{"gene":"MAU2","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":2000,"finding":"Scc2p (NIPBL ortholog) forms a complex with Scc4p (MAU2 ortholog) in budding yeast; in scc2 or scc4 mutants, cohesin complexes form normally but fail to bind centromeres and chromosome arms, establishing that the Scc2/Scc4 complex is required for loading cohesin onto chromosomes.","method":"Genetic epistasis, co-immunoprecipitation, chromatin binding assays in S. cerevisiae","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — foundational paper, multiple orthogonal methods, highly cited, replicated across organisms","pmids":["10882066"],"is_preprint":false},{"year":2006,"finding":"Human MAU2 (Scc4) is associated with NIPBL (Scc2), is bound to chromatin from telophase until prophase, and is required for association of cohesin with chromatin during interphase; siRNA depletion of MAU2 causes precocious sister-chromatid separation and prometaphase arrest.","method":"Co-immunoprecipitation, chromatin fractionation, siRNA knockdown, fluorescence microscopy in HeLa cells","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, chromatin fractionation, KD with defined phenotype; independently replicated","pmids":["16682347"],"is_preprint":false},{"year":2006,"finding":"Metazoan MAU2 orthologs (human MAU2, Drosophila MAU-2) interact with NIPBL/delangin/Nipped-B via N-terminal regions of both proteins; siRNA knockdown of human MAU2 causes precocious sister chromatid separation and impaired cohesin loading onto chromatin; MAU2 knockdown in Xenopus embryos phenocopies NIPBL knockdown.","method":"PSI-BLAST homology, protein-protein interaction mapping, siRNA knockdown, antisense morpholino in Xenopus","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods across species, interaction domain mapping, functional KD phenotypes","pmids":["16802858"],"is_preprint":false},{"year":2006,"finding":"Fission yeast Ssl3 (Scc4/MAU2 ortholog) forms a complex with Mis4 (Scc2/NIPBL ortholog) and is required in G1 for cohesin binding to chromosomes but is dispensable in G2 after cohesion is established.","method":"Genetic screen, co-immunoprecipitation, chromatin immunoprecipitation in S. pombe","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 — genetic and biochemical orthogonal methods in fission yeast ortholog","pmids":["16682348"],"is_preprint":false},{"year":2009,"finding":"Budding yeast Scc2/Scc4 co-localizes with cohesin at cohesin-associated regions (CARs) genome-wide; pericentromeric Scc2/Scc4 enrichment is kinetochore-dependent; Scc2/Scc4 association with CARs is independent of cohesin, indicating the loader directly determines cohesin distribution.","method":"ChIP-chip genome-wide mapping in S. cerevisiae","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — genome-wide mapping with multiple controls establishing loader-independent targeting","pmids":["19797771"],"is_preprint":false},{"year":2012,"finding":"Human Scc2/Scc4 (NIPBL/MAU2) complex was purified and shown to interact with human cohesin and the Smc1-Smc3 heterodimer (but not individual Smc subunits); both complexes load onto dsDNA containing prereplication complexes in vitro, and this loading is blocked by geminin or depletion of Scc2/Scc4.","method":"In vitro cohesin loading assay, purified protein reconstitution, co-immunoprecipitation, Xenopus extract depletion/rescue","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution of cohesin loading with purified human NIPBL/MAU2 complex","pmids":["22628566"],"is_preprint":false},{"year":2014,"finding":"The Scc2-Scc4 cohesin loader complex in budding yeast is recruited to broad nucleosome-free regions by the RSC chromatin remodeling complex; inactivation of either Scc2-Scc4 or RSC has similar effects on nucleosome positioning, gene expression, and sister chromatid cohesion.","method":"Genetic epistasis, ChIP-seq, nucleosome mapping, gene expression analysis in S. cerevisiae","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal genome-wide methods, epistasis, mechanistic link to chromatin remodeling","pmids":["25173104"],"is_preprint":false},{"year":2014,"finding":"Neural crest cell-specific inactivation of Mau2 in mice causes craniofacial defects; Mau2 single homozygous mutants showed a more severe phenotype than Nipbl;Mau2 double homozygous mutants, suggesting MAU2/NIPBL interaction may restrict NIPBL's role in gene expression regulation beyond cohesin loading.","method":"Conditional knockout (Cre-lox) mouse model, histology, immunofluorescence","journal":"Genesis (New York, N.Y. : 2000)","confidence":"Medium","confidence_rationale":"Tier 2 — clean conditional KO with defined phenotype, but mechanistic interpretation relies on indirect epistasis","pmids":["24700590"],"is_preprint":false},{"year":2015,"finding":"Crystal structure of Scc4 (MAU2 ortholog) bound to the N terminus of Scc2 reveals Scc4 is a TPR array that envelops an extended Scc2 peptide; a conserved surface patch on Scc4 is required for recruitment of Scc2/Scc4 to centromeres and for building pericentromeric cohesion.","method":"X-ray crystallography, yeast mutagenesis, ChIP, sister chromatid cohesion assay","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional mutagenesis validating centromere recruitment role","pmids":["26038942"],"is_preprint":false},{"year":2015,"finding":"Crystal structure of Scc4 (MAU2 ortholog) bound to Scc2 N-terminus shows Scc4 is a TPR superhelix enveloping an extended Scc2 N-terminus; EM reveals the Scc2-Scc4 loader has three domains (head, body, hook); the body and hook domains catalyze cohesin loading onto circular DNA in vitro, while Scc4 functions as a chromatin adaptor for loading onto chromatinized DNA.","method":"X-ray crystallography, electron microscopy, in vitro cohesin loading assay, deletion mutagenesis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 — crystal structure + EM + in vitro functional assay with deletion analysis","pmids":["26212329"],"is_preprint":false},{"year":2016,"finding":"A small N-terminal region of Scc4 (MAU2 ortholog) in budding yeast is required for cell viability, cohesion, cohesin loading, and Scc4 chromatin binding; Scc4 cannot bind cohesin in the absence of Scc2, revealing that Scc2 is required for Scc4-cohesin interaction.","method":"Random insertion/dominant negative genetic screen, cohesin loading assay, ChIP, co-immunoprecipitation in S. cerevisiae","journal":"G3 (Bethesda, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 — genetic screen with biochemical follow-up, single lab","pmids":["27280786"],"is_preprint":false},{"year":2011,"finding":"Specific NIPBL missense mutations found in Cornelia de Lange syndrome patients map to the MAU2-interacting domain of NIPBL and result in markedly reduced MAU2 binding, fine-mapping the minimal interaction domain between NIPBL and MAU2.","method":"Interaction domain mapping, co-immunoprecipitation, patient mutation analysis","journal":"European journal of human genetics : EJHG","confidence":"Medium","confidence_rationale":"Tier 3 — interaction domain mapping with patient mutations, single lab","pmids":["21934712"],"is_preprint":false},{"year":2020,"finding":"A MAU2 variant causing CdLS (deletion of seven amino acids) impairs the interaction between MAU2 and the NIPBL N-terminus; NIPBL lacking the N-terminal MAU2-binding domain (via alternative translation initiation) can still bind DNA and mediate cohesin loading, demonstrating that cohesin loading can occur independently of functional NIPBL/MAU2 complexes.","method":"Patient variant analysis, engineered cell lines with NIPBL truncation, co-immunoprecipitation, cohesin