{"gene":"MAU2","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2000,"finding":"Scc4 (yeast ortholog of MAU2) forms a complex with Scc2 and this heterodimeric complex is required for loading cohesin onto chromosomes. In scc4 mutants, cohesin complexes form normally but fail to bind centromeres and chromosome arms, establishing that Scc2/Scc4 facilitates cohesin loading rather than cohesin assembly.","method":"Genetic epistasis, co-immunoprecipitation, chromatin binding assays in budding yeast","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP and genetic epistasis in yeast, foundational study replicated across multiple subsequent labs","pmids":["10882066"],"is_preprint":false},{"year":2006,"finding":"Human MAU2 (SCC4) is the ortholog of yeast Scc4. It associates with NIPBL (Scc2 ortholog), is bound to chromatin from telophase until prophase, and is required for cohesin association with chromatin during interphase. Depletion of MAU2 causes precocious sister-chromatid separation and prometaphase arrest; mitotic chromosomes lack cohesin even though Sgo1/Bub1 are normally enriched at centromeres.","method":"siRNA knockdown, co-immunoprecipitation, chromatin fractionation, immunofluorescence in HeLa cells","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, chromatin fractionation, knockdown with defined phenotypic readout), replicated by independent lab in same issue","pmids":["16682347"],"is_preprint":false},{"year":2006,"finding":"Metazoan MAU2 orthologs (human MAU2, Drosophila MAU-2) bind delangin/Nipped-B (NIPBL orthologs), with the interaction domain mapped to the N-terminal regions of both proteins. siRNA knockdown of human MAU2 in HeLa cells causes precocious sister chromatid separation and impaired cohesin loading onto chromatin. MAU2 regulates chromosome segregation in C. elegans embryos by RNAi.","method":"Protein-protein interaction mapping (pulldown), siRNA knockdown, RNAi in C. elegans, Xenopus morpholino knockdown","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods across multiple model organisms, independent of PMID 16682347","pmids":["16802858"],"is_preprint":false},{"year":2006,"finding":"Fission yeast Ssl3 (Scc4 ortholog) forms a complex with Mis4 (Scc2 ortholog) and is required in G1 for cohesin binding to chromosomes but is dispensable in G2 when cohesion is already established, demonstrating that the Scc2/Scc4 loading complex is functionally conserved in S. pombe.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, genetic analysis in S. pombe","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP and ChIP with cell-cycle stage resolution, independent lab confirming conservation of loader function","pmids":["16682348"],"is_preprint":false},{"year":2009,"finding":"The Scc2/Scc4 loader determines the nonrandom chromosomal distribution of cohesin. Both Scc2 and Scc4 co-localize with cohesin at cohesin-associated regions (CARs), including pericentromeric regions where enrichment is kinetochore-dependent. Scc2/Scc4 association with CARs is independent of cohesin itself.","method":"Chromatin immunoprecipitation (ChIP) genome-wide mapping in budding yeast","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP with multiple controls, single lab but comprehensive methodology","pmids":["19797771"],"is_preprint":false},{"year":2012,"finding":"Purified human Scc2/Scc4 (NIPBL/MAU2) heterodimer interacts with human cohesin and the Smc1-Smc3 heterodimer (but not Smc1 or Smc3 alone) and loads cohesin onto dsDNA containing prereplication complexes in vitro. Loading requires pre-RC formation and is blocked by geminin.","method":"In vitro cohesin loading assay, co-immunoprecipitation of purified human proteins, Xenopus extract depletion/complementation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified human NIPBL/MAU2, depletion/rescue experiments, multiple orthogonal assays in one study","pmids":["22628566"],"is_preprint":false},{"year":2014,"finding":"The Scc2-Scc4 cohesin loader complex is recruited to broad nucleosome-free regions by the RSC chromatin remodeling complex, and the loader helps maintain these nucleosome-free regions. Inactivation of either Scc2-Scc4 or RSC produces similar effects on nucleosome positioning, gene expression, and sister chromatid cohesion, placing the loader downstream of RSC in chromatin organization.","method":"Genetic epistasis, nucleosome mapping (MNase-seq), gene expression analysis, chromatin immunoprecipitation in budding yeast","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP, MNase-seq, epistasis), replicated findings linking loader to chromatin remodeling","pmids":["25173104"],"is_preprint":false},{"year":2015,"finding":"Crystal structure of Scc4 (MAU2 ortholog) bound to the N-terminal peptide of Scc2 reveals that Scc4 is a TPR-repeat superhelix that envelops an extended Scc2 N-terminal peptide. A conserved surface patch on Scc4 is required for recruitment of Scc2/Scc4 to centromeres and for building pericentromeric cohesion, establishing the molecular basis for Scc4-dependent localization of cohesin loading.","method":"X-ray crystallography, yeast genetics (centromere recruitment assays, cohesion assays), mutagenesis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with functional mutagenesis and in vivo cohesion assays, multiple orthogonal validations","pmids":["26038942"],"is_preprint":false},{"year":2015,"finding":"Crystal structure of Scc4 bound to the Scc2 N-terminus shows Scc4 is a TPR superhelix entrapping an extended Scc2 N-terminal segment. EM analysis reveals the Scc2-Scc4 complex has three domains (head=Scc2N-Scc4, body, hook). In vitro cohesin loading assays show the body and hook domains are sufficient for loading onto circular DNA but not chromatinized DNA, suggesting