demonstrated"]},{"year":1998,"claim":"Showed MSH5–MSH4 heterodimer formation is conserved to humans, defining the molecular partnership underlying the genetic pathway.","evidence":"Yeast two-hybrid interaction, Northern blot expression profiling, radiation hybrid mapping","pmids":["9787078","10556423"],"confidence":"Medium","gaps":["Two-hybrid does not establish stoichiometry or in vivo complex","No DNA-binding activity tested"]},{"year":1999,"claim":"Demonstrated MSH5 is required for homolog synapsis in meiotic prophase I in a mammal, with loss causing both male and female sterility.","evidence":"Mouse Msh5 knockout with cytological staging of prophase I and apoptosis assessment","pmids":["10072381"],"confidence":"High","gaps":["Whether synapsis defect is direct or secondary to recombination failure not resolved","No molecular interaction with DNA shown"]},{"year":2000,"claim":"Placed MSH5 function downstream of DSB initiation, showing it converts breaks into crossovers rather than initiating recombination.","evidence":"C. elegans msh-5 mutants with radiation-induced DSB rescue experiments and chiasma quantification","pmids":["11014811"],"confidence":"High","gaps":["Did not identify the intermediate MSH5 binds","No structural basis for crossover specification"]},{"year":2007,"claim":"Extended MSH4/MSH5 function beyond meiosis to immunoglobulin class switch recombination, biasing repair toward classical end-joining.","evidence":"Msh5-null mouse phenotyping, Ig switch joint sequencing, MSH4-MSH5 binding assay with human variant","pmids":["17409188"],"confidence":"Medium","gaps":["Mechanism of microhomology suppression not defined","Direct role of MSH5 at switch regions vs. indirect effect unresolved"]},{"year":2008,"claim":"Linked MSH5 to epigenetic regulation in spermatogenesis via interaction with the H3K4 demethylase SMCY.","evidence":"Co-immunoprecipitation and immunohistochemistry co-localization in testicular germ cells","pmids":["18459961"],"confidence":"Medium","gaps":["Single-lab Co-IP without reciprocal validation","Functional consequence of recruitment to condensed DNA not established"]},{"year":2010,"claim":"Defined the biochemical role of MutSγ as stabilizing strand-invasion intermediates and Holliday junctions, with chromosome-size-dependent crossover thresholds.","evidence":"Site-directed mutagenesis of 57 residues with crossover frequency and synaptonemal complex assays in yeast","pmids":["20865162"],"confidence":"High","gaps":["No direct structural data on junction binding","Asymmetry between MSH4 and MSH5 subunits inferred from genetics only"]},{"year":2010,"claim":"Identified translational control of MSH5 levels by IFE-2 as a mechanism enabling crossover formation under temperature stress.","evidence":"ife-2 mutant analysis, polysome profiling, Western blot, and bivalent cytology in C. elegans","pmids":["20530576"],"confidence":"Medium","gaps":["Whether this regulation is conserved in mammals unknown","Direct binding of IFE-2 to msh-5 mRNA not shown"]},{"year":2012,"claim":"Revealed a mitochondrial role for human MSH5 in mtDNA repair through interactions with the replication/repair machinery.","evidence":"Subcellular fractionation, mtDNA binding, Co-IP with Twinkle and pol-gamma, oxidative-stress repair assay","pmids":["22917773"],"confidence":"Medium","gaps":["MSH4 dependence of mitochondrial function not tested","In vivo significance for mitochondrial disease correlative only"]},{"year":2013,"claim":"Provided a structural framework predicting how MutSγ binds DNA and how crossover mutations destabilize the complex.","evidence":"Homology modeling on MutS crystal structures integrated with mutant phenotype data","pmids":["24244354"],"confidence":"Low","gaps":["Computational model with no experimental structural validation","Predicted asymmetry and DNA-contact sites untested in this study"]},{"year":2019,"claim":"Demonstrated that MSH5 ATPase activity is essential for stable MutSγ foci and for all crossover classes in mammalian meiosis.","evidence":"ATPase-domain knock-in mouse with MutSγ/MutLγ foci, γH2AX, and chiasma cytology","pmids":["30944090"],"confidence":"High","gaps":["Biochemical ATP-hydrolysis cycle not directly measured","How ATPase state couples to MutLγ loading unresolved"]},{"year":2021,"claim":"Established MSH5 as a human meiotic infertility gene, with biallelic loss-of-function causing early prophase I arrest and azoospermia.","evidence":"Exome sequencing, segregation, γH2AX staining of patient spermatocytes, heterologous expression","pmids":["34755185"],"confidence":"Medium","gaps":["Female reproductive consequences in same cohort not characterized","Residual partial function of some variants not quantified"]},{"year":2021,"claim":"Mapped the chromosomal binding behavior of Msh5 genome-wide and established Red1-dependent axial loading at DSB hotspots.","evidence":"Meiotic ChIP-seq in spo11Δ, red1Δ, and zip3Δ yeast mutants","pmids":["34849874"],"confidence":"High","gaps":["Mechanism of