ChIP, alternative translation initiation mapping","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods in engineered cell lines, direct functional dissection of MAU2-NIPBL interaction","pmids":["32433956"],"is_preprint":false},{"year":2013,"finding":"NIPBL/MAU2 heterodimer localizes to chromosomal axes from zygotene to mid-pachytene in mammalian meiotic germ cells and relocalizes to chromocenters in spermatocytes; localization pattern is consistent with a role as loading factor for cohesin and condensin I but not Smc5/6.","method":"Immunofluorescence on meiotic chromosome spreads from mouse germ cells, co-localization with SMC complex subunits","journal":"Chromosoma","confidence":"Medium","confidence_rationale":"Tier 3 — localization by immunofluorescence with functional inference; single lab","pmids":["24287868"],"is_preprint":false},{"year":2004,"finding":"C. elegans mau-2 encodes a conserved protein that functions cell-autonomously within neurons for axonal migration guidance; MAU-2::GFP localizes to the cytoplasm of neurons; mau-2 interacts genetically with slt-1 (Slit ortholog) in guiding AVM axon, indicating mau-2 participates in guidance by a slt-1-independent mechanism.","method":"GFP fusion protein localization, cell-autonomous rescue experiments, genetic epistasis with slt-1 in C. elegans","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization and genetic epistasis, but in C. elegans developmental context","pmids":["15539489"],"is_preprint":false},{"year":2025,"finding":"NIPBL contains two clusters of LxxLL motifs: one interacts with MAU2 and is necessary for maintenance of the NIPBL-MAU2 heterodimer; the second binds steroid receptor ligand-binding domains. AlphaFold2 modeling and molecular docking reveal a GR-NIPBL-MAU2 ternary complex at enhancers, and multiple transcription factors interact with NIPBL-MAU2 to localize cohesin at enhancers.","method":"LxxLL motif mutagenesis, co-immunoprecipitation, AlphaFold2/molecular docking, ChIP-seq, transcriptional reporter assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2/3 — interaction mapping with mutagenesis and functional readouts, but ternary complex model relies partly on computational prediction","pmids":["40377219"],"is_preprint":false},{"year":2025,"finding":"Heterozygous MAU2 pathogenic variants cause a Cornelia de Lange syndrome subtype; in-frame variants impair NIPBL-MAU2 interaction, whereas truncating variants cause MAU2 haploinsufficiency and secondary reduction of NIPBL; heterozygous Mau2 knockout mice recapitulate short stature and microcephaly, confirming MAU2 disruption as causally sufficient for CdLS-related phenotypes.","method":"Patient variant functional analysis, NIPBL-MAU2 interaction assays, DNA methylation episignature profiling, heterozygous Mau2 KO mouse model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, mouse model validation, large patient cohort with functional analyses","pmids":["41912533"],"is_preprint":false}],"current_model":"MAU2 (Scc4) is a TPR-domain protein that forms a stable heterodimer with NIPBL (Scc2) through its N-terminal TPR superhelix enveloping an extended NIPBL N-terminal peptide; this NIPBL/MAU2 complex functions as the cohesin loader, directly mediating cohesin binding to chromatin (dependent on prereplication complex formation and RSC-mediated nucleosome-free regions), determining the genomic distribution of cohesin, and is required for sister chromatid cohesion, chromosome biorientation, and transcriptional regulation; additionally, transcription factors including steroid receptors form ternary complexes with NIPBL/MAU2 to recruit cohesin to enhancers, and loss-of-function MAU2 variants cause Cornelia de Lange syndrome by impairing NIPBL interaction or reducing NIPBL levels."},"narrative":{"teleology":[{"year":2000,"claim":"The fundamental question of how cohesin reaches chromosomes was answered by demonstrating that the Scc2/Scc4 (NIPBL/MAU2) complex is required not for cohesin assembly but specifically for its loading onto chromatin.","evidence":"Genetic epistasis, co-immunoprecipitation, and chromatin binding assays in S. cerevisiae","pmids":["10882066"],"confidence":"High","gaps":["Mechanism of loading catalysis unknown","Mammalian orthologs not yet identified","How the loader is targeted to specific chromosomal loci unresolved"]},{"year":2004,"claim":"Before its cohesin-loading role was established in metazoans, C. elegans mau-2 was found to function cell-autonomously in neurons for axon guidance, suggesting developmental roles potentially independent of cohesion.","evidence":"GFP localization, cell-autonomous rescue, genetic epistasis with slt-1 in C. elegans","pmids":["15539489"],"confidence":"Medium","gaps":["Whether axon guidance role is cohesin-dependent or independent was not tested","No biochemical interaction with worm Scc2 ortholog demonstrated in this study"]},{"year":2006,"claim":"Conservation of the Scc2/Scc4 cohesin-loading partnership was established across metazoans: human MAU2 binds NIPBL via N-terminal regions and is required for cohesin chromatin association, with depletion causing precocious sister chromatid separation.","evidence":"Co-immunoprecipitation, chromatin fractionation, siRNA knockdown in HeLa cells; morpholino knockdown in Xenopus; genetic and biochemical analysis in S. pombe","pmids":["16682347","16802858","16682348"],"confidence":"High","gaps":["Direct biochemical reconstitution of human cohesin loading not yet achieved","Cell-cycle regulation of loading not fully defined"]},{"year":2009,"claim":"Genome-wide mapping resolved how the loader determines cohesin distribution: Scc2/Scc4 co-localizes with cohesin at CARs, and its chromatin association is independent of cohesin, establishing the loader as an upstream determinant of cohesin positioning.","evidence":"ChIP-chip genome-wide mapping in S. cerevisiae","pmids":["19797771"],"confidence":"High","gaps":["Whether loader sites and cohesin final positions diverge in metazoans was unclear","Mechanism of loader recruitment to specific loci not identified"]},{"year":2011,"claim":"The clinical relevance of the NIPBL-MAU2 interaction was demonstrated when CdLS patient NIPBL missense mutations were shown to specifically disrupt MAU2 binding, fine-mapping the interaction domain.","evidence":"Interaction domain mapping and co-immunoprecipitation with patient-derived NIPBL mutations","pmids":["21934712"],"confidence":"Medium","gaps":["No MAU2 mutations in CdLS patients identified at this time","Functional consequence for cohesin loading not directly measured"]},{"year":2012,"claim":"Biochemical reconstitution demonstrated that purified human NIPBL/MAU2 complex directly loads cohesin onto prereplication-complex-containing DNA in vitro, establishing the sufficiency of the heterodimer for catalyzing loading.","evidence":"In vitro cohesin loading assay with purified proteins and Xenopus extract depletion/rescue","pmids":["22628566"],"confidence":"High","gaps":["Whether MAU2 contributes catalytically or only as an adaptor not resolved","Role of chromatin context in vitro only partially recapitulated"]},{"year":2014,"claim":"The chromatin context for loader recruitment was identified: RSC chromatin remodeling complex creates nucleosome-free regions that recruit Scc2/Scc4, linking chromatin architecture to cohesin loading site selection.","evidence":"ChIP-seq, nucleosome mapping, genetic epistasis, gene expression analysis in S. cerevisiae","pmids":["25173104"],"confidence":"High","gaps":["Whether equivalent remodelers recruit NIPBL/MAU2 in mammals not