Scc4 functions as a chromatin adaptor.","method":"X-ray crystallography, electron microscopy, in vitro cohesin loading assay on circular and chromatinized DNA","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure, EM, and functional in vitro loading assays with domain deletion analysis in one study","pmids":["26212329"],"is_preprint":false},{"year":2016,"finding":"A genetic screen identified functional domains in yeast Scc4 required for cohesin loading. The N-terminal region of Scc4 is dominant negative when overexpressed and essential for Scc2/Scc4 activity. Mutant alleles reduce but do not eliminate interaction of Scc4 with Scc2 or cohesin. Scc4 cannot bind cohesin in the absence of Scc2.","method":"Random insertion/dominant negative genetic screen, viability assays, cohesion assays, co-immunoprecipitation in budding yeast","journal":"G3 (Bethesda, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic screen with Co-IP validation, single lab, multiple readouts but no structural confirmation","pmids":["27280786"],"is_preprint":false},{"year":2004,"finding":"C. elegans MAU-2 protein localizes to the cytoplasm of neurons, is ubiquitously expressed in embryos and predominantly in the nervous system during morphogenesis, and functions cell-autonomously in individual neurons to guide axonal migrations. Genetic interaction with slt-1 reveals mau-2 participates in AVM axon guidance through a slt-1-independent mechanism.","method":"GFP fusion protein localization, tissue-specific rescue experiments, genetic epistasis with slt-1 in C. elegans","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging of GFP fusion, cell-autonomous rescue, and genetic epistasis in C. elegans, single lab","pmids":["15539489"],"is_preprint":false},{"year":2011,"finding":"Specific NIPBL missense mutations that cause Cornelia de Lange syndrome map to the MAU2-interacting domain of NIPBL and result in markedly reduced MAU2 binding, establishing that disruption of the NIPBL-MAU2 interaction is a pathogenic mechanism in CdLS.","method":"Protein-protein interaction mapping, co-immunoprecipitation, clinical variant analysis","journal":"European journal of human genetics : EJHG","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction mapping with clinical variants, single lab, Co-IP-based evidence","pmids":["21934712"],"is_preprint":false},{"year":2013,"finding":"NIPBL/MAU2 heterodimer localizes to chromosomal axes from zygotene to mid-pachytene in mammalian germ cells of both sexes during meiotic prophase I. In spermatocytes it relocalizes to chromocenters, while in oocytes it remains on chromosomal axes throughout prophase. Its localization pattern is consistent with a role as a loading factor for cohesin and condensin I (but not SMC5/6) during meiosis.","method":"Immunofluorescence localization in mouse spermatocytes and oocytes, co-localization with SMC complex markers","journal":"Chromosoma","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct immunolocalization in primary cells across sexes, but no functional perturbation of MAU2 specifically in this study","pmids":["24287868"],"is_preprint":false},{"year":2014,"finding":"Neural crest cell-specific inactivation of Mau2 in mice strongly affects craniofacial development. Early neural crest cell proliferation and migration are only moderately affected, suggesting cohesin loading is more critical for later developmental gene regulation. Mau2 single homozygous mutants showed a more severe craniofacial phenotype than Nipbl;Mau2 double homozygous mutants, suggesting the Mau2/Nipbl interaction may also restrict Nipbl's role in gene expression regulation.","method":"Conditional gene knockout in mice (Cre-lox), phenotypic analysis of neural crest-specific knockouts","journal":"Genesis (New York, N.Y. : 2000)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO mouse with defined cell-type specificity and epistasis between Mau2 and Nipbl, single lab","pmids":["24700590"],"is_preprint":false},{"year":2020,"finding":"A MAU2 variant (7 amino acid in-frame deletion) causing CdLS impairs the interaction between MAU2 and the NIPBL N-terminus. However, cohesin loading can occur independently of a functional NIPBL/MAU2 complex: an NIPBL truncating mutation leads to alternative translation initiation producing an NIPBL form lacking the MAU2-binding N-terminus, which can still bind DNA and mediate cohesin loading.","method":"Patient variant characterization, co-immunoprecipitation, engineered cell lines with NIPBL truncating mutations, cohesin ChIP","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple engineered cell lines, Co-IP, cohesin ChIP, multiple orthogonal approaches in one study establishing both the interaction requirement and its dispensability under certain conditions","pmids":["32433956"],"is_preprint":false},{"year":2025,"finding":"NIPBL contains two clusters of LxxLL motifs: one interacts with MAU2 and is necessary for maintaining the NIPBL-MAU2 heterodimer; the second binds the ligand-binding domains of steroid receptors. The glucocorticoid receptor (GR), NIPBL, and MAU2 form a ternary complex (modeled by AlphaFold2 and molecular docking), and this interaction is important for GR-dependent gene regulation. Multiple transcription factors interact with NIPBL-MAU2 to localize cohesin at enhancers.","method":"LxxLL motif mutagenesis, co-immunoprecipitation, AlphaFold2 structural modeling with molecular docking, transcriptional reporter assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and functional assays combined with computational structural modeling; AlphaFold2 predictions support but do not replace experimental structure determination","pmids":["40377219"],"is_preprint":false},{"year":2025,"finding":"18 individuals with 15 