Red1-mediated recruitment not defined","Centromere association function unexplained"]},{"year":2022,"claim":"Confirmed in humans that MSH5/MutSγ axial loading is required for meiotic synapsis and DSB repair.","evidence":"Patient exome sequencing with chromosomal spreading and MutSγ immunofluorescence in spermatocytes","pmids":["35742973"],"confidence":"Medium","gaps":["Single study on patient material","Whether the human axial-loading factor is a Red1 ortholog not addressed"]},{"year":2024,"claim":"Provided direct evidence that Msh5 engages heteroduplex-containing recombination intermediates, refining its substrate at DSB hotspots.","evidence":"ChIP-seq in heterozygous hybrid yeast with SNP-based read assignment and chimeric read detection","pmids":["38124392"],"confidence":"Medium","gaps":["Causal effect of mismatch density on crossover outcome not established","Single-lab observation"]},{"year":null,"claim":"How the MSH5 ATPase cycle, heteroduplex recognition, and Red1-dependent axial loading are mechanistically coupled to MutLγ recruitment and crossover designation remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No experimentally determined structure of the MutSγ–DNA complex","Human axial-loading factor analogous to Red1 not identified","Biochemical reconstitution of MutSγ sliding-clamp dynamics on junctions lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[6,12,14]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[10]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[8,16]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[12,13]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[8]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,17]}],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0,2,10,11]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[8,16]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4]}],"complexes":["MutSγ (MSH4-MSH5)"],"partners":["MSH4","SMCY","TWNK","POLG","RED1","YB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43196","full_name":"MutS protein homolog 5","aliases":[],"length_aa":834,"mass_kda":92.9,"function":"Involved in DNA mismatch repair and meiotic recombination processes. Facilitates crossovers between homologs during meiosis (By similarity)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/O43196/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MSH5","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MSH5","total_profiled":1310},"omim":[{"mim_id":"619938","title":"PREMATURE OVARIAN FAILURE 20; POF20","url":"https://www.omim.org/entry/619938"},{"mim_id":"619937","title":"SPERMATOGENIC FAILURE 74; SPGF74","url":"https://www.omim.org/entry/619937"},{"mim_id":"618166","title":"CYCLIN N-TERMINAL DOMAIN-CONTAINING PROTEIN 1; CNTD1","url":"https://www.omim.org/entry/618166"},{"mim_id":"618038","title":"SHORTAGE IN CHIASMATA 1; SHOC1","url":"https://www.omim.org/entry/618038"},{"mim_id":"617545","title":"MINICHROMOSOME MAINTENANCE DOMAIN-CONTAINING PROTEIN 2; MCMDC2","url":"https://www.omim.org/entry/617545"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli fibrillar center","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"testis","ntpm":11.3}],"url":"https://www.proteinatlas.org/search/MSH5"},"hgnc":{"alias_symbol":["G7"],"prev_symbol":[]},"alphafold":{"accession":"O43196","domains":[{"cath_id":"3.30.420.110","chopping":"51-214","consensus_level":"high","plddt":83.6658,"start":51,"end":214},{"cath_id":"1.10.1420.10","chopping":"222-399_518-543","consensus_level":"medium","plddt":87.4443,"start":222,"end":543},{"cath_id":"1.10.1420.10","chopping":"408-504","consensus_level":"medium","plddt":82.1051,"start":408,"end":504},{"cath_id":"3.40.50.300","chopping":"548-752","consensus_level":"high","plddt":86.3202,"start":548,"end":752},{"cath_id":"1.10.287","chopping":"788-834","consensus_level":"high","plddt":66.8013,"start":788,"end":834}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43196","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43196-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43196-F1-predicted_aligned_error_v6.png","plddt_mean":82.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MSH5","jax_strain_url":"https://www.jax.org/strain/search?query=MSH5"},"sequence":{"accession":"O43196","fasta_url":"https://rest.uniprot.org/uniprotkb/O43196.