{"gene":"PDS5B","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2013,"finding":"Pds5B is essential for cohesion establishment by enabling Smc3 acetylation by cohesin acetyltransferases Esco1/2 and subsequent Sororin binding; Pds5B is specifically required for centromeric cohesion (while both Pds5A and Pds5B contribute to telomere and arm cohesion); depletion of Pds5B reduces Aurora B accumulation at the inner centromere, impairing error correction and promoting chromosome mis-segregation and aneuploidy.","method":"siRNA knockdown of Pds5A/B in vertebrate somatic cells, immunofluorescence, cohesion assays, flow cytometry for aneuploidy","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional assays with multiple orthogonal readouts (cohesion, acetylation, Aurora B localization, chromosome segregation), single lab but multiple orthogonal methods with rigorous controls","pmids":["24141881"],"is_preprint":false},{"year":2017,"finding":"The mitotic histone kinase Haspin binds directly to Pds5B through a conserved YGA/R motif in its non-catalytic N-terminus (similar to Wapl's YSR-motif-dependent binding to Pds5B); this Haspin–Pds5B interaction protects centromeric cohesion in mitosis by antagonizing Wapl-mediated cohesin release, and disruption of the interaction causes weakened centromeric cohesion and premature chromatid separation.","method":"Co-IP, knockout/knockin experiments, centromeric targeting of N-terminal Haspin fragments, rescue assays, immunofluorescence","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction mapped to defined motif, multiple functional rescue experiments, mechanistic epistasis with Wapl and Sgo1","pmids":["28343965"],"is_preprint":false},{"year":2016,"finding":"Pds5B forms a curved HEAT-repeat structure that bridges the Smc3–Scc1 and SA1–Scc1 interfaces, contacting all other cohesin subunits and forming an integral part of the cohesin ring; structural modeling shows Pds5B encircles the nucleotide-binding domains of Smc1 and Smc3.","method":"Single-particle electron microscopy of engineered 'bonsai' cohesin, chemical crosslinking-mass spectrometry, in silico modelling","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structural determination with EM and crosslinking-MS on reconstituted complex, multiple orthogonal methods in one study","pmids":["27549742"],"is_preprint":false},{"year":2012,"finding":"APRIN (PDS5B) is a BRCA2-associated protein that, after DNA damage (hydroxyurea/aphidicolin), associates with BRCA2 and other cohesin components in early S-phase; APRIN expression is required for the nuclear localisation of RAD51 and BRCA2 and for efficient homologous recombination; BRCA2 missense variants of unknown significance compromise the BRCA2–APRIN interaction.","method":"Proteomic profiling/Co-IP to identify BRCA2 interaction, siRNA knockdown, HR reporter assay, immunofluorescence for RAD51/BRCA2 nuclear localisation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — proteomic identification plus reciprocal Co-IP plus functional HR assay plus localisation, multiple orthogonal methods in one rigorous study","pmids":["22293751"],"is_preprint":false},{"year":2016,"finding":"APRIN (PDS5B) interacts directly with RAD51, PALB2, and BRCA2; APRIN binds DNA with affinity for D-loop structures and ssDNA; APRIN stimulates RAD51-mediated DNA strand invasion and strongly promotes annealing of complementary-strand DNA, counteracting the RPA inhibitory effect on RAD51 loading; APRIN depletion has no impact on class switch recombination, indicating a specific role in homologous recombination independent of cohesin.","method":"Purified protein pull-downs, in vitro DNA strand invasion assay, ssDNA binding assay, D-loop binding assay, class switch recombination assay, siRNA knockdown","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of HR activities with purified proteins, multiple biochemical assays, negative control (no CSR effect), single lab","pmids":["27924011"],"is_preprint":false},{"year":2019,"finding":"PDS5B (APRIN) interacts with the human Shu complex members SWS1 and SWSAP1, and with SPIDR, functioning in the same genetic pathway upon DNA damage; PDS5B promotes RAD51 recruitment to DNA repair foci and is required for replication fork restart following stalling.","method":"CRISPR/Cas9 deletion of Shu complex members, Co-IP to identify PDS5B and SPIDR as Shu interactors, RAD51 foci assay, sister chromatid exchange assay, sensitivity to MMS and mitomycin C","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, genetic epistasis via CRISPR KO, multiple functional readouts (RAD51 foci, SCE, drug sensitivity), single lab","pmids":["31665741"],"is_preprint":false},{"year":2007,"finding":"PDS5B (APRIN) knockout mice die shortly after birth with multiple congenital anomalies (heart defects, cleft palate, rib fusion, short limbs, distal colon aganglionosis, abnormal sympathetic neuron migration/projections, germ cell depletion); unexpectedly, no cohesion defects were detected in Pds5B−/− cells; PDS5B shows high expression in post-mitotic neurons and nucleolar localization, suggesting functions beyond chromosomal cohesion.","method":"Knockout mouse generation and phenotypic analysis, BrdU incorporation, immunofluorescence for cohesion markers, subcellular localisation studies","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — germline knockout with comprehensive developmental phenotyping, localisation data, negative result (no cohesion defect) rigorously established","pmids":["17652350"],"is_preprint":false},{"year":2000,"finding":"AS3 (PDS5B) protein expression mediates the androgen-induced proliferative shutoff in prostate cancer cells; tetracycline-regulated sense AS3 expression inhibits cell proliferation, whereas antisense AS3 blocks androgen-induced endogenous AS3 mRNA and abolishes the androgen-induced