{"gene":"USP26","run_date":"2026-04-28T23:00:23","timeline":{"discoveries":[{"year":2010,"finding":"USP26 is a nuclear protein that binds to androgen receptor (AR) via three nuclear receptor interaction motifs, modulates AR ubiquitination, and counteracts hormone-induced AR ubiquitination, thereby stabilizing AR and contributing to AR transcriptional activity. USP26 assembles with AR and other cofactors in subnuclear foci.","method":"shRNA library screen, co-immunoprecipitation, ubiquitination assay, immunofluorescence, nuclear fractionation","journal":"Molecular cancer research : MCR","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, ubiquitination assay, nuclear localization with functional consequence, replicated by multiple subsequent studies","pmids":["20501646"],"is_preprint":false},{"year":2015,"finding":"USP26 is recruited to DNA double-strand breaks (DSBs) where it removes RNF168-induced ubiquitin conjugates, limiting the spreading of RAP80-BRCA1 from DSBs, and promoting the association of BRCA1 with PALB2 to facilitate homologous recombination (HR). Depletion of USP26 disrupts HR execution, an effect alleviated by simultaneous depletion of RAP80.","method":"Genetic screen, siRNA depletion, laser micro-irradiation/DSB induction, immunofluorescence, epistasis (double knockdown), HR reporter assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with defined phenotypic readout, multiple orthogonal methods, clear pathway placement","pmids":["26101254"],"is_preprint":false},{"year":2017,"finding":"USP26 deubiquitinates and stabilizes SMAD7, acting as a negative regulator of TGF-β signaling. TGF-β rapidly induces USP26 expression, and USP26 in turn limits ubiquitin-mediated turnover of SMAD7; knockdown of USP26 destabilizes SMAD7, leading to TGF-β receptor stabilization and enhanced p-SMAD2 levels.","method":"siRNA knockdown, co-immunoprecipitation, ubiquitination assay, western blot, cycloheximide chase","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, ubiquitination assay, loss-of-function with defined signaling phenotype, moderate evidence","pmids":["28381482"],"is_preprint":false},{"year":2017,"finding":"USP26 negatively regulates somatic cell reprogramming by removing K48-linked polyubiquitination from CBX4 and CBX6 (PRC1 complex components), stabilizing them. Accumulated CBX4 and CBX6 repress pluripotency genes Sox2 and Nanog through PRC1-mediated H2A ubiquitination at their promoters.","method":"Overexpression, knockdown, co-immunoprecipitation, ubiquitination assay (K48-linkage specific), reprogramming efficiency assay, ChIP","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including linkage-specific ubiquitination assay, functional reprogramming readout, defined pathway placement","pmids":["28839133"],"is_preprint":false},{"year":2019,"finding":"USP26 deubiquitinates and stabilizes Snail (SNAI1), an EMT transcription factor, promoting cancer cell migration and invasion. Identified via DUB library screen.","method":"DUB library screen, co-immunoprecipitation, ubiquitination assay, cycloheximide chase, migration/invasion assay","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and ubiquitination assay with functional cellular readout, single lab","pmids":["30763716"],"is_preprint":false},{"year":2016,"finding":"USP26 binds to Mdm2 through its coiled-coil C-terminal domain, deubiquitinates Mdm2, and stabilizes it. USP26 itself can be ubiquitinated by HeLa cell extract and has a defined half-life in HEK293 cells.","method":"Co-transfection, co-immunoprecipitation, cell-free ubiquitination assay, half-life determination (cycloheximide chase)","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro ubiquitination assay and Co-IP, single lab, moderate evidence","pmids":["27810359"],"is_preprint":false},{"year":2016,"finding":"The USP26 R344W missense mutation reduces binding affinity and deubiquitinating activity of USP26 toward AR, eliminating USP26's inhibitory effect on AR transcriptional activity in HeLa and TM4 cells.","method":"Immunoprecipitation, ubiquitination assay, luciferase reporter assay, site-directed mutagenesis","journal":"Reproductive sciences","confidence":"Medium","confidence_rationale":"Tier 1-2 — in vitro deubiquitination assay with mutagenesis and functional reporter assay, single lab","pmids":["27089915"],"is_preprint":false},{"year":2017,"finding":"The USP26 Q156H mutant loses deubiquitinase enzymatic activity, while 18 other tested USP26 variants retain wild-type activity. Artificially constructed truncation mutants (E174# and E189# split constructs) also lose activity, demonstrating requirement for intact protein.","method":"Site-directed mutagenesis, USP cleavage assay (Ub-Met-β-gal