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43196/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43196"}},"corpus_meta":[{"pmid":"7622037","id":"PMC_7622037","title":"MSH5, a novel MutS homolog, facilitates meiotic reciprocal recombination between homologs in Saccharomyces cerevisiae but not mismatch repair.","date":"1995","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/7622037","citation_count":343,"is_preprint":false},{"pmid":"10072381","id":"PMC_10072381","title":"Mouse MutS-like protein Msh5 is required for proper chromosome synapsis in male and female meiosis.","date":"1999","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/10072381","citation_count":289,"is_preprint":false},{"pmid":"11137219","id":"PMC_11137219","title":"Identification of HLA-G7 as a new splice variant of the HLA-G mRNA and expression of soluble HLA-G5, -G6, and -G7 transcripts in human transfected cells.","date":"2000","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11137219","citation_count":265,"is_preprint":false},{"pmid":"11014811","id":"PMC_11014811","title":"Caenorhabditis elegans msh-5 is required for both normal and radiation-induced meiotic crossing over but not for completion of meiosis.","date":"2000","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11014811","citation_count":223,"is_preprint":false},{"pmid":"8486285","id":"PMC_8486285","title":"Sequences of genes encoding naphthalene dioxygenase in Pseudomonas putida strains G7 and NCIB 9816-4.","date":"1993","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/8486285","citation_count":221,"is_preprint":false},{"pmid":"17409188","id":"PMC_17409188","title":"Role for Msh5 in the regulation of Ig class switch recombination.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17409188","citation_count":124,"is_preprint":false},{"pmid":"32112110","id":"PMC_32112110","title":"Long noncoding RNA HCP5 participates in premature ovarian insufficiency by transcriptionally regulating MSH5 and DNA damage repair via 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Section F, Structural biology and crystallization communications","url":"https://pubmed.ncbi.nlm.nih.gov/22232182","citation_count":9,"is_preprint":false},{"pmid":"18601605","id":"PMC_18601605","title":"The silent hemoglobin alpha chain variant Hb Riccarton [alpha51(CE9)Gly-->Ser] may affect HbA1c determination on the HLC-723 G7 analyzer.","date":"2008","source":"Clinical chemistry and laboratory medicine","url":"https://pubmed.ncbi.nlm.nih.gov/18601605","citation_count":9,"is_preprint":false},{"pmid":"26406233","id":"PMC_26406233","title":"Combination Testing Using a Single MSH5 Variant alongside HLA Haplotypes Improves the Sensitivity of Predicting Coeliac Disease Risk in the Polish Population.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26406233","citation_count":8,"is_preprint":false},{"pmid":"11908946","id":"PMC_11908946","title":"Cross-reactive mycobacterial and self hsp60 epitope recognition in I-A(g7) expressing NOD, NOD-asp and Biozzi AB/H mice.","date":"2002","source":"Journal of autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/11908946","citation_count":8,"is_preprint":false},{"pmid":"29018805","id":"PMC_29018805","title":"Insight into the Selectivity of the G7-18NATE Inhibitor Peptide for the Grb7-SH2 Domain Target.","date":"2017","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/29018805","citation_count":8,"is_preprint":false},{"pmid":"31278516","id":"PMC_31278516","title":"Evidence for camels (Camelus bactrianus) as the main intermediate host of Echinococcus granulosus sensu lato G6/G7 in Mongolia.","date":"2019","source":"Parasitology research","url":"https://pubmed.ncbi.nlm.nih.gov/31278516","citation_count":8,"is_preprint":false},{"pmid":"38124392","id":"PMC_38124392","title":"Heterozygosity alters Msh5 binding to meiotic chromosomes in the baker's yeast.","date":"2024","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38124392","citation_count":7,"is_preprint":false},{"pmid":"11581177","id":"PMC_11581177","title":"Relative resistance to nasally induced tolerance in non-obese diabetic mice but not other I-A(g7)-expressing mouse strains.","date":"2001","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11581177","citation_count":7,"is_preprint":false},{"pmid":"15368281","id":"PMC_15368281","title":"Self-peptides that bind with low affinity to the diabetes-associated I-A(g7) molecule readily induce T cell tolerance in non-obese diabetic mice.","date":"2004","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15368281","citation_count":7,"is_preprint":false},{"pmid":"37430391","id":"PMC_37430391","title":"RAD51C-RAD51D interplays with MSH5 and regulates crossover maturation in rice meiosis.","date":"2023","source":"The New phytologist","url":"https://pubmed.ncbi.nlm.nih.gov/37430391","citation_count":6,"is_preprint":false},{"pmid":"35181406","id":"PMC_35181406","title":"Early developmental, meiosis-specific proteins - Spo11, Msh4-1, and Msh5 - Affect subsequent genome reorganization in Paramecium tetraurelia.","date":"2022","source":"Biochimica et biophysica acta. Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/35181406","citation_count":6,"is_preprint":false},{"pmid":"20542071","id":"PMC_20542071","title":"MSH5 is not a genetic predisposing factor for immunoglobulin A deficiency but marks the HLA-DRB1*0102 subgroup carrying susceptibility.","date":"2010","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20542071","citation_count":6,"is_preprint":false},{"pmid":"27784303","id":"PMC_27784303","title":"Event-specific detection of transgenic potato AV43-6-G7 using real-time and digital PCR methods.","date":"2016","source":"BMC biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/27784303","citation_count":6,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51924,"output_tokens":4622,"usd":0.112551,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12756,"output_tokens":4408,"usd":0.08699,"stage2_stop_reason":"end_turn"},"total_usd":0.199541,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"MSH5 (yeast) is required for meiotic reciprocal recombination between homologs but not for mismatch repair or gene conversion. Double-mutant analysis with msh4Δ demonstrated that MSH4 and MSH5 are in the same epistasis group, likely functioning together in facilitating interhomolog crossovers during meiosis.\",\n      \"method\": \"Genetic screen, deletion mutants, spore viability assays, recombination assays, msh4 msh5 double-mutant epistasis analysis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean epistasis analysis with double mutants, multiple phenotypic readouts (crossover frequency, nondisjunction, spore viability), replicated across subsequent studies in multiple organisms\",\n      \"pmids\": [\"7622037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Human MSH5 and MSH4 proteins physically interact, as demonstrated by yeast two-hybrid analysis, indicating they form a heterodimer conserved from yeast to humans. Human MSH5 is encoded at 6p22.3-p21.3 and is expressed most highly in testis, thymus, and immune tissues.\",\n      \"method\": \"Yeast two-hybrid interaction analysis, Northern blot, radiation hybrid mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid for interaction, corroborated by mouse Msh5-hMSH4 interaction in a separate study\",\n      \"pmids\": [\"9787078\", \"10556423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Mouse Msh5 knockout causes meiotic defects in both sexes (male and female sterility), with an extended zygotene stage, impaired and aberrant chromosome synapsis, and subsequent apoptotic cell death, demonstrating that Msh5 promotes synapsis of homologous chromosomes during meiotic prophase I.\",\n      \"method\": \"Gene knockout (disruption), histological and cytological examination of meiotic prophase I stages\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cytological phenotype, independently replicated in subsequent studies\",\n      \"pmids\": [\"10072381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"C. elegans msh-5 is required for meiotic crossing over and chiasma formation. Artificially induced DNA breaks do not bypass the requirement for msh-5, placing msh-5 function after the initiation step of meiotic recombination (i.e., after DSB formation). msh-5 mutants can repair breaks but accomplish repair without producing crossovers.\",\n      \"method\": \"msh-5 deletion mutants, chiasma/crossover frequency quantification, radiation-induced DSB experiments, cytological analysis\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal experiments (genetic, cytological, radiation rescue), establishes pathway position\",\n      \"pmids\": [\"11014811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MSH5 (and its obligate heterodimer partner MSH4) plays a role in regulating immunoglobulin class switch recombination (CSR). Msh5-null mice show long microhomologies at Ig switch joints and IgG3 deficiency. A human MSH5 variant with two nonsynonymous polymorphisms shows impaired binding to MSH4, and patients carrying disease-associated MSH5 alleles exhibit increased donor/acceptor microhomology at Ig switch joints. MSH4/5 heterodimers promote resolution of DNA breaks by classical non-homologous end-joining while suppressing an alternative microhomology-mediated pathway.\",\n      \"method\": \"Congenic mouse analysis, Msh5-null mouse phenotyping, sequencing of Ig switch joints, MSH4-MSH5 binding assay with variant protein\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (mouse KO, human variant binding assay, switch joint sequencing) in single study\",\n      \"pmids\": [\"17409188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SMCY (a Y-chromosome-encoded histone H3K4 demethylase) physically interacts with MSH5 in human testicular germ cells (NEC8 cell line), forming a distinct complex. SMCY and MSH5 co-localize at a specific stage of meiotic prophase during murine spermatogenesis, suggesting SMCY recruits MSH5 to condensed DNA as part of epigenetic regulation during meiosis.\",\n      \"method\": \"Co-immunoprecipitation (biochemical protein interaction), immunohistochemistry, histone demethylase activity assay\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP interaction identified plus co-localization by IHC, single lab\",\n      \"pmids\": [\"18459961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The Msh4-Msh5 complex stabilizes single-end invasion intermediates and Holliday junctions during meiosis. Mutagenesis of 57 residues in yeast Msh4 and Msh5 identified threshold mutants with reduced crossovers on large/medium chromosomes but near-wild-type levels on small chromosomes. The Msh5 subunit was more sensitive to mutagenesis, and complex assembly defects were observed.