anti-proliferative effect.","method":"Stable tetracycline-regulated sense and antisense AS3 cell lines, cell proliferation assays, RT-PCR","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — regulated expression and antisense rescue in two independent stable cell lines, single lab, no direct molecular mechanism beyond correlation with proliferation arrest","pmids":["10963680"],"is_preprint":false},{"year":2002,"finding":"AS3 (PDS5B) protein is expressed in nuclei of >90% of epithelial cells of the intact rat prostate and is absent in castrated rats or during the proliferative phase of androgen-induced regeneration; AS3 is not expressed in BrdU-incorporating (proliferating) cells, confirming its role as a mediator of proliferative arrest in vivo.","method":"Immunohistochemistry of rat prostate sections (intact, castrated, testosterone-replaced groups), BrdU co-labelling, tetracycline-regulated AS3 cell lines","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in situ localisation linked to functional state, complemented by regulated cell line data, single lab, no downstream molecular mechanism identified","pmids":["12072405"],"is_preprint":false},{"year":2007,"finding":"APRIN (PDS5B) is a paralog of Pds5 that arose by gene duplication in early vertebrates; it localises to the euchromatin/heterochromatin interface in interphase nuclei; unlike canonical Pds5 proteins, APRIN contains HMG-like domains (hallmarks of chromatin regulators) and a defined DNA-binding domain and nuclear import signal, suggesting it acquired novel chromatin-regulatory functions in vertebrates.","method":"Comparative sequence/domain analysis, subcellular localisation by immunofluorescence, nuclear fractionation, domain mapping","journal":"The Journal of steroid biochemistry and molecular biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — localisation established by fractionation and immunofluorescence, domain architecture supported by cloning and homology, single lab","pmids":["17997301"],"is_preprint":false},{"year":2010,"finding":"PDS5B expression is precisely coordinated with stem cell differentiation in embryonal carcinoma cells; PDS5B knockdown disrupts Oct4, Nanog, and SOX2 patterns, blocks differentiation, and results in cells that fail to progress beyond the proneural progenitor phase with retained c-Myc expression, resembling cancer-initiating cells.","method":"siRNA knockdown in embryonal carcinoma stem cell model, immunofluorescence for pluripotency and differentiation markers (Oct4, Nanog, SOX2, Mash-1, E-cadherin, N-cadherin, c-Myc)","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined KD phenotype with multiple molecular markers, single lab, no pathway rescue experiment","pmids":["20383194"],"is_preprint":false},{"year":2010,"finding":"Mouse PDS5B is abundantly expressed in testis compared to other tissues; immunofluorescence shows high expression in spermatogonia with depletion from chromatin upon meiotic entry; during first meiotic prophase, PDS5B associates with axial chromosome cores and this association occurs independently of synaptonemal complex proteins SYCP1 and SYCP3, indicating PDS5B is an integral component of the cohesin-defined chromosome axis.","method":"Western blotting across tissues, immunofluorescence on spermatocyte spreads, analysis in SYCP1/SYCP3 knockout backgrounds","journal":"Genes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localisation in multiple genetic backgrounds establishing axis association independently of SC, single lab","pmids":["24710098"],"is_preprint":false},{"year":2019,"finding":"PDS5B is a direct target of miR-223 in pancreatic cancer cells; PDS5B exhibits tumor-suppressive function, and ectopic overexpression of PDS5B reverses miR-223-mediated tumor progression (proliferation and invasion) in pancreatic cancer cells.","method":"Luciferase reporter assay (3′-UTR targeting), overexpression rescue experiments, MTT, FACS, Transwell invasion, animal studies","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct target validated by luciferase assay and functional rescue, single lab","pmids":["30776580"],"is_preprint":false},{"year":2019,"finding":"PDS5B positively regulates the expression of Ptch2, thereby influencing Sonic hedgehog signaling; Ptch2 downregulation abolishes PDS5B-mediated anti-tumor activity (growth inhibition, apoptosis, reduced migration/invasion) in pancreatic cancer cells; PDS5B expression positively correlates with Ptch2 levels in patient samples.","method":"Overexpression and knockdown transfection, MTT, FACS, western blotting, wound healing, Transwell invasion, immunohistochemistry, rescue with Ptch2 knockdown","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rescue epistasis experiment links PDS5B to Ptch2/Hedgehog axis, multiple functional readouts, single lab","pmids":["31233836"],"is_preprint":false},{"year":2013,"finding":"PDS5B harbors frameshift mutations in mononucleotide repeat coding sequences in 20.3% of gastric and colorectal cancers with high microsatellite instability (but not in MSS/MSI-low tumors); loss of PDS5B protein expression is detected by IHC in 19–47% of gastric and colorectal cancers and is more common in tumors with frameshift mutations or high MSI.","method":"SSCP analysis and DNA sequencing of 91 gastric and 100 colorectal cancers, immunohistochemistry","journal":"Human pathology","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — mutation and protein loss documented in patient specimens, but no functional/mechanistic experiment performed","pmids":["23850494"],"is_preprint":false},{"year":2015,"finding":"Homozygous disruption of the Pds5b gene (by integration of a Her2 transgene concatemer into Pds5b) causes embryonic lethality in mice, confirming the essential role of Pds5b in embryonic development.","method":"Whole genome sequencing