heterozygous MAU2 variants display CdLS phenotypes. In-frame MAU2 variants predominantly impair NIPBL-MAU2 interaction, while truncating variants cause MAU2 haploinsufficiency and lead to NIPBL reduction. A heterozygous Mau2 knockout mouse model recapitulates the human phenotype (short stature, microcephaly), confirming MAU2 disruption as causal.","method":"Patient variant functional analysis, co-immunoprecipitation, Western blot, DNA methylation episignature analysis, heterozygous Mau2 knockout mouse model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional analyses of multiple variants across 18 patients, mouse KO model recapitulation, multiple orthogonal methods","pmids":["41912533"],"is_preprint":false},{"year":2019,"finding":"In maize, DEK15/SCC4 (MAU2 ortholog) interacts with chromatin remodeling proteins (CHB102, CHB105, CHB106) identified by yeast two-hybrid, suggesting a mechanism for cohesin loading onto chromatin via chromatin remodelers, consistent with findings in yeast.","method":"Yeast two-hybrid screen, genetic positional cloning, chromosome segregation analysis","journal":"The Plant cell","confidence":"Low","confidence_rationale":"Tier 3 / Weak — yeast two-hybrid only for protein interactions, plant ortholog may not directly inform human MAU2 mechanism","pmids":["30705131"],"is_preprint":false}],"current_model":"MAU2 (SCC4) forms an obligate heterodimer with NIPBL (SCC2/delangin) through an N-terminal interaction interface; Scc4/MAU2 is a TPR-repeat superhelix that envelops the Scc2/NIPBL N-terminal peptide (crystal structure resolved), and a conserved surface patch on MAU2 recruits the loader complex to centromeres and other cohesin-associated regions to determine the genomic distribution of cohesin loading; the NIPBL/MAU2 complex catalyzes ATP-dependent loading of the cohesin ring onto DNA, a process that in vivo requires pre-replication complex formation and, at specific loci, recruitment via the RSC chromatin remodeling complex and direct interactions with transcription factors (including steroid receptors) that form ternary complexes with NIPBL/MAU2 at enhancers; loss of MAU2 results in failure of cohesin to associate with chromatin, precocious sister chromatid separation, and mitotic arrest, and MAU2 haploinsufficiency in humans and mice causes Cornelia de Lange syndrome."},"narrative":{"mechanistic_narrative":"MAU2 (SCC4) is an essential cohesin-loading factor that, together with NIPBL (SCC2), directs the ATP-dependent topological loading of the cohesin ring onto chromatin to enable sister chromatid cohesion and chromosome organization [PMID:10882066, PMID:16682347, PMID:22628566]. MAU2 forms an obligate heterodimer with NIPBL through an N-terminal interface: MAU2 is a TPR-repeat superhelix that envelops an extended NIPBL N-terminal peptide, and MAU2 cannot engage cohesin in the absence of NIPBL [PMID:26038942, PMID:26212329, PMID:27280786]. The heterodimer interacts with the Smc1–Smc3 heterodimer and loads cohesin onto double-stranded DNA, a reaction that in vitro requires pre-replication complex formation [PMID:22628566]. MAU2 determines where loading occurs: a conserved MAU2 surface patch recruits the loader to centromeres to build pericentromeric cohesion, and MAU2 acts as a chromatin adaptor enabling loading onto chromatinized—not merely naked—DNA [PMID:26038942, PMID:26212329]. Genomic targeting is further shaped by the RSC chromatin remodeling complex, which recruits the loader to nucleosome-free regions [PMID:25173104], and by transcription factors including the glucocorticoid receptor, which form ternary complexes with NIPBL–MAU2 to position cohesin at enhancers [PMID:40377219]. Loss of MAU2 abolishes cohesin association with chromatin and causes precocious sister chromatid separation and prometaphase arrest [PMID:16682347, PMID:16802858]. Beyond mitotic chromosomes, the heterodimer localizes to meiotic chromosomal axes [PMID:24287868], and MAU2 supports craniofacial and neural crest development in mice [PMID:24700590]. Heterozygous MAU2 variants that impair the NIPBL interaction or cause MAU2 haploinsufficiency cause Cornelia de Lange syndrome, recapitulated in a heterozygous Mau2 knockout mouse [PMID:32433956, PMID:41912533].","teleology":[{"year":2000,"claim":"Established that cohesin loading onto chromosomes is a distinct step from cohesin assembly, mediated by a dedicated Scc2/Scc4 complex.","evidence":"Genetic epistasis, co-immunoprecipitation and chromatin binding assays in budding yeast","pmids":["10882066"],"confidence":"High","gaps":["Did not resolve the molecular mechanism of loading","Mammalian relevance not yet shown"]},{"year":2006,"claim":"Demonstrated that the loader is conserved across metazoans and fungi, with MAU2/Scc4 binding NIPBL/Scc2 via N-terminal regions and being required for cohesin chromatin association and faithful chromosome segregation.","evidence":"siRNA knockdown, Co-IP, chromatin fractionation in HeLa cells; interaction domain mapping and RNAi across Drosophila, C. elegans, Xenopus; Co-IP/ChIP with cell-cycle resolution in S. pombe","pmids":["16682347","16802858","16682348"],"confidence":"High","gaps":["Direct enzymatic loading not yet reconstituted","Determinants of genomic targeting unknown"]},{"year":2009,"claim":"Showed that the loader, not cohesin itself, dictates the nonrandom genomic distribution of cohesin, with kinetochore-dependent enrichment at pericentromeres.","evidence":"Genome-wide ChIP mapping of Scc2 and Scc4 in budding yeast","pmids":["19797771"],"confidence":"High","gaps":["Recruitment cues to specific loci not defined","Yeast-only mapping"]},{"year":2012,"claim":"Reconstituted human NIPBL/MAU2 loading of cohesin in vitro and linked it to DNA replication licensing.","evidence":"In vitro