established","Direct physical interaction between RSC and Scc2/Scc4 not demonstrated"]},{"year":2015,"claim":"Crystal structures of the Scc4-Scc2 N-terminal complex revealed the molecular architecture: MAU2 is a TPR superhelix enveloping an extended NIPBL peptide; a conserved surface patch on MAU2 mediates centromere recruitment, while the catalytic activity resides in NIPBL body/hook domains, establishing MAU2 as a chromatin adaptor rather than a catalytic subunit.","evidence":"X-ray crystallography, electron microscopy, in vitro cohesin loading assay, mutagenesis in yeast","pmids":["26038942","26212329"],"confidence":"High","gaps":["Full-length Scc2/Scc4 structure not resolved","How the conserved surface patch recognizes centromeric chromatin features unknown"]},{"year":2016,"claim":"Dissection of MAU2 functional domains showed that a small N-terminal region is essential for viability and cohesion, and that MAU2 cannot engage cohesin without NIPBL, clarifying the obligate dependency within the heterodimer.","evidence":"Random insertion/dominant negative screen, cohesin loading assay, ChIP, co-immunoprecipitation in S. cerevisiae","pmids":["27280786"],"confidence":"Medium","gaps":["Which specific contacts on the N-terminal region mediate its essential function not mapped","Whether findings extend to mammalian MAU2 not tested"]},{"year":2020,"claim":"A surprising separation of function was uncovered: an alternative NIPBL isoform lacking the MAU2-binding domain can still load cohesin, demonstrating that MAU2-independent cohesin loading occurs and reframing MAU2 as a regulatory rather than absolutely essential loading subunit.","evidence":"Engineered NIPBL truncation cell lines, co-immunoprecipitation, cohesin ChIP, CdLS patient variant analysis","pmids":["32433956"],"confidence":"High","gaps":["Whether MAU2-independent loading is sufficient for all genomic loci or only a subset unclear","Relative contribution of MAU2-dependent vs -independent loading in vivo not quantified"]},{"year":2025,"claim":"The NIPBL-MAU2 heterodimer was shown to serve as a platform for transcription factor-directed cohesin recruitment: steroid receptors bind NIPBL LxxLL motifs to form ternary complexes that target cohesin to enhancers, and MAU2 loss-of-function variants were established as a direct genetic cause of Cornelia de Lange syndrome.","evidence":"LxxLL motif mutagenesis, co-immunoprecipitation, ChIP-seq, reporter assays, patient variant functional analysis, heterozygous Mau2 KO mouse model, DNA methylation episignature profiling","pmids":["40377219","41912533"],"confidence":"High","gaps":["Ternary complex structure relies partly on computational prediction and awaits direct structural validation","Full spectrum of transcription factors that recruit NIPBL/MAU2 to enhancers not defined","Whether CdLS pathology is primarily due to cohesin loading deficits or transcriptional dysregulation remains unresolved"]},{"year":null,"claim":"Key unresolved questions include the precise mechanism by which MAU2 recognizes and adapts to distinct chromatin environments (centromeres, enhancers, nucleosome-free regions), the quantitative contribution of MAU2-dependent versus MAU2-independent cohesin loading across the genome, and whether MAU2 has cohesin-independent functions in development.","evidence":"","pmids":[],"confidence":"High","gaps":["No full-length human NIPBL/MAU2 structure available","MAU2 chromatin receptor identity unknown","Cohesin-independent developmental roles not formally excluded"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,5,8,9]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,1,4,8,13]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,13]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,1,3]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[6,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[11,12,16]}],"complexes":["NIPBL/MAU2 cohesin loader complex"],"partners":["NIPBL","SMC1A","SMC3"],"other_free_text":[]},"mechanistic_narrative":"MAU2 (Scc4) is a TPR-domain protein that heterodimerizes with NIPBL (Scc2) to form the cohesin loader complex, which is essential for loading cohesin onto chromosomes and establishing sister chromatid cohesion [PMID:10882066, PMID:16682347, PMID:22628566]. Structurally, MAU2 forms a TPR superhelix that envelops an extended N-terminal peptide of NIPBL; it functions as a chromatin adaptor directing cohesin loading to specific genomic sites including centromeres and nucleosome-free regions generated by chromatin remodelers, while NIPBL catalyzes the loading reaction itself [PMID:26038942, PMID:26212329, PMID:25173104]. Transcription factors including steroid receptors form ternary complexes with NIPBL/MAU2 to recruit cohesin to enhancers, linking the loader to transcriptional regulation [PMID:40377219]. Heterozygous loss-of-function MAU2 variants cause Cornelia de Lange syndrome, with in-frame mutations disrupting NIPBL interaction and truncating variants causing MAU2 haploinsufficiency with secondary NIPBL reduction [PMID:41912533]."},"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 proteins.","date":"2000","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/10882066","citation_count":612,"is_preprint":false},{"pmid":"16682347","id":"PMC_16682347","title":"Human Scc4 is required for cohesin binding to chromatin, sister-chromatid cohesion, and mitotic progression.","date":"2006","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/16682347","citation_count":209,"is_preprint":false},{"pmid":"19251361","id":"PMC_19251361","title":"Berberine suppresses in vitro migration and invasion of human SCC-4 tongue squamous cancer cells through the inhibitions of FAK, IKK, NF-kappaB, u-PA and MMP-2 and -9.","date":"2009","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/19251361","citation_count":129,"is_preprint":false},{"pmid":"25173104","id":"PMC_25173104","title":"The Scc2-Scc4 complex acts in sister chromatid cohesion and transcriptional regulation by maintaining nucleosome-free regions.","date":"2014","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25173104","citation_count":110,"is_preprint":false},{"pmid":"19846952","id":"PMC_19846952","title":"Berberine induced apoptosis via promoting the expression of caspase-8, -9 and -3, apoptosis-inducing factor and endonuclease G in SCC-4 human tongue squamous carcinoma cancer cells.","date":"2009","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/19846952","citation_count":104,"is_preprint":false},{"pmid":"19331169","id":"PMC_19331169","title":"Emodin induces apoptosis of human tongue squamous cancer SCC-4 cells through reactive oxygen species and mitochondria-dependent pathways.","date":"2009","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/19331169","citation_count":92,"is_preprint":false},{"pmid":"16802858","id":"PMC_16802858","title":"Metazoan Scc4 homologs link sister chromatid cohesion to cell and axon migration guidance.","date":"2006","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/16802858","citation_count":86,"is_preprint":false},{"pmid":"18674953","id":"PMC_18674953","title":"Gypenosides induced G0/G1 arrest via CHk2 and apoptosis through endoplasmic reticulum stress and mitochondria-dependent pathways in human tongue cancer SCC-4 cells.","date":"2008","source":"Oral oncology","url":"https://pubmed.ncbi.nlm.nih.gov/18674953","citation_count":76,"is_preprint":false},{"pmid":"20032398","id":"PMC_20032398","title":"Aloe-emodin induces cell death through S-phase arrest and caspase-dependent pathways in human tongue squamous cancer SCC-4 