to map transgene integration site, homozygous Her2+/+ (Pds5b−/−) mouse viability analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — whole genome sequencing identifies causal disruption, independent replication of Pds5b−/− lethality consistent with prior knockout study","pmids":["26334628"],"is_preprint":false}],"current_model":"PDS5B (APRIN) is a vertebrate-specific cohesin-associated HEAT-repeat protein that forms an integral structural component of the cohesin ring by contacting all cohesin subunits; it enables cohesion establishment by facilitating Smc3 acetylation and Sororin recruitment, is specifically required for centromeric cohesion and Aurora B accumulation at centromeres, and protects centromeric cohesin by binding the mitotic kinase Haspin (via a YGA/R motif) to antagonize Wapl; beyond cohesion, PDS5B interacts with BRCA2, PALB2, and RAD51 to promote homologous recombination by stimulating RAD51-mediated strand invasion and antagonizing RPA inhibition of RAD51 loading, and it also interacts with the Shu complex (SWS1/SWSAP1/SPIDR) for replication fork restart; PDS5B additionally mediates androgen-induced proliferative arrest, regulates stem/progenitor cell differentiation programs, associates with meiotic chromosome axes in spermatocytes, and its loss causes developmental defects resembling Cornelia de Lange syndrome."},"narrative":{"mechanistic_narrative":"PDS5B (APRIN/AS3) is a vertebrate HEAT-repeat cohesin-associated protein that functions both in sister chromatid cohesion and in homologous recombination repair [PMID:24141881, PMID:22293751]. Within the cohesin ring it forms a curved structure bridging the Smc3–Scc1 and SA1–Scc1 interfaces, contacting all other cohesin subunits and encircling the Smc1/Smc3 nucleotide-binding domains [PMID:27549742]. PDS5B enables cohesion establishment by facilitating Smc3 acetylation by Esco1/2 and subsequent Sororin binding, and is specifically required for centromeric cohesion and for Aurora B accumulation at the inner centromere, so its loss drives chromosome mis-segregation and aneuploidy [PMID:24141881]. It protects centromeric cohesin in mitosis by binding the histone kinase Haspin through a conserved YGA/R motif, antagonizing Wapl-mediated cohesin release [PMID:28343965]. Independently of cohesin, PDS5B promotes homologous recombination: it associates with BRCA2 and is required for nuclear localization of RAD51 and BRCA2 [PMID:22293751], binds RAD51, PALB2, and BRCA2 directly along with D-loop and ssDNA structures to stimulate RAD51-mediated strand invasion and counteract RPA inhibition of RAD51 loading [PMID:27924011], and acts in the Shu-complex pathway (SWS1, SWSAP1, SPIDR) to promote RAD51 foci formation and replication fork restart [PMID:31665741]. Beyond these roles, PDS5B mediates androgen-induced proliferative arrest in prostate cells [PMID:10963680, PMID:12072405], coordinates stem/progenitor differentiation programs [PMID:20383194], and associates with the meiotic chromosome axis in spermatocytes [PMID:24710098]. Knockout mice die perinatally with multiple congenital anomalies resembling Cornelia de Lange syndrome, yet without detectable cohesion defects, indicating essential developmental functions distinct from its cohesion role [PMID:17652350].","teleology":[{"year":2000,"claim":"Established the first functional readout for PDS5B as AS3, identifying it as a mediator of androgen-induced proliferative shutoff before its cohesin role was known.","evidence":"tetracycline-regulated sense/antisense AS3 expression and proliferation assays in prostate cancer cells","pmids":["10963680"],"confidence":"Medium","gaps":["No molecular mechanism beyond correlation with proliferation arrest","Link to chromatin/cohesin function not yet made"]},{"year":2002,"claim":"Confirmed in vivo that AS3/PDS5B expression marks non-proliferating prostate epithelium, anchoring its anti-proliferative role to physiological androgen state.","evidence":"immunohistochemistry of intact, castrated, and testosterone-replaced rat prostate with BrdU co-labelling","pmids":["12072405"],"confidence":"Medium","gaps":["No downstream molecular effector identified","Mechanism linking androgen signaling to PDS5B expression unresolved"]},{"year":2007,"claim":"Defined PDS5B as a vertebrate Pds5 paralog with novel chromatin-regulatory domains, and showed via knockout that it is developmentally essential with functions seemingly beyond cohesion.","evidence":"comparative domain analysis, fractionation/immunofluorescence localization, and germline knockout mouse phenotyping","pmids":["17997301","17652350"],"confidence":"Medium","gaps":["No cohesion defect detected, leaving developmental mechanism unexplained","Function of HMG-like/DNA-binding domains not tested","Nucleolar localization role uncharacterized"]},{"year":2010,"claim":"Extended PDS5B function to cell-fate programs by linking it to differentiation control.","evidence":"siRNA knockdown in embryonal carcinoma stem cells with pluripotency/differentiation marker profiling","pmids":["20383194"],"confidence":"Medium","gaps":["No rescue experiment","Mechanism connecting PDS5B to Oct4/Nanog/SOX2 regulation unknown"]},{"year":2012,"claim":"Identified PDS5B/APRIN as a BRCA2-associated protein required for RAD51/BRCA2 nuclear localization and efficient HR, opening its DNA-repair role.","evidence":"proteomic Co-IP, siRNA knockdown, HR reporter assay, immunofluorescence after replication stress","pmids":["22293751"],"confidence":"High","gaps":["Direct biochemical activity not yet defined","Distinction from cohesin role not established at this stage"]},{"year":2013,"claim":"Resolved the core mitotic mechanism: PDS5B enables Smc3 acetylation/Sororin loading and is specifically required for centromeric cohesion and Aurora B accumulation.","evidence":"siRNA knockdown of Pds5A/B with