loading assay with purified human proteins, Co-IP, Xenopus extract depletion/complementation; loading required pre-RC and was blocked by geminin","pmids":["22628566"],"confidence":"High","gaps":["Role of MAU2 versus NIPBL in catalysis not separated","Chromatin-template requirements not addressed"]},{"year":2014,"claim":"Placed the loader downstream of chromatin remodeling, showing RSC recruits the complex to nucleosome-free regions, and connected MAU2 to developmental gene regulation in mammals.","evidence":"MNase-seq, ChIP and genetic epistasis in yeast; conditional neural-crest Mau2 knockout in mice","pmids":["25173104","24700590"],"confidence":"Medium","gaps":["Direct RSC–MAU2 contact not structurally defined","How loader maintains nucleosome-free regions unresolved"]},{"year":2015,"claim":"Defined the molecular basis of the heterodimer: MAU2 is a TPR superhelix wrapping the NIPBL N-terminus, with a conserved surface patch driving centromere recruitment and a chromatin-adaptor role for loading onto nucleosomal DNA.","evidence":"X-ray crystallography, electron microscopy, in vitro loading on circular and chromatinized DNA, and in vivo cohesion/recruitment assays in yeast","pmids":["26038942","26212329"],"confidence":"High","gaps":["Structure of the full loader engaging cohesin not resolved","Human structural confirmation absent"]},{"year":2016,"claim":"Genetically dissected MAU2/Scc4 functional domains, confirming its N-terminal region is essential and that it requires NIPBL to engage cohesin.","evidence":"Dominant-negative insertion screen, viability/cohesion assays, Co-IP in budding yeast","pmids":["27280786"],"confidence":"Medium","gaps":["No structural confirmation of mutant defects","Yeast-only analysis"]},{"year":2020,"claim":"Revealed that the NIPBL–MAU2 interaction, though required normally, can be bypassed: an N-terminally truncated NIPBL lacking the MAU2-binding region still binds DNA and loads cohesin.","evidence":"Patient variant characterization, Co-IP, engineered NIPBL-truncation cell lines, cohesin ChIP","pmids":["32433956"],"confidence":"High","gaps":["Physiological contribution of MAU2-independent loading unclear","Efficiency relative to intact heterodimer not quantified"]},{"year":2025,"claim":"Connected loader targeting to transcription factor signaling, showing NIPBL LxxLL motifs bridge MAU2 and steroid receptors to form ternary complexes positioning cohesin at enhancers.","evidence":"LxxLL mutagenesis, Co-IP, AlphaFold2 modeling with docking, reporter assays","pmids":["40377219"],"confidence":"Medium","gaps":["Ternary complex structure is computational, not experimentally determined","Direct MAU2 contacts with receptors not mapped"]},{"year":2025,"claim":"Confirmed MAU2 as a causal CdLS gene, distinguishing two pathogenic mechanisms—impaired NIPBL interaction versus MAU2 haploinsufficiency with secondary NIPBL reduction—and recapitulating the phenotype in mice.","evidence":"Functional analysis of 15 variants across 18 patients, Co-IP, Western blot, methylation episignature, heterozygous Mau2 knockout mouse","pmids":["41912533"],"confidence":"High","gaps":["Mechanism linking cohesin loading defect to specific craniofacial/growth phenotypes unresolved","Genotype-phenotype correlations incomplete"]},{"year":null,"claim":"How MAU2-dependent loader targeting integrates chromatin remodeling, replication licensing, and transcription-factor cues to specify cohesin loading sites genome-wide remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified human structure of the loader engaging chromatin and cohesin","Quantitative contribution of each targeting pathway unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7,8,9]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[5,8]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[1,4,12]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[6,15]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[13,16]}],"complexes":["NIPBL/MAU2 cohesin loader complex"],"partners":["NIPBL","SMC1","SMC3","NR3C1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y6X3","full_name":"MAU2 chromatid cohesion factor homolog","aliases":["Cohesin loading complex subunit SCC4 homolog"],"length_aa":613,"mass_kda":69.1,"function":"Plays an important role in the loading of the cohesin complex on to DNA. Forms a heterodimeric complex (also known as cohesin loading complex) with NIPBL/SCC2 which mediates the loading of the cohesin complex onto chromatin (PubMed:22628566, PubMed:28167679). Plays a role in sister chromatid cohesion and normal progression through prometaphase (PubMed:16682347, PubMed:16802858)","subcellular_location":"Nucleus, nucleoplasm; Nucleus; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q9Y6X3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAU2","classification":"Not Classified","n_dependent_lines":687,"n_total_lines":1208,"dependency_fraction":0.5687086092715232},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CBX1","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"SMC1A","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2},{"gene":"TOP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MAU2","total_profiled":1310},"omim":[{"mim_id":"621570","title":"CORNELIA DE LANGE SYNDROME 7; CDLS7","url":"https://www.omim.org/entry/621570"},{"mim_id":"614560","title":"MAU2 SISTER CHROMATID COHESION FACTOR; MAU2","url":"https://www.omim.org/entry/614560"},{"mim_id":"608667","title":"NIPPED-B-LIKE; NIPBL","url":"https://www.omim.org/entry/608667"},{"mim_id":"606062","title":"STRUCTURAL MAINTENANCE OF CHROMOSOMES 3; SMC3","url":"https://www.omim.org/entry/606062"},{"mim_id":"604358","title":"STROMAL ANTIGEN 1; STAG1","url":"https://www.omim.org/entry/604358"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MAU2"},"hgnc":{"alias_symbol":["MGC75361","mau-2","MAU2L","SCC4"],"prev_symbol":["KIAA0892"]},"alphafold":{"accession":"Q9Y6X3","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6X3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6X3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6X3-F1-predicted_aligned_error_v6.png","plddt_mean":91.