\",\n      \"method\": \"Site-directed mutagenesis (57 residues), spore viability assays, genetic crossover frequency measurement, synaptonemal complex assembly analysis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — extensive mutagenesis of 57 residues with multiple functional readouts in single rigorous study\",\n      \"pmids\": [\"20865162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The C. elegans translation initiation factor IFE-2 upregulates MSH-5 (and MSH-4) protein synthesis at elevated temperatures by shifting their mRNAs from free messenger ribonucleoproteins to polysomes, thereby enabling crossover formation at high temperatures.\",\n      \"method\": \"ife-2 deletion mutant analysis, polysome profiling of msh-4/msh-5 mRNAs, Western blot for MSH-5 protein levels, cytological analysis of bivalents/univalents\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (polysome profiling, Western blot, cytology) in single study\",\n      \"pmids\": [\"20530576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Human MSH5 localizes to mitochondria in both germ and somatic cells, binds to mtDNA, and interacts with Twinkle helicase and DNA polymerase gamma. hMSH5 stimulates mtDNA repair in response to oxidative stress-induced DNA damage. Subsarcolemmal accumulation of hMSH5 was observed in COX-negative muscle fibers of mitochondrial myopathy patients.\",\n      \"method\": \"Subcellular fractionation/localization, mtDNA binding assay, co-immunoprecipitation (Twinkle helicase and pol-gamma), mtDNA repair assay under oxidative stress, immunofluorescence\",\n      \"journal\": \"Mitochondrion\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (fractionation, Co-IP, functional repair assay) in single lab study\",\n      \"pmids\": [\"22917773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Homology modeling of the S. cerevisiae Msh4-Msh5 complex, informed by MutS crystal structures, predicts that mutations affecting meiotic crossovers likely alter protein stability and/or DNA binding interactions. The model predicts structural asymmetry within the Msh4-Msh5 complex and identifies sites important for complex formation and DNA binding.\",\n      \"method\": \"Homology modeling based on MutS crystal structures, evolutionary analysis, integration with existing mutant phenotype data\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational modeling only, no direct structural validation or mutagenesis performed in this study\",\n      \"pmids\": [\"24244354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A mutation in the ATP-binding domain of Msh5 (Msh5ATPase) prevents accumulation of MutSγ (MSH4/MSH5) foci during prophase I. Despite this, most spermatocytes progress further than complete Msh5-null mice. Msh5ATPase spermatocytes show persistent DSBs, incomplete homolog pairing, failure to accumulate MutLγ (MLH1/MLH3), and complete absence of chiasmata—indicating a functional MutSγ complex is required for all crossover events (both class I and class II pathways) in mammalian meiosis.\",\n      \"method\": \"ATPase domain mutagenesis (knock-in mouse), immunofluorescence for MutSγ/MutLγ foci, cytological analysis of DSBs (γH2AX), diakinesis chiasma counting\",\n      \"journal\": \"G3 (Bethesda, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ATPase mutagenesis knock-in with multiple orthogonal cytological readouts; reveals requirement for functional complex in all COs\",\n      \"pmids\": [\"30944090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Biallelic loss-of-function variants in MSH5 cause meiotic arrest in early prophase I in humans, establishing MSH5 as a cause of male infertility (non-obstructive azoospermia). γH2AX staining revealed arrest at early prophase I. Heterologous expression of LoF variants confirmed MSH5 protein truncation or complete loss.\",\n      \"method\": \"Exome sequencing, segregation analysis, γH2AX staining of patient spermatocytes, heterologous protein expression in HEK293T cells\",\n      \"journal\": \"Human reproduction (Oxford, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple patients with biallelic variants, functional validation of protein truncation in vitro, cytological phenotype in patient cells\",\n      \"pmids\": [\"34755185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In S. cerevisiae meiosis, Msh5 specifically associates with DSB hotspots, chromosome axes, and centromeres genome-wide. Efficient binding to DSB hotspots and chromosome axes requires DSB formation and resection and is enhanced by double Holliday junction structures. The axis protein Red1 is required for Msh5 association with chromosome axes and DSB hotspots (but not centromeres). Centromere association of Msh5 is independent of Zip3.