cells.","date":"2009","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/20032398","citation_count":63,"is_preprint":false},{"pmid":"26038942","id":"PMC_26038942","title":"Structural evidence for Scc4-dependent localization of cohesin loading.","date":"2015","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/26038942","citation_count":61,"is_preprint":false},{"pmid":"19414420","id":"PMC_19414420","title":"Rhein induced apoptosis through the endoplasmic reticulum stress, caspase- and mitochondria-dependent pathways in SCC-4 human tongue squamous cancer cells.","date":"2009","source":"In vivo (Athens, Greece)","url":"https://pubmed.ncbi.nlm.nih.gov/19414420","citation_count":57,"is_preprint":false},{"pmid":"16682348","id":"PMC_16682348","title":"A screen for cohesion mutants uncovers Ssl3, the fission yeast counterpart of the cohesin loading factor Scc4.","date":"2006","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/16682348","citation_count":55,"is_preprint":false},{"pmid":"19797771","id":"PMC_19797771","title":"The Scc2/Scc4 cohesin loader determines the distribution of cohesin on budding yeast chromosomes.","date":"2009","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/19797771","citation_count":54,"is_preprint":false},{"pmid":"18210755","id":"PMC_18210755","title":"Baicalein induces apoptosis in SCC-4 human tongue cancer cells via a Ca2+-dependent mitochondrial pathway.","date":"2007","source":"In vivo (Athens, Greece)","url":"https://pubmed.ncbi.nlm.nih.gov/18210755","citation_count":53,"is_preprint":false},{"pmid":"26212329","id":"PMC_26212329","title":"Structural Studies Reveal the Functional Modularity of the Scc2-Scc4 Cohesin Loader.","date":"2015","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/26212329","citation_count":52,"is_preprint":false},{"pmid":"24859325","id":"PMC_24859325","title":"Gallic acid inhibits migration and invasion of SCC-4 human oral cancer cells through actions of NF-κB, Ras and matrix metalloproteinase-2 and -9.","date":"2014","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/24859325","citation_count":50,"is_preprint":false},{"pmid":"32433956","id":"PMC_32433956","title":"MAU2 and NIPBL Variants Impair the Heterodimerization of the Cohesin Loader Subunits and Cause Cornelia de Lange Syndrome.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/32433956","citation_count":49,"is_preprint":false},{"pmid":"18507059","id":"PMC_18507059","title":"Gypenosides inhibited invasion and migration of human tongue cancer SCC4 cells through down-regulation of NFkappaB and matrix metalloproteinase-9.","date":"2008","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/18507059","citation_count":47,"is_preprint":false},{"pmid":"28181380","id":"PMC_28181380","title":"Fisetin-induced apoptosis of human oral cancer SCC-4 cells through reactive oxygen species production, endoplasmic reticulum stress, caspase-, and mitochondria-dependent signaling pathways.","date":"2017","source":"Environmental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/28181380","citation_count":45,"is_preprint":false},{"pmid":"30705131","id":"PMC_30705131","title":"Maize Dek15 Encodes the Cohesin-Loading Complex Subunit SCC4 and Is Essential for Chromosome Segregation and Kernel Development.","date":"2019","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/30705131","citation_count":40,"is_preprint":false},{"pmid":"22628566","id":"PMC_22628566","title":"In vitro loading of human cohesin on DNA by the human Scc2-Scc4 loader complex.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/22628566","citation_count":36,"is_preprint":false},{"pmid":"21887696","id":"PMC_21887696","title":"Induction of apoptotic death by curcumin in human tongue squamous cell carcinoma SCC-4 cells is mediated through endoplasmic reticulum stress and mitochondria-dependent pathways.","date":"2011","source":"Cell biochemistry and function","url":"https://pubmed.ncbi.nlm.nih.gov/21887696","citation_count":35,"is_preprint":false},{"pmid":"21571996","id":"PMC_21571996","title":"Scc1 (CP0432) and Scc4 (CP0033) function as a type III secretion chaperone for CopN of Chlamydia pneumoniae.","date":"2011","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/21571996","citation_count":30,"is_preprint":false},{"pmid":"21934712","id":"PMC_21934712","title":"Isolated NIBPL missense mutations that cause Cornelia de Lange syndrome alter MAU2 interaction.","date":"2011","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/21934712","citation_count":25,"is_preprint":false},{"pmid":"2897254","id":"PMC_2897254","title":"2,3,7,8-Tetrachlorodibenzo-p-dioxin and polycyclic aromatic hydrocarbons suppress retinoid-induced tissue transglutaminase in SCC-4 cultured human squamous carcinoma cells.","date":"1988","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/2897254","citation_count":25,"is_preprint":false},{"pmid":"20925121","id":"PMC_20925121","title":"Capsaicin induces apoptosis in SCC-4 human tongue cancer cells through mitochondria-dependent and -independent pathways.","date":"2010","source":"Environmental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/20925121","citation_count":24,"is_preprint":false},{"pmid":"24700590","id":"PMC_24700590","title":"Neural crest cell-specific inactivation of Nipbl or Mau2 during mouse development results in a late onset of craniofacial defects.","date":"2014","source":"Genesis (New York, N.Y. : 2000)","url":"https://pubmed.ncbi.nlm.nih.gov/24700590","citation_count":23,"is_preprint":false},{"pmid":"24922656","id":"PMC_24922656","title":"RAD001 enhances the radiosensitivity of SCC4 oral cancer cells by inducing cell cycle arrest at the G2/M checkpoint.","date":"2014","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/24922656","citation_count":23,"is_preprint":false},{"pmid":"15539489","id":"PMC_15539489","title":"mau-2 acts cell-autonomously to guide axonal migrations in Caenorhabditis elegans.","date":"2004","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/15539489","citation_count":22,"is_preprint":false},{"pmid":"24287868","id":"PMC_24287868","title":"Localisation of the SMC loading complex Nipbl/Mau2 during mammalian meiotic prophase I.","date":"2013","source":"Chromosoma","url":"https://pubmed.ncbi.nlm.nih.gov/24287868","citation_count":21,"is_preprint":false},{"pmid":"29098808","id":"PMC_29098808","title":"Casticin impairs cell growth and induces cell apoptosis via cell cycle arrest in human oral cancer SCC-4 cells.","date":"2017","source":"Environmental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/29098808","citation_count":20,"is_preprint":false},{"pmid":"21591240","id":"PMC_21591240","title":"Safrole induces cell death in human tongue squamous cancer SCC-4 cells through mitochondria-dependent caspase activation cascade apoptotic signaling pathways.","date":"2011","source":"Environmental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/21591240","citation_count":19,"is_preprint":false},{"pmid":"28983595","id":"PMC_28983595","title":"Bufalin induced apoptosis in SCC‑4 human tongue cancer cells by decreasing Bcl‑2 and increasing Bax expression via the mitochondria‑dependent pathway.","date":"2017","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/28983595","citation_count":19,"is_preprint":false},{"pmid":"32568739","id":"PMC_32568739","title":"Association of the NCAN-TM6SF2-CILP2-PBX4-SUGP1-MAU2 SNPs and gene-gene and gene-environment interactions with serum lipid levels.