and GST-Ub52 substrates)","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro enzymatic assay with mutagenesis, single lab","pmids":["29111204"],"is_preprint":false},{"year":2019,"finding":"Usp26 mutation in mice (backcrossed to DBA/2 background) causes sterility or subfertility with atrophic testes, reduced spermatid numbers, malformed sperm head morphology, unsynapsed chromosomes in pachynema, and defective chiasma formation in diplonema, leading to apoptosis of metaphase spermatocytes.","method":"Mouse knockout (gene targeting), histology, cytological analysis of spermatocytes, fertility assessment","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — clean KO mouse model with multiple defined cellular phenotypes, background-dependent effect characterized","pmids":["31551464"],"is_preprint":false},{"year":2021,"finding":"USP26 protein localizes at the XY body during male meiosis, and USP26 knockout in male mice results in incomplete sex chromosome pairing by destabilizing TEX11, leading to XY aneuploid spermatozoa and elevated rates of 41,XXY offspring.","method":"Knockout mouse model, immunofluorescence (XY body localization), co-immunoprecipitation/interaction with TEX11, sperm FISH for aneuploidy, offspring karyotyping","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — direct localization experiment tied to functional consequence, genetic KO with defined molecular mechanism (TEX11 destabilization), clinical validation","pmids":["33978233"],"is_preprint":false},{"year":2022,"finding":"USP26 is a downstream target of RNF12 (RLIM): RNF12 relieves REX1-mediated repression of Usp26 transcription, leading to increased USP26 abundance. USP26 then forms a complex with RNF12 and prevents RNF12 autoubiquitylation and proteasomal degradation, establishing a transcriptional feed-forward amplification loop required for germ cell differentiation and gametogenesis gene expression.","method":"Global quantitative proteomics, co-immunoprecipitation, ubiquitination assay, transcriptional reporter assay, in vitro germ cell differentiation, genetic interaction studies with TOKAS/infertility variants","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1-2 — proteomics discovery, reciprocal Co-IP, ubiquitination assay, in vitro functional validation, multiple orthogonal methods","pmids":["35857630"],"is_preprint":false},{"year":2022,"finding":"USP26 deubiquitinates and stabilizes TAZ (a Hippo pathway effector) in anaplastic thyroid cancer cells, in a deubiquitylation activity-dependent manner, regulating expression of TAZ/TEAD target genes (CTGF, ANKRD1, CYR61) and promoting cancer cell proliferation, migration, and invasion.","method":"Co-immunoprecipitation, ubiquitination assay, knockdown/rescue experiments, gene expression analysis, functional assays (proliferation, migration, invasion)","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and ubiquitination assay with activity-dependent rescue, single lab","pmids":["35397626"],"is_preprint":false},{"year":2024,"finding":"USP26 directly interacts with PRKN (Parkin), deubiquitinates it at the K129 site, and reduces its activity, thereby restraining PRKN-mediated mitophagy and promoting colorectal cancer tumorigenesis. A K129R mutation on PRKN diminishes its activation and ability to mediate mitophagy.","method":"Co-immunoprecipitation, ubiquitination assay (site-specific mutagenesis K129R), mitophagy assay, knockdown/overexpression with tumor growth readout","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — site-specific mutagenesis with functional readout, Co-IP, single lab","pmids":["38565942"],"is_preprint":false},{"year":2024,"finding":"HBV-encoded protein HBx induces USP26 expression by binding to the USP26 promoter. USP26 then associates with SIRT1 and stabilizes it by deubiquitination, promoting cell proliferation and impeding apoptosis to drive hepatocellular carcinoma tumorigenesis.","method":"sgRNA library screen, Usp26 knockout mouse model (HCC tumorigenesis), co-immunoprecipitation, ubiquitination assay, ChIP (HBx on USP26 promoter)","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — CRISPR screen, genetically engineered mouse model, ChIP, Co-IP and ubiquitination assay, multiple orthogonal methods","pmids":["39251623"],"is_preprint":false},{"year":2024,"finding":"USP26 deubiquitinates and stabilizes BAG3 (co-chaperone). The lysine acetyltransferase Tip60 acetylates USP26 at K134, enhancing USP26's binding affinity to BAG3 and promoting BAG3 deubiquitination and protein stability, thereby driving breast cancer progression.","method":"Co-immunoprecipitation, ubiquitination assay, acetylation assay, site-directed mutagenesis (K134), in vivo tumor