\",\n      \"method\": \"Chromatin immunoprecipitation and sequencing (ChIP-seq) in meiotic cells, analysis in spo11Δ, red1Δ, and zip3Δ mutants\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq with multiple genetic backgrounds establishing pathway requirements for chromosomal localization\",\n      \"pmids\": [\"34849874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A homozygous MSH5 frameshift mutation (c.1126del) in NOA patients abolishes chromosome axial localization of MutSγ in spermatocytes. Chromosomal spreading showed meiosis arrest at a zygotene-like stage with extensive failure of homologous synapsis and DSB repair, demonstrating that MSH5/MutSγ axial loading is essential for human meiotic synapsis and recombination.\",\n      \"method\": \"Patient exome sequencing, chromosomal spreading analysis of patient spermatocytes, immunofluorescence for MutSγ localization, γH2AX staining for DSB repair\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human patient material with direct cytological analysis of MutSγ localization and meiotic progression, single study\",\n      \"pmids\": [\"35742973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In heterozygous S. cerevisiae hybrids, Msh5 binding to DSB hotspots is reduced in regions of high heterozygosity (high mismatch density), consistent with Msh5 binding to heteroduplex-containing recombination intermediates. Chimeric sequence reads (heteroduplex DNA) were detected at Msh5-bound DSB hotspots.\",\n      \"method\": \"ChIP-seq in S288c-sp/YJM789 hybrid yeast, SNP-based read assignment, heteroduplex DNA detection via chimeric sequence reads\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq with SNP discrimination in hybrid strain, single lab study\",\n      \"pmids\": [\"38124392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"A specific point mutation in yeast MSH5 (msh5-14, resulting in Y823H substitution) — but not deletion of MSH5 — confers cellular tolerance to DNA alkylating agents (MNNG) in an O6-methylguanine DNA methyltransferase-deficient background. This gain-of-function effect is distinct from loss of mismatch repair.\",\n      \"method\": \"Isolation of MNNG-tolerant revertants, genetic mapping of mutation to MSH5, complementation with msh5 deletion vs. point mutant allele, MNNG survival assays\",\n      \"journal\": \"Cancer research / Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two papers by same lab confirm the Y823H substitution as responsible; point mutation vs. null comparison is mechanistically informative\",\n      \"pmids\": [\"9205082\", \"14557077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A homozygous missense mutation in human MSH5 (p.D487Y) identified in sisters with primary ovarian insufficiency (POI) impairs DNA homologous recombination repair in vitro, and the homologous mutation in mice results in atrophic ovaries without oocytes.\",\n      \"method\": \"Whole exome sequencing, in vitro functional DNA homologous recombination repair assay with mutant MSH5, mouse homologous mutation model\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional in vitro assay combined with mouse phenotype, single lab\",\n      \"pmids\": [\"28175301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The lncRNA HCP5 stabilizes the interaction between YB1 and ILF2, facilitating YB1 nuclear translocation in granulosa cells. HCP5 silencing reduces YB1 binding to the MSH5 promoter, thereby reducing MSH5 transcription. This identifies YB1 as a transcriptional activator of MSH5 that is regulated by HCP5.\",\n      \"method\": \"lncRNA knockdown, YB1 co-IP with ILF2, nuclear fractionation of YB1, chromatin immunoprecipitation (YB1 at MSH5 promoter), MSH5 expression measurement\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, fractionation, ChIP) in single study establishing transcriptional regulation of MSH5\",\n      \"pmids\": [\"32112110\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MSH5 functions as an obligate heterodimer with MSH4 (forming MutSγ) to promote meiotic crossover formation by binding to and stabilizing strand invasion intermediates and Holliday junctions at DSB hotspots on meiotic chromosomes—a function requiring MSH5 ATPase activity and Red1-dependent axial loading—and additionally plays roles in immunoglobulin class switch recombination (suppressing microhomology-mediated end-joining), mitochondrial DNA repair (via interactions with Twinkle helicase and DNA polymerase gamma), and transcriptional regulation by YB1; loss-of-function in humans causes male infertility through meiotic arrest and primary ovarian insufficiency in females.