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAU2","jax_strain_url":"https://www.jax.org/strain/search?query=MAU2"},"sequence":{"accession":"Q9Y6X3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y6X3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y6X3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6X3"}},"corpus_meta":[{"pmid":"10882066","id":"PMC_10882066","title":"Cohesin's binding to chromosomes depends on a separate complex consisting of Scc2 and Scc4 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In scc4 mutants, cohesin complexes form normally but fail to bind centromeres and chromosome arms, establishing that Scc2/Scc4 facilitates cohesin loading rather than cohesin assembly.\",\n      \"method\": \"Genetic epistasis, co-immunoprecipitation, chromatin binding assays in budding yeast\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP and genetic epistasis in yeast, foundational study replicated across multiple subsequent labs\",\n      \"pmids\": [\"10882066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Human MAU2 (SCC4) is the ortholog of yeast Scc4. It associates with NIPBL (Scc2 ortholog), is bound to chromatin from telophase until prophase, and is required for cohesin association with chromatin during interphase. Depletion of MAU2 causes precocious sister-chromatid separation and prometaphase arrest; mitotic chromosomes lack cohesin even though Sgo1/Bub1 are normally enriched at centromeres.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, chromatin fractionation, immunofluorescence in HeLa cells\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, chromatin fractionation, knockdown with defined phenotypic readout), replicated by independent lab in same issue\",\n      \"pmids\": [\"16682347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Metazoan MAU2 orthologs (human MAU2, Drosophila MAU-2) bind delangin/Nipped-B (NIPBL orthologs), with the interaction domain mapped to the N-terminal regions of both proteins. siRNA knockdown of human MAU2 in HeLa cells causes precocious sister chromatid separation and impaired cohesin loading onto chromatin. MAU2 regulates chromosome segregation in C. elegans embryos by RNAi.\",\n      \"method\": \"Protein-protein interaction mapping (pulldown), siRNA knockdown, RNAi in C. elegans, Xenopus morpholino knockdown\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods across multiple model organisms, independent of PMID 16682347\",\n      \"pmids\": [\"16802858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Fission yeast Ssl3 (Scc4 ortholog) forms a complex with Mis4 (Scc2 ortholog) and is required in G1 for cohesin binding to chromosomes but is dispensable in G2 when cohesion is already established, demonstrating that the Scc2/Scc4 loading complex is functionally conserved in S. pombe.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, genetic analysis in S. pombe\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP and ChIP with cell-cycle stage resolution, independent lab confirming conservation of loader function\",\n      \"pmids\": [\"16682348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The Scc2/Scc4 loader determines the nonrandom chromosomal distribution of cohesin. Both Scc2 and Scc4 co-localize with cohesin at cohesin-associated regions (CARs), including pericentromeric regions where enrichment is kinetochore-dependent. Scc2/Scc4 association with CARs is independent of cohesin itself.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) genome-wide mapping in budding yeast\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP with multiple controls, single lab but comprehensive methodology\",\n      \"pmids\": [\"19797771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Purified human Scc2/Scc4 (NIPBL/MAU2) heterodimer interacts with human cohesin and the Smc1-Smc3 heterodimer (but not Smc1 or Smc3 alone) and loads cohesin onto dsDNA containing prereplication complexes in vitro. Loading requires pre-RC formation and is blocked by geminin.\",\n      \"method\": \"In vitro cohesin loading assay, co-immunoprecipitation of purified human proteins, Xenopus extract depletion/complementation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified human NIPBL/MAU2, depletion/rescue experiments, multiple orthogonal assays in one study\",\n      \"pmids\": [\"22628566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The Scc2-Scc4 cohesin loader complex is recruited to broad nucleosome-free regions by the RSC chromatin remodeling complex, and the loader helps maintain these nucleosome-free regions. Inactivation of either Scc2-Scc4 or RSC produces similar effects on nucleosome positioning, gene expression, and sister chromatid cohesion, placing the loader downstream of RSC in chromatin organization.\",\n      \"method\": \"Genetic epistasis, nucleosome mapping (MNase-seq), gene expression analysis, chromatin immunoprecipitation in budding yeast\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP, MNase-seq, epistasis), replicated findings linking loader to chromatin remodeling\",\n      \"pmids\": [\"25173104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of Scc4 (MAU2 ortholog) bound to the N-terminal peptide of Scc2 reveals that Scc4 is a TPR-repeat superhelix that envelops an extended Scc2 N-terminal peptide. A conserved surface patch on Scc4 is required for recruitment of Scc2/Scc4 to centromeres and for building pericentromeric cohesion, establishing the molecular basis for Scc4-dependent localization of cohesin loading.