cohesion, acetylation, Aurora B localization, and aneuploidy readouts","pmids":["24141881"],"confidence":"High","gaps":["Mechanism of Aurora B recruitment downstream of PDS5B not detailed","Did not reconcile with absence of cohesion defect in knockout cells"]},{"year":2016,"claim":"Provided the structural basis for PDS5B as an integral cohesin component and biochemically reconstituted its HR-stimulating activities.","evidence":"single-particle EM and crosslinking-MS of bonsai cohesin; purified-protein strand-invasion, ssDNA, and D-loop binding assays","pmids":["27549742","27924011"],"confidence":"High","gaps":["High-resolution structure of full-length PDS5B in cohesin lacking","How DNA-binding and cohesin roles are coordinated unresolved"]},{"year":2017,"claim":"Defined the molecular interaction protecting centromeric cohesion: Haspin binds PDS5B via a YGA/R motif to antagonize Wapl.","evidence":"Co-IP, knockin/knockout, centromeric targeting and rescue assays with Wapl/Sgo1 epistasis","pmids":["28343965"],"confidence":"High","gaps":["Structural detail of the YGA/R-PDS5B interface not resolved","Quantitative competition with Wapl binding not measured"]},{"year":2019,"claim":"Connected PDS5B to the Shu-complex/replication-fork-restart pathway and confirmed both its essentiality and tumor-suppressive roles.","evidence":"CRISPR KO and Co-IP with Shu members, RAD51 foci/SCE/drug-sensitivity assays; miR-223 luciferase targeting and Ptch2/Hedgehog rescue in pancreatic cancer; transgene-disruption mouse lethality","pmids":["31665741","30776580","31233836","26334628"],"confidence":"Medium","gaps":["How PDS5B integrates Shu-complex and BRCA2/RAD51 functions unclear","Mechanism of Ptch2 regulation not defined","Relationship between tumor-suppressor and cohesin/HR roles unresolved"]},{"year":null,"claim":"How PDS5B's cohesin-structural, HR-promoting, developmental, and differentiation functions are mechanistically partitioned and coordinated within a single protein remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["The cohesion-independent developmental defects in knockout mice lack a molecular mechanism","No unified model explaining nucleolar localization and chromatin-regulatory domains","Mechanistic basis for the Cornelia de Lange-like phenotype not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[4,9]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,8,9]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[6]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,11]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,2,1]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[3,4,5]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[5]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6,10]}],"complexes":["cohesin","Shu complex"],"partners":["HASPIN","BRCA2","RAD51","PALB2","SWS1","SWSAP1","SPIDR","WAPL"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NTI5","full_name":"Sister chromatid cohesion protein PDS5 homolog B","aliases":["Androgen-induced proliferation inhibitor","Androgen-induced prostate proliferative shutoff-associated protein AS3"],"length_aa":1447,"mass_kda":164.7,"function":"Regulator of sister chromatid cohesion in mitosis which may stabilize cohesin complex association with chromatin. May couple sister chromatid cohesion during mitosis to DNA replication. Cohesion ensures that chromosome partitioning is accurate in both meiotic and mitotic cells and plays an important role in DNA repair. Plays a role in androgen-induced proliferative arrest in prostate cells","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9NTI5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PDS5B","classification":"Not Classified","n_dependent_lines":82,"n_total_lines":1208,"dependency_fraction":0.06788079470198675},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SMC1A","stoichiometry":10.0},{"gene":"STAG2","stoichiometry":10.0},{"gene":"RAD21","stoichiometry":4.0},{"gene":"CASP2","stoichiometry":0.2},{"gene":"STAG1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PDS5B","total_profiled":1310},"omim":[{"mim_id":"606462","title":"RAD21 COHESIN COMPLEX COMPONENT; RAD21","url":"https://www.omim.org/entry/606462"},{"mim_id":"605333","title":"PDS5 COHESIN-ASSOCIATED FACTOR B; PDS5B","url":"https://www.omim.org/entry/605333"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PDS5B"},"hgnc":{"alias_symbol":["AS3","KIAA0979","FLJ23236","CG008"],"prev_symbol":["APRIN"]},"alphafold":{"accession":"Q9NTI5","domains":[{"cath_id":"-","chopping":"9-152","consensus_level":"medium","plddt":90.4194,"start":9,"end":152},{"cath_id":"1.25.10.10","chopping":"273-464","consensus_level":"medium","plddt":96.4042,"start":273,"end":464},{"cath_id":"-","chopping":"485-614","consensus_level":"medium","plddt":92.5714,"start":485,"end":614},{"cath_id":"-","chopping":"739-900","consensus_level":"medium","plddt":95.2809,"start":739,"end":900},{"cath_id":"-","chopping":"990-1120","consensus_level":"medium","plddt":92.6578,"start":990,"end":1120}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NTI5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NTI5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NTI5-F1-predicted_aligned_error_v6.png","plddt_mean":80.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PDS5B","jax_strain_url":"https://www.jax.org/strain/search?query=PDS5B"},"sequence":{"accession":"Q9NTI5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NTI5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NTI5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NTI5"}},"corpus_meta":[{"pmid":"28985503","id":"PMC_28985503","title":"A Peptide Encoded by a Putative lncRNA HOXB-AS3 Suppresses Colon Cancer Growth.","date":"2017","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/28985503","citation_count":581,"is_preprint":false},{"pmid":"30286788","id":"PMC_30286788","title":"A novel long noncoding RNA HOXC-AS3 mediates tumorigenesis of gastric cancer by binding to YBX1.","date":"2018","source":"Genome biology","url":"https://pubmed.ncbi.nlm.nih.gov/30286788","citation_count":232,"is_preprint":false},{"pmid":"31837602","id":"PMC_31837602","title":"LncRNA MAGI2-AS3 Is Regulated by BRD4 and Promotes Gastric Cancer Progression via Maintaining ZEB1 Overexpression by Sponging miR-141/200a.","date":"2019","source":"Molecular therapy. 