model, structure-based virtual screening","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, ubiquitination/acetylation assays with mutagenesis, in vivo validation, single lab","pmids":["38880224"],"is_preprint":false},{"year":2024,"finding":"USP26 physically interacts with TRAF3 and removes K63-linked polyubiquitination from TRAF3, thereby suppressing TRAF3-mediated activation of the MAVS/TBK-1/IRF3 (type I interferon) signaling pathway during antiviral response.","method":"Co-immunoprecipitation, ubiquitination assay (K63-linkage specific), siRNA knockdown, IFN-β reporter assay, viral replication assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — linkage-specific ubiquitination assay, Co-IP, functional antiviral signaling readout, single lab","pmids":["39058724"],"is_preprint":false},{"year":2024,"finding":"USP26 deubiquitinates and stabilizes SIRT2; decreased USP26 expression leads to SIRT2 degradation via ubiquitination, causing mitochondrial dysfunction, BMSC senescence, and age-related decline in self-renewal and multipotency. HIF-1α transcriptionally upregulates USP26 by binding to -191 to -198 bp and -262 to -269 bp regions of the USP26 promoter.","method":"Knockdown/overexpression, co-immunoprecipitation, ubiquitination assay, ChIP (HIF-1α on USP26 promoter), mitochondrial function assay, BMSC differentiation assay","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, ubiquitination assay, ChIP with functional cellular readout, single lab","pmids":["39377219"],"is_preprint":false},{"year":2020,"finding":"USP26 co-immunoprecipitates with androgen receptor (AR) in Leydig cells (TM3), influences AR deubiquitination, and upregulates CCND1 and SPATA46 (cell cycle and spermatogenesis factors) while decreasing TP73 expression, promoting Leydig cell G1-G2 transition and proliferation through the AR signaling pathway.","method":"Co-immunoprecipitation, immunofluorescence, western blot, flow cytometry (cell cycle), overexpression/inhibition plasmids","journal":"Advances in clinical and experimental medicine","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP and partial mechanistic follow-up, single lab","pmids":["33064378"],"is_preprint":false},{"year":2020,"finding":"RAC1B upregulates SMAD7 protein by promoting USP26 transcription; USP26 in turn deubiquitinates SMAD7, stabilizing it and suppressing TGF-β1-induced ALK5 signaling and cell migration in mesenchymal-type carcinoma cells.","method":"RNAi knockdown, overexpression/rescue, western blot, transcriptional reporter assay, cell migration assay","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis (RAC1B-USP26-SMAD7 axis), rescue experiments, functional migration readout, single lab","pmids":["32545415"],"is_preprint":false},{"year":2023,"finding":"USP26 interacts with and deubiquitinates KLF6, prolonging KLF6 protein stability. The functional interaction domain was mapped to amino acids 285-913 of USP26. Wild-type but not catalytic mutant USP26 attenuates KLF6 ubiquitination; USP26 overexpression inhibits HeLa cell proliferation and migration.","method":"DUB library screen, co-immunoprecipitation (domain mapping), ubiquitination assay, cycloheximide chase, shRNA knockdown, functional cellular assays","journal":"Computers in biology and medicine","confidence":"Medium","confidence_rationale":"Tier 2 — domain-mapped Co-IP, ubiquitination assay with catalytic mutant, functional readout, single lab","pmids":["38064851"],"is_preprint":false},{"year":2025,"finding":"USP26 deubiquitinates and stabilizes c-Myc by suppressing its polyubiquitination and degradation, promoting aerobic glycolysis and cell proliferation in gastric cancer.","method":"Co-immunoprecipitation, ubiquitination assay, shRNA knockdown, functional proliferation/glycolysis assay","journal":"DNA and cell biology","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP and ubiquitination assay, single lab, no mutagenesis or structural validation","pmids":["41125405"],"is_preprint":false},{"year":2025,"finding":"In osteoblasts, USP26 loss leads to ubiquitin-mediated degradation of IL4I1 (interleukin-4-induced protein 1), reducing production of the tryptophan metabolite indole-3-acetic acid (IAA) and compromising B lymphopoiesis; USP26 deficiency in osteoblasts also decreases H3K18 lactylation at the KSRP promoter, reducing FSTL1 mRNA alternative splicing and elevating FSTL1, causing insulin resistance and multi-organ fibrosis.","method":"Osteoblast-specific conditional Usp26 knockout, transcriptomics, targeted metabolomics, in vivo/in vitro supplementation experiments, engineered exosome delivery","journal":"Journal of advanced research / Advanced science","confidence":"Low","confidence_rationale":"Tier 