\",\n      \"method\": \"X-ray crystallography, yeast genetics (centromere recruitment assays, cohesion assays), mutagenesis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with functional mutagenesis and in vivo cohesion assays, multiple orthogonal validations\",\n      \"pmids\": [\"26038942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of Scc4 bound to the Scc2 N-terminus shows Scc4 is a TPR superhelix entrapping an extended Scc2 N-terminal segment. EM analysis reveals the Scc2-Scc4 complex has three domains (head=Scc2N-Scc4, body, hook). In vitro cohesin loading assays show the body and hook domains are sufficient for loading onto circular DNA but not chromatinized DNA, suggesting Scc4 functions as a chromatin adaptor.\",\n      \"method\": \"X-ray crystallography, electron microscopy, in vitro cohesin loading assay on circular and chromatinized DNA\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure, EM, and functional in vitro loading assays with domain deletion analysis in one study\",\n      \"pmids\": [\"26212329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A genetic screen identified functional domains in yeast Scc4 required for cohesin loading. The N-terminal region of Scc4 is dominant negative when overexpressed and essential for Scc2/Scc4 activity. Mutant alleles reduce but do not eliminate interaction of Scc4 with Scc2 or cohesin. Scc4 cannot bind cohesin in the absence of Scc2.\",\n      \"method\": \"Random insertion/dominant negative genetic screen, viability assays, cohesion assays, co-immunoprecipitation in budding yeast\",\n      \"journal\": \"G3 (Bethesda, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic screen with Co-IP validation, single lab, multiple readouts but no structural confirmation\",\n      \"pmids\": [\"27280786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"C. elegans MAU-2 protein localizes to the cytoplasm of neurons, is ubiquitously expressed in embryos and predominantly in the nervous system during morphogenesis, and functions cell-autonomously in individual neurons to guide axonal migrations. Genetic interaction with slt-1 reveals mau-2 participates in AVM axon guidance through a slt-1-independent mechanism.\",\n      \"method\": \"GFP fusion protein localization, tissue-specific rescue experiments, genetic epistasis with slt-1 in C. elegans\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging of GFP fusion, cell-autonomous rescue, and genetic epistasis in C. elegans, single lab\",\n      \"pmids\": [\"15539489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Specific NIPBL missense mutations that cause Cornelia de Lange syndrome map to the MAU2-interacting domain of NIPBL and result in markedly reduced MAU2 binding, establishing that disruption of the NIPBL-MAU2 interaction is a pathogenic mechanism in CdLS.\",\n      \"method\": \"Protein-protein interaction mapping, co-immunoprecipitation, clinical variant analysis\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction mapping with clinical variants, single lab, Co-IP-based evidence\",\n      \"pmids\": [\"21934712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NIPBL/MAU2 heterodimer localizes to chromosomal axes from zygotene to mid-pachytene in mammalian germ cells of both sexes during meiotic prophase I. In spermatocytes it relocalizes to chromocenters, while in oocytes it remains on chromosomal axes throughout prophase. Its localization pattern is consistent with a role as a loading factor for cohesin and condensin I (but not SMC5/6) during meiosis.\",\n      \"method\": \"Immunofluorescence localization in mouse spermatocytes and oocytes, co-localization with SMC complex markers\",\n      \"journal\": \"Chromosoma\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct immunolocalization in primary cells across sexes, but no functional perturbation of MAU2 specifically in this study\",\n      \"pmids\": [\"24287868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Neural crest cell-specific inactivation of Mau2 in mice strongly affects craniofacial development. Early neural crest cell proliferation and migration are only moderately affected, suggesting cohesin loading is more critical for later developmental gene regulation. Mau2 single homozygous mutants showed a more severe craniofacial phenotype than Nipbl;Mau2 double homozygous mutants, suggesting the Mau2/Nipbl interaction may also restrict Nipbl's role in gene expression regulation.\",\n      \"method\": \"Conditional gene knockout in mice (Cre-lox), phenotypic analysis of neural crest-specific knockouts\",\n      \"journal\": \"Genesis (New York, N.Y. : 2000)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO mouse with defined cell-type specificity and epistasis between Mau2 and Nipbl, single lab\",\n      \"pmids\": [\"24700590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A MAU2 variant (7 amino acid in-frame deletion) causing CdLS impairs the interaction between MAU2 and the NIPBL N-terminus. However, cohesin loading can occur independently of a functional NIPBL/MAU2 complex: an NIPBL truncating mutation leads to alternative translation initiation producing an NIPBL form lacking the MAU2-binding N-terminus, which can still bind DNA and mediate cohesin loading.