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oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33643896","citation_count":14,"is_preprint":false},{"pmid":"18499069","id":"PMC_18499069","title":"Correlation of genomic and expression alterations of AS3 with esophageal squamous cell carcinoma.","date":"2008","source":"Journal of genetics and genomics = Yi chuan xue bao","url":"https://pubmed.ncbi.nlm.nih.gov/18499069","citation_count":13,"is_preprint":false},{"pmid":"35944561","id":"PMC_35944561","title":"LncRNA MAGI2-AS3 Inhibits Prostate Cancer Progression by Targeting the miR-142-3p.","date":"2022","source":"Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme","url":"https://pubmed.ncbi.nlm.nih.gov/35944561","citation_count":13,"is_preprint":false},{"pmid":"35253323","id":"PMC_35253323","title":"Transcriptional suppression of Dicer by HOXB-AS3/EZH2 complex dictates sorafenib resistance and cancer stemness.","date":"2022","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/35253323","citation_count":13,"is_preprint":false},{"pmid":"32546442","id":"PMC_32546442","title":"LncRNA MAGI2-AS3 is downregulated in the distant recurrence of hepatocellular carcinoma after surgical resection and affects migration and invasion via ROCK2.","date":"2020","source":"Annals of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/32546442","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51520,"output_tokens":4296,"usd":0.1095,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12307,"output_tokens":3458,"usd":0.073993,"stage2_stop_reason":"end_turn"},"total_usd":0.183493,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"Pds5B is essential for cohesion establishment by enabling Smc3 acetylation by cohesin acetyltransferases Esco1/2 and subsequent Sororin binding; Pds5B is specifically required for centromeric cohesion (while both Pds5A and Pds5B contribute to telomere and arm cohesion); depletion of Pds5B reduces Aurora B accumulation at the inner centromere, impairing error correction and promoting chromosome mis-segregation and aneuploidy.\",\n      \"method\": \"siRNA knockdown of Pds5A/B in vertebrate somatic cells, immunofluorescence, cohesion assays, flow cytometry for aneuploidy\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional assays with multiple orthogonal readouts (cohesion, acetylation, Aurora B localization, chromosome segregation), single lab but multiple orthogonal methods with rigorous controls\",\n      \"pmids\": [\"24141881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The mitotic histone kinase Haspin binds directly to Pds5B through a conserved YGA/R motif in its non-catalytic N-terminus (similar to Wapl's YSR-motif-dependent binding to Pds5B); this Haspin–Pds5B interaction protects centromeric cohesion in mitosis by antagonizing Wapl-mediated cohesin release, and disruption of the interaction causes weakened centromeric cohesion and premature chromatid separation.\",\n      \"method\": \"Co-IP, knockout/knockin experiments, centromeric targeting of N-terminal Haspin fragments, rescue assays, immunofluorescence\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction mapped to defined motif, multiple functional rescue experiments, mechanistic epistasis with Wapl and Sgo1\",\n      \"pmids\": [\"28343965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Pds5B forms a curved HEAT-repeat structure that bridges the Smc3–Scc1 and SA1–Scc1 interfaces, contacting all other cohesin subunits and forming an integral part of the cohesin ring; structural modeling shows Pds5B encircles the nucleotide-binding domains of Smc1 and Smc3.\",\n      \"method\": \"Single-particle electron microscopy of engineered 'bonsai' cohesin, chemical crosslinking-mass spectrometry, in silico modelling\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural determination with EM and crosslinking-MS on reconstituted complex, multiple orthogonal methods in one study\",\n      \"pmids\": [\"27549742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"APRIN (PDS5B) is a BRCA2-associated protein that, after DNA damage (hydroxyurea/aphidicolin), associates with BRCA2 and other cohesin components in early S-phase; APRIN expression is required for the nuclear localisation of RAD51 and BRCA2 and for efficient homologous recombination; BRCA2 missense variants of unknown significance compromise the BRCA2–APRIN interaction.\",\n      \"method\": \"Proteomic profiling/Co-IP to identify BRCA2 interaction, siRNA knockdown, HR reporter assay, immunofluorescence for RAD51/BRCA2 nuclear localisation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomic identification plus reciprocal Co-IP plus functional HR assay plus localisation, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"22293751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"APRIN (PDS5B) interacts directly with RAD51, PALB2, and BRCA2; APRIN binds DNA with affinity for D-loop structures and ssDNA; APRIN stimulates RAD51-mediated DNA strand invasion and strongly promotes annealing of complementary-strand DNA, counteracting the RPA inhibitory effect on RAD51 loading; APRIN depletion has no impact on class switch recombination, indicating a specific role in homologous recombination independent of cohesin.