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MSH5 is a meiosis-specific MutS homolog that functions as an obligate heterodimer with MSH4 (forming MutS\\u03b3) to promote interhomolog crossover formation during meiotic recombination [#0, #1]. Genetic epistasis in yeast placed MSH5 and MSH4 in a single pathway required for reciprocal recombination but dispensable for mismatch repair [#0], and worm studies positioned its function downstream of DSB formation: msh-5 mutants repair breaks but fail to convert them into crossovers and chiasmata [#3]. Mechanistically, MutS\\u03b3 binds and stabilizes single-end invasion intermediates and Holliday junctions [#6], and genome-wide ChIP showed that Msh5 associates with DSB hotspots, chromosome axes, and centromeres, with hotspot/axis binding requiring DSB formation and resection, enhancement by double Holliday junctions, and dependence on the axis protein Red1 [#12]; binding is reduced in heteroduplex-rich regions, consistent with engagement of mismatch-containing recombination intermediates [#14]. A functional MSH5 ATPase domain is required for stable MutS\\u03b3 focus accumulation and for all classes of crossover, since ATPase mutants fail to load MutL\\u03b3, retain persistent DSBs, and lack chiasmata [#10]. Loss of MSH5 disrupts homolog synapsis and arrests meiosis with apoptosis in mouse knockouts [#2], and in humans biallelic loss-of-function and axial-loading-defective variants cause meiotic arrest and non-obstructive azoospermia in males [#11, #13], while a missense allele impairs homologous recombination repair and causes primary ovarian insufficiency in females [#16]. Beyond meiosis, MSH4/MSH5 heterodimers influence immunoglobulin class switch recombination by favoring classical end-joining over a microhomology-mediated pathway [#4], and human MSH5 localizes to mitochondria, binds mtDNA, and interacts with Twinkle helicase and DNA polymerase gamma to stimulate mtDNA repair under oxidative stress [#8]. MSH5 expression is transcriptionally activated by YB1 at its promoter under lncRNA HCP5 control [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established that MSH5 acts specifically in meiotic crossover formation rather than mismatch repair, and that it works in the same pathway as MSH4.\",\n      \"evidence\": \"Genetic deletion and msh4 msh5 double-mutant epistasis with recombination and spore viability readouts in yeast\",\n      \"pmids\": [\"7622037\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the biochemical activity of MSH5\", \"Heterodimer formation not directly demonstrated\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Showed MSH5\\u2013MSH4 heterodimer formation is conserved to humans, defining the molecular partnership underlying the genetic pathway.\",\n      \"evidence\": \"Yeast two-hybrid interaction, Northern blot expression profiling, radiation hybrid mapping\",\n      \"pmids\": [\"9787078\", \"10556423\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Two-hybrid does not establish stoichiometry or in vivo complex\", \"No DNA-binding activity tested\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstrated MSH5 is required for homolog synapsis in meiotic prophase I in a mammal, with loss causing both male and female sterility.\",\n      \"evidence\": \"Mouse Msh5 knockout with cytological staging of prophase I and apoptosis assessment\",\n      \"pmids\": [\"10072381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether synapsis defect is direct or secondary to recombination failure not resolved\", \"No molecular interaction with DNA shown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Placed MSH5 function downstream of DSB initiation, showing it converts breaks into crossovers rather than initiating recombination.\",\n      \"evidence\": \"C. elegans msh-5 mutants with radiation-induced DSB rescue experiments and chiasma quantification\",\n      \"pmids\": [\"11014811\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the intermediate MSH5 binds\", \"No structural basis for crossover specification\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Extended MSH4/MSH5 function beyond meiosis to immunoglobulin class switch recombination, biasing repair toward classical end-joining.\",\n      \"evidence\": \"Msh5-null mouse phenotyping, Ig switch joint sequencing, MSH4-MSH5 binding assay with human variant\",\n      \"pmids\": [\"17409188\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of microhomology suppression not defined\", \"Direct role of MSH5 at switch regions vs. indirect effect unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linked MSH5 to epigenetic regulation in spermatogenesis via interaction with the H3K4 demethylase SMCY.\",\n      \"evidence\": \"Co-immunoprecipitation and immunohistochemistry co-localization in testicular germ cells\",\n      \"pmids\": [\"18459961\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab Co-IP without reciprocal validation\", \"Functional consequence of recruitment to condensed DNA not established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the biochemical role of MutS\\u03b3 as stabilizing strand-invasion intermediates and Holliday junctions, with chromosome-size-dependent crossover thresholds.