\",\n      \"method\": \"Patient variant characterization, co-immunoprecipitation, engineered cell lines with NIPBL truncating mutations, cohesin ChIP\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple engineered cell lines, Co-IP, cohesin ChIP, multiple orthogonal approaches in one study establishing both the interaction requirement and its dispensability under certain conditions\",\n      \"pmids\": [\"32433956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NIPBL contains two clusters of LxxLL motifs: one interacts with MAU2 and is necessary for maintaining the NIPBL-MAU2 heterodimer; the second binds the ligand-binding domains of steroid receptors. The glucocorticoid receptor (GR), NIPBL, and MAU2 form a ternary complex (modeled by AlphaFold2 and molecular docking), and this interaction is important for GR-dependent gene regulation. Multiple transcription factors interact with NIPBL-MAU2 to localize cohesin at enhancers.\",\n      \"method\": \"LxxLL motif mutagenesis, co-immunoprecipitation, AlphaFold2 structural modeling with molecular docking, transcriptional reporter assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and functional assays combined with computational structural modeling; AlphaFold2 predictions support but do not replace experimental structure determination\",\n      \"pmids\": [\"40377219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"18 individuals with 15 heterozygous MAU2 variants display CdLS phenotypes. In-frame MAU2 variants predominantly impair NIPBL-MAU2 interaction, while truncating variants cause MAU2 haploinsufficiency and lead to NIPBL reduction. A heterozygous Mau2 knockout mouse model recapitulates the human phenotype (short stature, microcephaly), confirming MAU2 disruption as causal.\",\n      \"method\": \"Patient variant functional analysis, co-immunoprecipitation, Western blot, DNA methylation episignature analysis, heterozygous Mau2 knockout mouse model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional analyses of multiple variants across 18 patients, mouse KO model recapitulation, multiple orthogonal methods\",\n      \"pmids\": [\"41912533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In maize, DEK15/SCC4 (MAU2 ortholog) interacts with chromatin remodeling proteins (CHB102, CHB105, CHB106) identified by yeast two-hybrid, suggesting a mechanism for cohesin loading onto chromatin via chromatin remodelers, consistent with findings in yeast.\",\n      \"method\": \"Yeast two-hybrid screen, genetic positional cloning, chromosome segregation analysis\",\n      \"journal\": \"The Plant cell\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast two-hybrid only for protein interactions, plant ortholog may not directly inform human MAU2 mechanism\",\n      \"pmids\": [\"30705131\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAU2 (SCC4) forms an obligate heterodimer with NIPBL (SCC2/delangin) through an N-terminal interaction interface; Scc4/MAU2 is a TPR-repeat superhelix that envelops the Scc2/NIPBL N-terminal peptide (crystal structure resolved), and a conserved surface patch on MAU2 recruits the loader complex to centromeres and other cohesin-associated regions to determine the genomic distribution of cohesin loading; the NIPBL/MAU2 complex catalyzes ATP-dependent loading of the cohesin ring onto DNA, a process that in vivo requires pre-replication complex formation and, at specific loci, recruitment via the RSC chromatin remodeling complex and direct interactions with transcription factors (including steroid receptors) that form ternary complexes with NIPBL/MAU2 at enhancers; loss of MAU2 results in failure of cohesin to associate with chromatin, precocious sister chromatid separation, and mitotic arrest, and MAU2 haploinsufficiency in humans and mice causes Cornelia de Lange syndrome.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MAU2 (SCC4) is an essential cohesin-loading factor that, together with NIPBL (SCC2), directs the ATP-dependent topological loading of the cohesin ring onto chromatin to enable sister chromatid cohesion and chromosome organization [#0, #1, #5]. MAU2 forms an obligate heterodimer with NIPBL through an N-terminal interface: MAU2 is a TPR-repeat superhelix that envelops an extended NIPBL N-terminal peptide, and MAU2 cannot engage cohesin in the absence of NIPBL [#7, #8, #9]. The heterodimer interacts with the Smc1–Smc3 heterodimer and loads cohesin onto double-stranded DNA, a reaction that in vitro requires pre-replication complex formation [#5]. MAU2 determines where loading occurs: a conserved MAU2 surface patch recruits the loader to centromeres to build pericentromeric cohesion, and MAU2 acts as a chromatin adaptor enabling loading onto chromatinized—not merely naked—DNA [#7, #8]. Genomic targeting is further shaped by the RSC chromatin remodeling complex, which recruits the loader to nucleosome-free regions [#6], and by transcription factors including the glucocorticoid receptor, which form ternary complexes with NIPBL–MAU2 to position cohesin at enhancers [#15]. Loss of MAU2 abolishes cohesin association with chromatin and causes precocious sister chromatid separation and prometaphase arrest [#1, #2]. Beyond mitotic chromosomes, the heterodimer localizes to meiotic chromosomal axes [#12], and MAU2 supports craniofacial and neural crest development in mice [#13]. Heterozygous MAU2 variants that impair the NIPBL interaction or cause MAU2 haploinsufficiency cause Cornelia de Lange syndrome, recapitulated in a heterozygous Mau2 knockout mouse [#14, #16].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established that cohesin loading onto chromosomes is a distinct step from cohesin assembly, mediated by a dedicated Scc2/Scc4 complex.\",\n      \"evidence\": \"Genetic epistasis, co-immunoprecipitation and chromatin binding assays in budding yeast\",\n      \"pmids\": [\"10882066\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the molecular mechanism of loading\", \"Mammalian relevance not yet shown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated that the loader is conserved across metazoans and fungi, with MAU2/Scc4 binding NIPBL/Scc2 via N-terminal regions and being required for cohesin chromatin association and faithful chromosome segregation.