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/32568739","citation_count":15,"is_preprint":false},{"pmid":"31360193","id":"PMC_31360193","title":"Suppression of the long non-coding RNA MALAT-1 impairs the growth and migration of human tongue squamous cell carcinoma SCC4 cells.","date":"2018","source":"Archives of medical science : AMS","url":"https://pubmed.ncbi.nlm.nih.gov/31360193","citation_count":14,"is_preprint":false},{"pmid":"24485831","id":"PMC_24485831","title":"Methotrexate enhances 5-aminolevulinic acid-mediated photodynamic therapy-induced killing of human SCC4 cells by upregulation of coproporphyrinogen oxidase.","date":"2014","source":"Journal of the Formosan Medical Association = Taiwan yi zhi","url":"https://pubmed.ncbi.nlm.nih.gov/24485831","citation_count":11,"is_preprint":false},{"pmid":"28137757","id":"PMC_28137757","title":"The Arabidopsis homolog of Scc4/MAU2 is essential for embryogenesis.","date":"2017","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/28137757","citation_count":8,"is_preprint":false},{"pmid":"32424009","id":"PMC_32424009","title":"Context-Dependent Action of Scc4 Reinforces Control of the Type III Secretion System.","date":"2020","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/32424009","citation_count":8,"is_preprint":false},{"pmid":"27280786","id":"PMC_27280786","title":"Identification of Functional Domains in the Cohesin Loader Subunit Scc4 by a Random Insertion/Dominant Negative Screen.","date":"2016","source":"G3 (Bethesda, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/27280786","citation_count":7,"is_preprint":false},{"pmid":"7861005","id":"PMC_7861005","title":"Differential regulation of plasminogen activation in normal keratinocytes and SCC-4 cells by fibroblasts.","date":"1995","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/7861005","citation_count":7,"is_preprint":false},{"pmid":"27221634","id":"PMC_27221634","title":"4-Hydroxybutenolide impairs cell migration, and invasion of human oral cancer SCC-4 cells via the inhibition of NF-κB and MAPK signaling pathways.","date":"2016","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/27221634","citation_count":6,"is_preprint":false},{"pmid":"40377219","id":"PMC_40377219","title":"Transcription factors form a ternary complex with NIPBL/MAU2 to localize cohesin at enhancers.","date":"2025","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/40377219","citation_count":5,"is_preprint":false},{"pmid":"31545893","id":"PMC_31545893","title":"Purification of Tag-Free Chlamydia trachomatis Scc4 for Structural Studies Using Sarkosyl-Assisted on-Column Complex Dissociation.","date":"2019","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31545893","citation_count":5,"is_preprint":false},{"pmid":"32871773","id":"PMC_32871773","title":"Casticin Inhibits In Vivo Growth of Xenograft Tumors of Human Oral Cancer SCC-4 Cells.","date":"2020","source":"In vivo (Athens, Greece)","url":"https://pubmed.ncbi.nlm.nih.gov/32871773","citation_count":5,"is_preprint":false},{"pmid":"37962004","id":"PMC_37962004","title":"Clinical study and genetic analysis of Cornelia de Lange syndrome caused by a novel MAU2 gene variant in a Chinese boy.","date":"2023","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37962004","citation_count":4,"is_preprint":false},{"pmid":"34848464","id":"PMC_34848464","title":"Cetyltrimethylammonium Bromide Disrupts Mesenchymal Characteristics of Human Tongue Squamous Cell Carcinoma SCC4 Cells Through Modulating Canonical TGF-β/Smad/miR-181b/TIMP3 Signaling Pathway.","date":"2021","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/34848464","citation_count":4,"is_preprint":false},{"pmid":"35645143","id":"PMC_35645143","title":"Betanin alleviates inflammation and ameliorates apoptosis on human oral squamous cancer cells SCC131 and SCC4 through the NF-κB/PI3K/Akt signaling pathway.","date":"2022","source":"Journal of biochemical and molecular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/35645143","citation_count":4,"is_preprint":false},{"pmid":"27964702","id":"PMC_27964702","title":"Minichromosome Maintenance Complex is Required for Checkpoint Kinase 2 Chromatin Loading and its Phosphorylation to DNA Damage Response in SCC-4 Cells.","date":"2017","source":"Protein and peptide letters","url":"https://pubmed.ncbi.nlm.nih.gov/27964702","citation_count":4,"is_preprint":false},{"pmid":"33114427","id":"PMC_33114427","title":"Chain-Selective Isotopic Labeling of the Heterodimeric Type III Secretion Chaperone, Scc4:Scc1, Reveals the Total Structural Rearrangement of the Chlamydia trachomatis Bi-Functional Protein, Scc4.","date":"2020","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/33114427","citation_count":2,"is_preprint":false},{"pmid":"39713324","id":"PMC_39713324","title":"Transcription factors form a ternary complex with NIPBL/MAU2 to localize cohesin at enhancers.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39713324","citation_count":2,"is_preprint":false},{"pmid":"37456874","id":"PMC_37456874","title":"In-silico, evolutionary, and functional analysis of CHUP1 and its related proteins in Bienertia sinuspersici-a comparative study across C3, C4, CAM, and SCC4 model plants.","date":"2023","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/37456874","citation_count":2,"is_preprint":false},{"pmid":"33222274","id":"PMC_33222274","title":"RhoA/ROCKs signaling is increased by treatment with TKI-258 and leads to increased apoptosis in SCC-4 oral squamous cell carcinoma cell line.","date":"2020","source":"Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology","url":"https://pubmed.ncbi.nlm.nih.gov/33222274","citation_count":2,"is_preprint":false},{"pmid":"30230390","id":"PMC_30230390","title":"SCC4 cell monolayers as an alternative sublingual barrier model: influence of nanoencapsulation on carvedilol transport.","date":"2018","source":"Drug development and industrial pharmacy","url":"https://pubmed.ncbi.nlm.nih.gov/30230390","citation_count":2,"is_preprint":false},{"pmid":"32617786","id":"PMC_32617786","title":"Backbone and sidechain resonance assignments and secondary structure of Scc4 from Chlamydia trachomatis.","date":"2020","source":"Biomolecular NMR assignments","url":"https://pubmed.ncbi.nlm.nih.gov/32617786","citation_count":1,"is_preprint":false},{"pmid":"28980916","id":"PMC_28980916","title":"Cetuximab has an inhibitory effect on cell motility in SCC-4 oral squamous cell carcinoma cell line.","date":"2017","source":"Cellular and molecular biology (Noisy-le-Grand, France)","url":"https://pubmed.ncbi.nlm.nih.gov/28980916","citation_count":1,"is_preprint":false},{"pmid":"31983155","id":"PMC_31983155","title":"Rho GTPases are Involved on Regulation of Cytodifferentiation of SCC-4 Oral Squamous Cell Carcinoma Cell Line: A Preliminary Study.","date":"2020","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/31983155","citation_count":1,"is_preprint":false},{"pmid":"41332805","id":"PMC_41332805","title":"Pathogenic variants in the cohesin loader subunit MAU2 lead to a new Cornelia de Lange Syndrome subtype.","date":"2025","source":"medRxiv : the preprint server for health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41332805","citation_count":0,"is_preprint":false},{"pmid":"38857716","id":"PMC_38857716","title":"Insights into the association of the Chlamydia trachomatis type III secretion chaperone complex, Scc4:Scc1, from sequential expression in Escherichia coli.","date":"2024","source":"Protein expression and purification","url":"https://pubmed.ncbi.nlm.nih.gov/38857716","citation_count":0,"is_preprint":false},{"pmid":"41912533","id":"PMC_41912533","title":"Pathogenic variants in the cohesin loader subunit MAU2 underlie a distinct Cornelia de Lange Syndrome