\",\n      \"evidence\": \"Site-directed mutagenesis of 57 residues with crossover frequency and synaptonemal complex assays in yeast\",\n      \"pmids\": [\"20865162\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No direct structural data on junction binding\", \"Asymmetry between MSH4 and MSH5 subunits inferred from genetics only\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified translational control of MSH5 levels by IFE-2 as a mechanism enabling crossover formation under temperature stress.\",\n      \"evidence\": \"ife-2 mutant analysis, polysome profiling, Western blot, and bivalent cytology in C. elegans\",\n      \"pmids\": [\"20530576\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this regulation is conserved in mammals unknown\", \"Direct binding of IFE-2 to msh-5 mRNA not shown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed a mitochondrial role for human MSH5 in mtDNA repair through interactions with the replication/repair machinery.\",\n      \"evidence\": \"Subcellular fractionation, mtDNA binding, Co-IP with Twinkle and pol-gamma, oxidative-stress repair assay\",\n      \"pmids\": [\"22917773\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MSH4 dependence of mitochondrial function not tested\", \"In vivo significance for mitochondrial disease correlative only\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided a structural framework predicting how MutS\\u03b3 binds DNA and how crossover mutations destabilize the complex.\",\n      \"evidence\": \"Homology modeling on MutS crystal structures integrated with mutant phenotype data\",\n      \"pmids\": [\"24244354\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Computational model with no experimental structural validation\", \"Predicted asymmetry and DNA-contact sites untested in this study\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated that MSH5 ATPase activity is essential for stable MutS\\u03b3 foci and for all crossover classes in mammalian meiosis.\",\n      \"evidence\": \"ATPase-domain knock-in mouse with MutS\\u03b3/MutL\\u03b3 foci, \\u03b3H2AX, and chiasma cytology\",\n      \"pmids\": [\"30944090\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical ATP-hydrolysis cycle not directly measured\", \"How ATPase state couples to MutL\\u03b3 loading unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established MSH5 as a human meiotic infertility gene, with biallelic loss-of-function causing early prophase I arrest and azoospermia.\",\n      \"evidence\": \"Exome sequencing, segregation, \\u03b3H2AX staining of patient spermatocytes, heterologous expression\",\n      \"pmids\": [\"34755185\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Female reproductive consequences in same cohort not characterized\", \"Residual partial function of some variants not quantified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapped the chromosomal binding behavior of Msh5 genome-wide and established Red1-dependent axial loading at DSB hotspots.\",\n      \"evidence\": \"Meiotic ChIP-seq in spo11\\u0394, red1\\u0394, and zip3\\u0394 yeast mutants\",\n      \"pmids\": [\"34849874\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of Red1-mediated recruitment not defined\", \"Centromere association function unexplained\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Confirmed in humans that MSH5/MutS\\u03b3 axial loading is required for meiotic synapsis and DSB repair.\",\n      \"evidence\": \"Patient exome sequencing with chromosomal spreading and MutS\\u03b3 immunofluorescence in spermatocytes\",\n      \"pmids\": [\"35742973\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study on patient material\", \"Whether the human axial-loading factor is a Red1 ortholog not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided direct evidence that Msh5 engages heteroduplex-containing recombination intermediates, refining its substrate at DSB hotspots.\",\n      \"evidence\": \"ChIP-seq in heterozygous hybrid yeast with SNP-based read assignment and chimeric read detection\",\n      \"pmids\": [\"38124392\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal effect of mismatch density on crossover outcome not established\", \"Single-lab observation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the MSH5 ATPase cycle, heteroduplex recognition, and Red1-dependent axial loading are mechanistically coupled to MutL\\u03b3 recruitment and crossover designation remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No experimentally determined structure of the MutS\\u03b3\\u2013DNA complex\", \"Human axial-loading factor analogous to Red1 not identified\", \"Biochemical reconstitution of MutS\\u03b3 sliding-clamp dynamics on junctions lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [6, 12, 14]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [8, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [12, 13]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0, 2, 10, 11]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [8, 16]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\"MutS\\u03b3 (MSH4-MSH5)\"],\n    \"partners\": [\"MSH4\", \"SMCY\", \"TWNK\", \"POLG\", \"RED1\", \"YB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}