\",\n      \"method\": \"Purified protein pull-downs, in vitro DNA strand invasion assay, ssDNA binding assay, D-loop binding assay, class switch recombination assay, siRNA knockdown\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of HR activities with purified proteins, multiple biochemical assays, negative control (no CSR effect), single lab\",\n      \"pmids\": [\"27924011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PDS5B (APRIN) interacts with the human Shu complex members SWS1 and SWSAP1, and with SPIDR, functioning in the same genetic pathway upon DNA damage; PDS5B promotes RAD51 recruitment to DNA repair foci and is required for replication fork restart following stalling.\",\n      \"method\": \"CRISPR/Cas9 deletion of Shu complex members, Co-IP to identify PDS5B and SPIDR as Shu interactors, RAD51 foci assay, sister chromatid exchange assay, sensitivity to MMS and mitomycin C\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, genetic epistasis via CRISPR KO, multiple functional readouts (RAD51 foci, SCE, drug sensitivity), single lab\",\n      \"pmids\": [\"31665741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PDS5B (APRIN) knockout mice die shortly after birth with multiple congenital anomalies (heart defects, cleft palate, rib fusion, short limbs, distal colon aganglionosis, abnormal sympathetic neuron migration/projections, germ cell depletion); unexpectedly, no cohesion defects were detected in Pds5B−/− cells; PDS5B shows high expression in post-mitotic neurons and nucleolar localization, suggesting functions beyond chromosomal cohesion.\",\n      \"method\": \"Knockout mouse generation and phenotypic analysis, BrdU incorporation, immunofluorescence for cohesion markers, subcellular localisation studies\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — germline knockout with comprehensive developmental phenotyping, localisation data, negative result (no cohesion defect) rigorously established\",\n      \"pmids\": [\"17652350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"AS3 (PDS5B) protein expression mediates the androgen-induced proliferative shutoff in prostate cancer cells; tetracycline-regulated sense AS3 expression inhibits cell proliferation, whereas antisense AS3 blocks androgen-induced endogenous AS3 mRNA and abolishes the androgen-induced anti-proliferative effect.\",\n      \"method\": \"Stable tetracycline-regulated sense and antisense AS3 cell lines, cell proliferation assays, RT-PCR\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — regulated expression and antisense rescue in two independent stable cell lines, single lab, no direct molecular mechanism beyond correlation with proliferation arrest\",\n      \"pmids\": [\"10963680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"AS3 (PDS5B) protein is expressed in nuclei of >90% of epithelial cells of the intact rat prostate and is absent in castrated rats or during the proliferative phase of androgen-induced regeneration; AS3 is not expressed in BrdU-incorporating (proliferating) cells, confirming its role as a mediator of proliferative arrest in vivo.\",\n      \"method\": \"Immunohistochemistry of rat prostate sections (intact, castrated, testosterone-replaced groups), BrdU co-labelling, tetracycline-regulated AS3 cell lines\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in situ localisation linked to functional state, complemented by regulated cell line data, single lab, no downstream molecular mechanism identified\",\n      \"pmids\": [\"12072405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"APRIN (PDS5B) is a paralog of Pds5 that arose by gene duplication in early vertebrates; it localises to the euchromatin/heterochromatin interface in interphase nuclei; unlike canonical Pds5 proteins, APRIN contains HMG-like domains (hallmarks of chromatin regulators) and a defined DNA-binding domain and nuclear import signal, suggesting it acquired novel chromatin-regulatory functions in vertebrates.\",\n      \"method\": \"Comparative sequence/domain analysis, subcellular localisation by immunofluorescence, nuclear fractionation, domain mapping\",\n      \"journal\": \"The Journal of steroid biochemistry and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — localisation established by fractionation and immunofluorescence, domain architecture supported by cloning and homology, single lab\",\n      \"pmids\": [\"17997301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PDS5B expression is precisely coordinated with stem cell differentiation in embryonal carcinoma cells; PDS5B knockdown disrupts Oct4, Nanog, and SOX2 patterns, blocks differentiation, and results in cells that fail to progress beyond the proneural progenitor phase with retained c-Myc expression, resembling cancer-initiating cells.\",\n      \"method\": \"siRNA knockdown in embryonal carcinoma stem cell model, immunofluorescence for pluripotency and differentiation markers (Oct4, Nanog, SOX2, Mash-1, E-cadherin, N-cadherin, c-Myc)\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined KD phenotype with multiple molecular markers, single lab, no pathway rescue experiment\",\n      \"pmids\": [\"20383194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Mouse PDS5B is abundantly expressed in testis compared to other tissues; immunofluorescence shows high expression in spermatogonia with depletion from chromatin upon meiotic entry; during first meiotic prophase, PDS5B associates with axial chromosome cores and this association occurs independently of synaptonemal complex proteins SYCP1 and SYCP3, indicating PDS5B is an integral component of the cohesin-defined chromosome axis.