subtype.","date":"2026","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41912533","citation_count":0,"is_preprint":false},{"pmid":"31792476","id":"PMC_31792476","title":"[Effects of microRNA-218 on proliferation, apoptosis and invasion of human tongue cancer cell line SCC-4 and SCC-9].","date":"2019","source":"Shanghai kou qiang yi xue = Shanghai journal of stomatology","url":"https://pubmed.ncbi.nlm.nih.gov/31792476","citation_count":0,"is_preprint":false},{"pmid":"40878940","id":"PMC_40878940","title":"[Expression of Concern] 4‑Hydroxybutenolide impairs cell migration, and invasion of human oral cancer SCC‑4 cells via the inhibition of NF‑κB and MAPK signaling pathways.","date":"2025","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40878940","citation_count":0,"is_preprint":false},{"pmid":"25543600","id":"PMC_25543600","title":"[Effects of 5-aza-2-deoxycytidine on methylation status of RECK gene and cancer cell invasion in tongue cancer SCC-4 cells].","date":"2014","source":"Shanghai kou qiang yi xue = Shanghai journal of stomatology","url":"https://pubmed.ncbi.nlm.nih.gov/25543600","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.11.05.24316758","title":"Potential causal links between genetic variants in<i>SAMM50</i>,<i>SUGP1</i>,<i>MAU2</i>, and<i>GATAD2A</i>and liver fat in individuals with normal weight","date":"2024-11-05","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.05.24316758","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":32266,"output_tokens":3993,"usd":0.078346},"stage2":{"model":"claude-opus-4-6","input_tokens":7425,"output_tokens":2834,"usd":0.161963},"total_usd":0.240309,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"Scc2p (NIPBL ortholog) forms a complex with Scc4p (MAU2 ortholog) in budding yeast; in scc2 or scc4 mutants, cohesin complexes form normally but fail to bind centromeres and chromosome arms, establishing that the Scc2/Scc4 complex is required for loading cohesin onto chromosomes.\",\n      \"method\": \"Genetic epistasis, co-immunoprecipitation, chromatin binding assays in S. cerevisiae\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — foundational paper, multiple orthogonal methods, highly cited, replicated across organisms\",\n      \"pmids\": [\"10882066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Human MAU2 (Scc4) is associated with NIPBL (Scc2), is bound to chromatin from telophase until prophase, and is required for association of cohesin with chromatin during interphase; siRNA depletion of MAU2 causes precocious sister-chromatid separation and prometaphase arrest.\",\n      \"method\": \"Co-immunoprecipitation, chromatin fractionation, siRNA knockdown, fluorescence microscopy in HeLa cells\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, chromatin fractionation, KD with defined phenotype; independently replicated\",\n      \"pmids\": [\"16682347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Metazoan MAU2 orthologs (human MAU2, Drosophila MAU-2) interact with NIPBL/delangin/Nipped-B via N-terminal regions of both proteins; siRNA knockdown of human MAU2 causes precocious sister chromatid separation and impaired cohesin loading onto chromatin; MAU2 knockdown in Xenopus embryos phenocopies NIPBL knockdown.\",\n      \"method\": \"PSI-BLAST homology, protein-protein interaction mapping, siRNA knockdown, antisense morpholino in Xenopus\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods across species, interaction domain mapping, functional KD phenotypes\",\n      \"pmids\": [\"16802858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Fission yeast Ssl3 (Scc4/MAU2 ortholog) forms a complex with Mis4 (Scc2/NIPBL ortholog) and is required in G1 for cohesin binding to chromosomes but is dispensable in G2 after cohesion is established.\",\n      \"method\": \"Genetic screen, co-immunoprecipitation, chromatin immunoprecipitation in S. pombe\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic and biochemical orthogonal methods in fission yeast ortholog\",\n      \"pmids\": [\"16682348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Budding yeast Scc2/Scc4 co-localizes with cohesin at cohesin-associated regions (CARs) genome-wide; pericentromeric Scc2/Scc4 enrichment is kinetochore-dependent; Scc2/Scc4 association with CARs is independent of cohesin, indicating the loader directly determines cohesin distribution.\",\n      \"method\": \"ChIP-chip genome-wide mapping in S. cerevisiae\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide mapping with multiple controls establishing loader-independent targeting\",\n      \"pmids\": [\"19797771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Human Scc2/Scc4 (NIPBL/MAU2) complex was purified and shown to interact with human cohesin and the Smc1-Smc3 heterodimer (but not individual Smc subunits); both complexes load onto dsDNA containing prereplication complexes in vitro, and this loading is blocked by geminin or depletion of Scc2/Scc4.\",\n      \"method\": \"In vitro cohesin loading assay, purified protein reconstitution, co-immunoprecipitation, Xenopus extract depletion/rescue\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of cohesin loading with purified human NIPBL/MAU2 complex\",\n      \"pmids\": [\"22628566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The Scc2-Scc4 cohesin loader complex in budding yeast is recruited to broad nucleosome-free regions by the RSC chromatin remodeling complex; inactivation of either Scc2-Scc4 or RSC has similar effects on nucleosome positioning, gene expression, and sister chromatid cohesion.\",\n      \"method\": \"Genetic epistasis, ChIP-seq, nucleosome mapping, gene expression analysis in S. cerevisiae\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal genome-wide methods, epistasis, mechanistic link to chromatin remodeling\",\n      \"pmids\": [\"25173104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Neural crest cell-specific inactivation of Mau2 in mice causes craniofacial defects; Mau2 single homozygous mutants showed a more severe phenotype than Nipbl;Mau2 double homozygous mutants, suggesting MAU2/NIPBL interaction may restrict NIPBL's role in gene expression regulation beyond cohesin loading.\",\n      \"method\": \"Conditional knockout (Cre-lox) mouse model, histology, immunofluorescence\",\n      \"journal\": \"Genesis (New York, N.Y. : 2000)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO with defined phenotype, but mechanistic interpretation relies on indirect epistasis\",\n      \"pmids\": [\"24700590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of Scc4 (MAU2 ortholog) bound to the N terminus of Scc2 reveals Scc4 is a TPR array that envelops an extended Scc2 peptide; a conserved surface patch on Scc4 is required for recruitment of Scc2/Scc4 to centromeres and for building pericentromeric cohesion.\",\n      \"method\": \"X-ray crystallography, yeast mutagenesis, ChIP, sister chromatid cohesion assay\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional mutagenesis validating centromere recruitment role\",\n      \"pmids\": [\"26038942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of Scc4 (MAU2 ortholog) bound to Scc2 N-terminus shows Scc4 is a TPR superhelix enveloping an extended Scc2 N-terminus; EM reveals the Scc2-Scc4 loader has three domains (head, body, hook); the body and hook domains catalyze cohesin loading onto circular DNA in vitro, while Scc4 functions as a chromatin adaptor for loading onto chromatinized DNA.