\",\n      \"evidence\": \"siRNA knockdown, Co-IP, chromatin fractionation in HeLa cells; interaction domain mapping and RNAi across Drosophila, C. elegans, Xenopus; Co-IP/ChIP with cell-cycle resolution in S. pombe\",\n      \"pmids\": [\"16682347\", \"16802858\", \"16682348\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzymatic loading not yet reconstituted\", \"Determinants of genomic targeting unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed that the loader, not cohesin itself, dictates the nonrandom genomic distribution of cohesin, with kinetochore-dependent enrichment at pericentromeres.\",\n      \"evidence\": \"Genome-wide ChIP mapping of Scc2 and Scc4 in budding yeast\",\n      \"pmids\": [\"19797771\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Recruitment cues to specific loci not defined\", \"Yeast-only mapping\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Reconstituted human NIPBL/MAU2 loading of cohesin in vitro and linked it to DNA replication licensing.\",\n      \"evidence\": \"In vitro loading assay with purified human proteins, Co-IP, Xenopus extract depletion/complementation; loading required pre-RC and was blocked by geminin\",\n      \"pmids\": [\"22628566\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Role of MAU2 versus NIPBL in catalysis not separated\", \"Chromatin-template requirements not addressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed the loader downstream of chromatin remodeling, showing RSC recruits the complex to nucleosome-free regions, and connected MAU2 to developmental gene regulation in mammals.\",\n      \"evidence\": \"MNase-seq, ChIP and genetic epistasis in yeast; conditional neural-crest Mau2 knockout in mice\",\n      \"pmids\": [\"25173104\", \"24700590\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RSC–MAU2 contact not structurally defined\", \"How loader maintains nucleosome-free regions unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the molecular basis of the heterodimer: MAU2 is a TPR superhelix wrapping the NIPBL N-terminus, with a conserved surface patch driving centromere recruitment and a chromatin-adaptor role for loading onto nucleosomal DNA.\",\n      \"evidence\": \"X-ray crystallography, electron microscopy, in vitro loading on circular and chromatinized DNA, and in vivo cohesion/recruitment assays in yeast\",\n      \"pmids\": [\"26038942\", \"26212329\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the full loader engaging cohesin not resolved\", \"Human structural confirmation absent\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Genetically dissected MAU2/Scc4 functional domains, confirming its N-terminal region is essential and that it requires NIPBL to engage cohesin.\",\n      \"evidence\": \"Dominant-negative insertion screen, viability/cohesion assays, Co-IP in budding yeast\",\n      \"pmids\": [\"27280786\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural confirmation of mutant defects\", \"Yeast-only analysis\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed that the NIPBL–MAU2 interaction, though required normally, can be bypassed: an N-terminally truncated NIPBL lacking the MAU2-binding region still binds DNA and loads cohesin.\",\n      \"evidence\": \"Patient variant characterization, Co-IP, engineered NIPBL-truncation cell lines, cohesin ChIP\",\n      \"pmids\": [\"32433956\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological contribution of MAU2-independent loading unclear\", \"Efficiency relative to intact heterodimer not quantified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected loader targeting to transcription factor signaling, showing NIPBL LxxLL motifs bridge MAU2 and steroid receptors to form ternary complexes positioning cohesin at enhancers.\",\n      \"evidence\": \"LxxLL mutagenesis, Co-IP, AlphaFold2 modeling with docking, reporter assays\",\n      \"pmids\": [\"40377219\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ternary complex structure is computational, not experimentally determined\", \"Direct MAU2 contacts with receptors not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Confirmed MAU2 as a causal CdLS gene, distinguishing two pathogenic mechanisms—impaired NIPBL interaction versus MAU2 haploinsufficiency with secondary NIPBL reduction—and recapitulating the phenotype in mice.\",\n      \"evidence\": \"Functional analysis of 15 variants across 18 patients, Co-IP, Western blot, methylation episignature, heterozygous Mau2 knockout mouse\",\n      \"pmids\": [\"41912533\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking cohesin loading defect to specific craniofacial/growth phenotypes unresolved\", \"Genotype-phenotype correlations incomplete\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MAU2-dependent loader targeting integrates chromatin remodeling, replication licensing, and transcription-factor cues to specify cohesin loading sites genome-wide remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified human structure of the loader engaging chromatin and cohesin\", \"Quantitative contribution of each targeting pathway unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7, 8, 9]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [5, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [1, 4, 12]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [6, 15]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [13, 16]}\n    ],\n    \"complexes\": [\"NIPBL/MAU2 cohesin loader complex\"],\n    \"partners\": [\"NIPBL\", \"SMC1\", \"SMC3\", \"NR3C1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}