\",\n      \"method\": \"Western blotting across tissues, immunofluorescence on spermatocyte spreads, analysis in SYCP1/SYCP3 knockout backgrounds\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localisation in multiple genetic backgrounds establishing axis association independently of SC, single lab\",\n      \"pmids\": [\"24710098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PDS5B is a direct target of miR-223 in pancreatic cancer cells; PDS5B exhibits tumor-suppressive function, and ectopic overexpression of PDS5B reverses miR-223-mediated tumor progression (proliferation and invasion) in pancreatic cancer cells.\",\n      \"method\": \"Luciferase reporter assay (3′-UTR targeting), overexpression rescue experiments, MTT, FACS, Transwell invasion, animal studies\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct target validated by luciferase assay and functional rescue, single lab\",\n      \"pmids\": [\"30776580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PDS5B positively regulates the expression of Ptch2, thereby influencing Sonic hedgehog signaling; Ptch2 downregulation abolishes PDS5B-mediated anti-tumor activity (growth inhibition, apoptosis, reduced migration/invasion) in pancreatic cancer cells; PDS5B expression positively correlates with Ptch2 levels in patient samples.\",\n      \"method\": \"Overexpression and knockdown transfection, MTT, FACS, western blotting, wound healing, Transwell invasion, immunohistochemistry, rescue with Ptch2 knockdown\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rescue epistasis experiment links PDS5B to Ptch2/Hedgehog axis, multiple functional readouts, single lab\",\n      \"pmids\": [\"31233836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PDS5B harbors frameshift mutations in mononucleotide repeat coding sequences in 20.3% of gastric and colorectal cancers with high microsatellite instability (but not in MSS/MSI-low tumors); loss of PDS5B protein expression is detected by IHC in 19–47% of gastric and colorectal cancers and is more common in tumors with frameshift mutations or high MSI.\",\n      \"method\": \"SSCP analysis and DNA sequencing of 91 gastric and 100 colorectal cancers, immunohistochemistry\",\n      \"journal\": \"Human pathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — mutation and protein loss documented in patient specimens, but no functional/mechanistic experiment performed\",\n      \"pmids\": [\"23850494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Homozygous disruption of the Pds5b gene (by integration of a Her2 transgene concatemer into Pds5b) causes embryonic lethality in mice, confirming the essential role of Pds5b in embryonic development.\",\n      \"method\": \"Whole genome sequencing to map transgene integration site, homozygous Her2+/+ (Pds5b−/−) mouse viability analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — whole genome sequencing identifies causal disruption, independent replication of Pds5b−/− lethality consistent with prior knockout study\",\n      \"pmids\": [\"26334628\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PDS5B (APRIN) is a vertebrate-specific cohesin-associated HEAT-repeat protein that forms an integral structural component of the cohesin ring by contacting all cohesin subunits; it enables cohesion establishment by facilitating Smc3 acetylation and Sororin recruitment, is specifically required for centromeric cohesion and Aurora B accumulation at centromeres, and protects centromeric cohesin by binding the mitotic kinase Haspin (via a YGA/R motif) to antagonize Wapl; beyond cohesion, PDS5B interacts with BRCA2, PALB2, and RAD51 to promote homologous recombination by stimulating RAD51-mediated strand invasion and antagonizing RPA inhibition of RAD51 loading, and it also interacts with the Shu complex (SWS1/SWSAP1/SPIDR) for replication fork restart; PDS5B additionally mediates androgen-induced proliferative arrest, regulates stem/progenitor cell differentiation programs, associates with meiotic chromosome axes in spermatocytes, and its loss causes developmental defects resembling Cornelia de Lange syndrome.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PDS5B (APRIN/AS3) is a vertebrate HEAT-repeat cohesin-associated protein that functions both in sister chromatid cohesion and in homologous recombination repair [#0, #3]. Within the cohesin ring it forms a curved structure bridging the Smc3–Scc1 and SA1–Scc1 interfaces, contacting all other cohesin subunits and encircling the Smc1/Smc3 nucleotide-binding domains [#2]. PDS5B enables cohesion establishment by facilitating Smc3 acetylation by Esco1/2 and subsequent Sororin binding, and is specifically required for centromeric cohesion and for Aurora B accumulation at the inner centromere, so its loss drives chromosome mis-segregation and aneuploidy [#0]. It protects centromeric cohesin in mitosis by binding the histone kinase Haspin through a conserved YGA/R motif, antagonizing Wapl-mediated cohesin release [#1]. Independently of cohesin, PDS5B promotes homologous recombination: it associates with BRCA2 and is required for nuclear localization of RAD51 and BRCA2 [#3], binds RAD51, PALB2, and BRCA2 directly along with D-loop and ssDNA structures to stimulate RAD51-mediated strand invasion and counteract RPA inhibition of RAD51 loading [#4], and acts in the Shu-complex pathway (SWS1, SWSAP1, SPIDR) to promote RAD51 foci formation and replication fork restart [#5]. Beyond these roles, PDS5B mediates androgen-induced proliferative arrest in prostate cells [#7, #8], coordinates stem/progenitor differentiation programs [#10], and associates with the meiotic chromosome axis in spermatocytes [#11]. Knockout mice die perinatally with multiple congenital anomalies resembling Cornelia de Lange syndrome, yet without detectable cohesion defects, indicating essential developmental functions distinct from its cohesion role [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established the first functional readout for PDS5B as AS3, identifying it as a mediator of androgen-induced proliferative shutoff before its cohesin role was known.