\",\n      \"method\": \"X-ray crystallography, electron microscopy, in vitro cohesin loading assay, deletion mutagenesis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure + EM + in vitro functional assay with deletion analysis\",\n      \"pmids\": [\"26212329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A small N-terminal region of Scc4 (MAU2 ortholog) in budding yeast is required for cell viability, cohesion, cohesin loading, and Scc4 chromatin binding; Scc4 cannot bind cohesin in the absence of Scc2, revealing that Scc2 is required for Scc4-cohesin interaction.\",\n      \"method\": \"Random insertion/dominant negative genetic screen, cohesin loading assay, ChIP, co-immunoprecipitation in S. cerevisiae\",\n      \"journal\": \"G3 (Bethesda, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic screen with biochemical follow-up, single lab\",\n      \"pmids\": [\"27280786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Specific NIPBL missense mutations found in Cornelia de Lange syndrome patients map to the MAU2-interacting domain of NIPBL and result in markedly reduced MAU2 binding, fine-mapping the minimal interaction domain between NIPBL and MAU2.\",\n      \"method\": \"Interaction domain mapping, co-immunoprecipitation, patient mutation analysis\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — interaction domain mapping with patient mutations, single lab\",\n      \"pmids\": [\"21934712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A MAU2 variant causing CdLS (deletion of seven amino acids) impairs the interaction between MAU2 and the NIPBL N-terminus; NIPBL lacking the N-terminal MAU2-binding domain (via alternative translation initiation) can still bind DNA and mediate cohesin loading, demonstrating that cohesin loading can occur independently of functional NIPBL/MAU2 complexes.\",\n      \"method\": \"Patient variant analysis, engineered cell lines with NIPBL truncation, co-immunoprecipitation, cohesin ChIP, alternative translation initiation mapping\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in engineered cell lines, direct functional dissection of MAU2-NIPBL interaction\",\n      \"pmids\": [\"32433956\"],\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 meiotic germ cells and relocalizes to chromocenters in spermatocytes; localization pattern is consistent with a role as loading factor for cohesin and condensin I but not Smc5/6.\",\n      \"method\": \"Immunofluorescence on meiotic chromosome spreads from mouse germ cells, co-localization with SMC complex subunits\",\n      \"journal\": \"Chromosoma\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — localization by immunofluorescence with functional inference; single lab\",\n      \"pmids\": [\"24287868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"C. elegans mau-2 encodes a conserved protein that functions cell-autonomously within neurons for axonal migration guidance; MAU-2::GFP localizes to the cytoplasm of neurons; mau-2 interacts genetically with slt-1 (Slit ortholog) in guiding AVM axon, indicating mau-2 participates in guidance by a slt-1-independent mechanism.\",\n      \"method\": \"GFP fusion protein localization, cell-autonomous rescue experiments, genetic epistasis with slt-1 in C. elegans\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization and genetic epistasis, but in C. elegans developmental context\",\n      \"pmids\": [\"15539489\"],\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 maintenance of the NIPBL-MAU2 heterodimer; the second binds steroid receptor ligand-binding domains. AlphaFold2 modeling and molecular docking reveal a GR-NIPBL-MAU2 ternary complex at enhancers, and multiple transcription factors interact with NIPBL-MAU2 to localize cohesin at enhancers.\",\n      \"method\": \"LxxLL motif mutagenesis, co-immunoprecipitation, AlphaFold2/molecular docking, ChIP-seq, transcriptional reporter assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — interaction mapping with mutagenesis and functional readouts, but ternary complex model relies partly on computational prediction\",\n      \"pmids\": [\"40377219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Heterozygous MAU2 pathogenic variants cause a Cornelia de Lange syndrome subtype; in-frame variants impair NIPBL-MAU2 interaction, whereas truncating variants cause MAU2 haploinsufficiency and secondary reduction of NIPBL; heterozygous Mau2 knockout mice recapitulate short stature and microcephaly, confirming MAU2 disruption as causally sufficient for CdLS-related phenotypes.\",\n      \"method\": \"Patient variant functional analysis, NIPBL-MAU2 interaction assays, DNA methylation episignature profiling, heterozygous Mau2 KO mouse model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, mouse model validation, large patient cohort with functional analyses\",\n      \"pmids\": [\"41912533\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAU2 (Scc4) is a TPR-domain protein that forms a stable heterodimer with NIPBL (Scc2) through its N-terminal TPR superhelix enveloping an extended NIPBL N-terminal peptide; this NIPBL/MAU2 complex functions as the cohesin loader, directly mediating cohesin binding to chromatin (dependent on prereplication complex formation and RSC-mediated nucleosome-free regions), determining the genomic distribution of cohesin, and is required for sister chromatid cohesion, chromosome biorientation, and transcriptional regulation; additionally, transcription factors including steroid receptors form ternary complexes with NIPBL/MAU2 to recruit cohesin to enhancers, and loss-of-function MAU2 variants cause Cornelia de Lange syndrome by impairing NIPBL interaction or reducing NIPBL levels.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MAU2 (Scc4) is a TPR-domain protein that heterodimerizes with NIPBL (Scc2) to form the cohesin loader complex, which is essential for loading cohesin onto chromosomes and establishing sister chromatid cohesion [PMID:10882066, PMID:16682347, PMID:22628566]. Structurally, MAU2 forms a TPR superhelix that envelops an extended N-terminal peptide of NIPBL; it functions as a chromatin adaptor directing cohesin loading to specific genomic sites including centromeres and nucleosome-free regions generated by chromatin remodelers, while NIPBL catalyzes the loading reaction itself [PMID:26038942, PMID:26212329, PMID:25173104]. Transcription factors including steroid receptors form ternary complexes with NIPBL/MAU2 to recruit cohesin to enhancers, linking the loader to transcriptional regulation [PMID:40377219]. Heterozygous loss-of-function MAU2 variants cause Cornelia de Lange syndrome, with in-frame mutations disrupting NIPBL interaction and truncating variants causing MAU2 haploinsufficiency with secondary NIPBL reduction [PMID:41912533].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"The fundamental question of how cohesin reaches chromosomes was answered by demonstrating that the Scc2/Scc4 (NIPBL/MAU2) complex is required not for cohesin assembly but specifically for its loading onto chromatin.\",\n      \"evidence\": \"Genetic epistasis, co-immunoprecipitation, and chromatin binding assays in S. cerevisiae\",\n      \"pmids\": [\"10882066\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of loading catalysis unknown\", \"Mammalian orthologs not yet identified\", \"How the loader is targeted to specific chromosomal loci unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Before its cohesin-loading role was established in metazoans, C. elegans mau-2 was found to function cell-autonomously in neurons for axon guidance, suggesting developmental roles potentially independent of cohesion.\",\n      \"evidence\": \"GFP localization, cell-autonomous rescue, genetic epistasis with slt-1 in C. elegans\",\n      \"pmids\": [\"15539489\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether axon guidance role is cohesin-dependent or independent was not tested\", \"No biochemical interaction with worm Scc2 ortholog demonstrated in this study\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Conservation of the Scc2/Scc4 cohesin-loading partnership was established across metazoans: human MAU2 binds NIPBL via N-terminal regions and is required for cohesin chromatin association, with depletion causing precocious sister chromatid separation.\",\n      \"evidence\": \"Co-immunoprecipitation, chromatin fractionation, siRNA knockdown in HeLa cells; morpholino knockdown in Xenopus; genetic and biochemical analysis in S. pombe\",\n      \"pmids\": [\"16682347\", \"16802858\", \"16682348\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical reconstitution of human cohesin loading not yet achieved\", \"Cell-cycle regulation of loading not fully defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Genome-wide mapping resolved how the loader determines cohesin distribution: Scc2/Scc4 co-localizes with cohesin at CARs, and its chromatin association is independent of cohesin, establishing the loader as an upstream determinant of cohesin positioning.\",\n      \"evidence\": \"ChIP-chip genome-wide mapping in S. cerevisiae\",\n      \"pmids\": [\"19797771\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether loader sites and cohesin final positions diverge in metazoans was unclear\", \"Mechanism of loader recruitment to specific loci not identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"The clinical relevance of the NIPBL-MAU2 interaction was demonstrated when CdLS patient NIPBL missense mutations were shown to specifically disrupt MAU2 binding, fine-mapping the interaction domain.\",\n      \"evidence\": \"Interaction domain mapping and co-immunoprecipitation with patient-derived NIPBL mutations\",\n      \"pmids\": [\"21934712\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No MAU2 mutations in CdLS patients identified at this time\", \"Functional consequence for cohesin loading not directly measured\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Biochemical reconstitution demonstrated that purified human NIPBL/MAU2 complex directly loads cohesin onto prereplication-complex-containing DNA in vitro, establishing the sufficiency of the heterodimer for catalyzing loading.\",\n      \"evidence\": \"In vitro cohesin loading assay with purified proteins and Xenopus extract depletion/rescue\",\n      \"pmids\": [\"22628566\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MAU2 contributes catalytically or only as an adaptor not resolved\", \"Role of chromatin context in vitro only partially recapitulated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The chromatin context for loader recruitment was identified: RSC chromatin remodeling complex creates nucleosome-free regions that recruit Scc2/Scc4, linking chromatin architecture to cohesin loading site selection.\",\n      \"evidence\": \"ChIP-seq, nucleosome mapping, genetic epistasis, gene expression analysis in S. cerevisiae\",\n      \"pmids\": [\"25173104\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether equivalent remodelers recruit NIPBL/MAU2 in mammals not established\", \"Direct physical interaction between RSC and Scc2/Scc4 not demonstrated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Crystal structures of the Scc4-Scc2 N-terminal complex revealed the molecular architecture: MAU2 is a TPR superhelix enveloping an extended NIPBL peptide; a conserved surface patch on MAU2 mediates centromere recruitment, while the catalytic activity resides in NIPBL body/hook domains, establishing MAU2 as a chromatin adaptor rather than a catalytic subunit.\",\n      \"evidence\": \"X-ray crystallography, electron microscopy, in vitro cohesin loading assay, mutagenesis in yeast\",\n      \"pmids\": [\"26038942\", \"26212329\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length Scc2/Scc4 structure not resolved\", \"How the conserved surface patch recognizes centromeric chromatin features unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Dissection of MAU2 functional domains showed that a small N-terminal region is essential for viability and cohesion, and that MAU2 cannot engage cohesin without NIPBL, clarifying the obligate dependency within the heterodimer.\",\n      \"evidence\": \"Random insertion/dominant negative screen, cohesin loading assay, ChIP, co-immunoprecipitation in S. cerevisiae\",\n      \"pmids\": [\"27280786\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which specific contacts on the N-terminal region mediate its essential function not mapped\", \"Whether findings extend to mammalian MAU2 not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A surprising separation of function was uncovered: an alternative NIPBL isoform lacking the MAU2-binding domain can still load cohesin, demonstrating that MAU2-independent cohesin loading occurs and reframing MAU2 as a regulatory rather than absolutely essential loading subunit.\",\n      \"evidence\": \"Engineered NIPBL truncation cell lines, co-immunoprecipitation, cohesin ChIP, CdLS patient variant analysis\",\n      \"pmids\": [\"32433956\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MAU2-independent loading is sufficient for all genomic loci or only a subset unclear\", \"Relative contribution of MAU2-dependent vs -independent loading in vivo not quantified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The NIPBL-MAU2 heterodimer was shown to serve as a platform for transcription factor-directed cohesin recruitment: steroid receptors bind NIPBL LxxLL motifs to form ternary complexes that target cohesin to enhancers, and MAU2 loss-of-function variants were established as a direct genetic cause of Cornelia de Lange syndrome.\",\n      \"evidence\": \"LxxLL motif mutagenesis, co-immunoprecipitation, ChIP-seq, reporter assays, patient variant functional analysis, heterozygous Mau2 KO mouse model, DNA methylation episignature profiling\",\n      \"pmids\": [\"40377219\", \"41912533\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ternary complex structure relies partly on computational prediction and awaits direct structural validation\", \"Full spectrum of transcription factors that recruit NIPBL/MAU2 to enhancers not defined\", \"Whether CdLS pathology is primarily due to cohesin loading deficits or transcriptional dysregulation remains unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the precise mechanism by which MAU2 recognizes and adapts to distinct chromatin environments (centromeres, enhancers, nucleosome-free regions), the quantitative contribution of MAU2-dependent versus MAU2-independent cohesin loading across the genome, and whether MAU2 has cohesin-independent functions in development.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No full-length human NIPBL/MAU2 structure available\", \"MAU2 chromatin receptor identity unknown\", \"Cohesin-independent developmental roles not formally excluded\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 5, 8, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 1, 4, 8, 13]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [6, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [11, 12, 16]}\n    ],\n    \"complexes\": [\n      \"NIPBL/MAU2 cohesin loader complex\"\n    ],\n    \"partners\": [\n      \"NIPBL\",\n      \"SMC1A\",\n      \"SMC3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}