\",\n      \"evidence\": \"tetracycline-regulated sense/antisense AS3 expression and proliferation assays in prostate cancer cells\",\n      \"pmids\": [\"10963680\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular mechanism beyond correlation with proliferation arrest\", \"Link to chromatin/cohesin function not yet made\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Confirmed in vivo that AS3/PDS5B expression marks non-proliferating prostate epithelium, anchoring its anti-proliferative role to physiological androgen state.\",\n      \"evidence\": \"immunohistochemistry of intact, castrated, and testosterone-replaced rat prostate with BrdU co-labelling\",\n      \"pmids\": [\"12072405\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No downstream molecular effector identified\", \"Mechanism linking androgen signaling to PDS5B expression unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined PDS5B as a vertebrate Pds5 paralog with novel chromatin-regulatory domains, and showed via knockout that it is developmentally essential with functions seemingly beyond cohesion.\",\n      \"evidence\": \"comparative domain analysis, fractionation/immunofluorescence localization, and germline knockout mouse phenotyping\",\n      \"pmids\": [\"17997301\", \"17652350\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No cohesion defect detected, leaving developmental mechanism unexplained\", \"Function of HMG-like/DNA-binding domains not tested\", \"Nucleolar localization role uncharacterized\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended PDS5B function to cell-fate programs by linking it to differentiation control.\",\n      \"evidence\": \"siRNA knockdown in embryonal carcinoma stem cells with pluripotency/differentiation marker profiling\",\n      \"pmids\": [\"20383194\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No rescue experiment\", \"Mechanism connecting PDS5B to Oct4/Nanog/SOX2 regulation unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified PDS5B/APRIN as a BRCA2-associated protein required for RAD51/BRCA2 nuclear localization and efficient HR, opening its DNA-repair role.\",\n      \"evidence\": \"proteomic Co-IP, siRNA knockdown, HR reporter assay, immunofluorescence after replication stress\",\n      \"pmids\": [\"22293751\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical activity not yet defined\", \"Distinction from cohesin role not established at this stage\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved the core mitotic mechanism: PDS5B enables Smc3 acetylation/Sororin loading and is specifically required for centromeric cohesion and Aurora B accumulation.\",\n      \"evidence\": \"siRNA knockdown of Pds5A/B with cohesion, acetylation, Aurora B localization, and aneuploidy readouts\",\n      \"pmids\": [\"24141881\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of Aurora B recruitment downstream of PDS5B not detailed\", \"Did not reconcile with absence of cohesion defect in knockout cells\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided the structural basis for PDS5B as an integral cohesin component and biochemically reconstituted its HR-stimulating activities.\",\n      \"evidence\": \"single-particle EM and crosslinking-MS of bonsai cohesin; purified-protein strand-invasion, ssDNA, and D-loop binding assays\",\n      \"pmids\": [\"27549742\", \"27924011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution structure of full-length PDS5B in cohesin lacking\", \"How DNA-binding and cohesin roles are coordinated unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the molecular interaction protecting centromeric cohesion: Haspin binds PDS5B via a YGA/R motif to antagonize Wapl.\",\n      \"evidence\": \"Co-IP, knockin/knockout, centromeric targeting and rescue assays with Wapl/Sgo1 epistasis\",\n      \"pmids\": [\"28343965\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of the YGA/R-PDS5B interface not resolved\", \"Quantitative competition with Wapl binding not measured\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected PDS5B to the Shu-complex/replication-fork-restart pathway and confirmed both its essentiality and tumor-suppressive roles.\",\n      \"evidence\": \"CRISPR KO and Co-IP with Shu members, RAD51 foci/SCE/drug-sensitivity assays; miR-223 luciferase targeting and Ptch2/Hedgehog rescue in pancreatic cancer; transgene-disruption mouse lethality\",\n      \"pmids\": [\"31665741\", \"30776580\", \"31233836\", \"26334628\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How PDS5B integrates Shu-complex and BRCA2/RAD51 functions unclear\", \"Mechanism of Ptch2 regulation not defined\", \"Relationship between tumor-suppressor and cohesin/HR roles unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PDS5B's cohesin-structural, HR-promoting, developmental, and differentiation functions are mechanistically partitioned and coordinated within a single protein remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The cohesion-independent developmental defects in knockout mice lack a molecular mechanism\", \"No unified model explaining nucleolar localization and chromatin-regulatory domains\", \"Mechanistic basis for the Cornelia de Lange-like phenotype not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [4, 9]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 8, 9]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 2, 1]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [3, 4, 5]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6, 10]}\n    ],\n    \"complexes\": [\n      \"cohesin\",\n      \"Shu complex\"\n    ],\n    \"partners\": [\n      \"Haspin\",\n      \"BRCA2\",\n      \"RAD51\",\n      \"PALB2\",\n      \"SWS1\",\n      \"SWSAP1\",\n      \"SPIDR\",\n      \"WAPL\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}