3 — conditional KO with multiple phenotypes but mechanistic links (IL4I1 ubiquitination, H3K18LA) need more direct biochemical validation","pmids":["41687771","41417635"],"is_preprint":false},{"year":2014,"finding":"USP26 protein is expressed and co-localizes with androgen receptor predominantly in Leydig cell nuclei in human testis, with additional expression in spermatogonia, primary spermatocytes, round spermatids, and Sertoli cells, consistent with a role in regulating AR during spermatogenesis.","method":"Immunofluorescence co-localization, immunohistochemistry on human testis tissue arrays, multiplex qRT-PCR","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — direct protein localization by immunofluorescence with functional implication (AR co-localization), moderate evidence","pmids":["24922532"],"is_preprint":false}],"current_model":"USP26 is an X-linked deubiquitinating enzyme that stabilizes multiple substrate proteins — including androgen receptor (AR), SMAD7, Snail, CBX4/CBX6 (PRC1 components), TAZ, PRKN, SIRT1, SIRT2, BAG3, KLF6, c-Myc, Mdm2, TEX11, and TRAF3 — by removing their ubiquitin chains, thereby regulating AR transcriptional signaling, TGF-β pathway amplitude, homologous recombination at DNA double-strand breaks (by counteracting RAP80-BRCA1 spreading), meiotic sex chromosome pairing (localizing to the XY body and stabilizing TEX11), cellular reprogramming (via PRC1), and innate antiviral immunity (by removing K63-linked ubiquitin from TRAF3), with its own activity regulated by Tip60-mediated K134 acetylation and transcriptional induction by HIF-1α and HBx."},"narrative":{"teleology":[{"year":2010,"claim":"Identifying USP26 as a nuclear DUB that directly binds and deubiquitinates AR established its first known enzymatic substrate and placed it within androgen signaling in the testis.","evidence":"shRNA screen, Co-IP, ubiquitination assay in mammalian cells","pmids":["20501646"],"confidence":"High","gaps":["No in vivo confirmation of AR stabilization by USP26","Structural basis of NR-box–AR interaction not resolved"]},{"year":2014,"claim":"Demonstrating USP26–AR co-localization in Leydig cell nuclei of human testis confirmed physiological relevance of the USP26–AR interaction identified in cell lines.","evidence":"Immunofluorescence co-localization and immunohistochemistry on human testis tissue arrays","pmids":["24922532"],"confidence":"Medium","gaps":["No functional readout in primary human tissue","Expression in other testicular cell types not linked to specific substrates"]},{"year":2015,"claim":"Revealing that USP26 counteracts RNF168-induced ubiquitin at DSBs to restrict RAP80-BRCA1 spreading and promote HR expanded USP26 function beyond hormone signaling into the DNA damage response.","evidence":"Genetic screen, laser micro-irradiation, epistasis with RAP80 depletion, HR reporter assay","pmids":["26101254"],"confidence":"High","gaps":["Direct deubiquitination of specific histone marks at DSBs not demonstrated biochemically","Contribution relative to other DSB-associated DUBs not quantified"]},{"year":2016,"claim":"Identification of Mdm2 as a USP26 substrate and characterization of the R344W mutation's impact on AR deubiquitination began defining USP26's substrate diversity and catalytic requirements.","evidence":"Co-IP, cell-free ubiquitination assay, site-directed mutagenesis with reporter assays","pmids":["27810359","27089915"],"confidence":"Medium","gaps":["Mdm2 stabilization not tested in vivo","Functional consequence of R344W on spermatogenesis not established in animal model"]},{"year":2017,"claim":"Discovery that USP26 stabilizes SMAD7 to dampen TGF-β signaling, stabilizes CBX4/CBX6 to suppress reprogramming, and that Q156H abolishes catalytic activity established USP26 as a multi-pathway regulator and refined enzymatic mechanism.","evidence":"Co-IP, K48-linkage-specific ubiquitination assay, reprogramming efficiency assay, ChIP, in vitro cleavage assay with mutagenesis","pmids":["28381482","28839133","29111204"],"confidence":"High","gaps":["Structural basis for substrate selectivity among diverse targets unknown","In vivo TGF-β regulation by USP26 not tested in knockout model"]},{"year":2019,"claim":"Usp26 knockout mice revealed essential roles in meiotic chromosome synapsis and chiasma formation, providing the first genetic evidence that USP26 is required for male fertility.","evidence":"Gene-targeted mouse (DBA/2 background), histology, cytological analysis of spermatocytes","pmids":["31551464"],"confidence":"High","gaps":["Molecular substrate mediating synapsis defect not identified in this study","Background-dependent penetrance mechanism unknown"]},{"year":2019,"claim":"Identification of Snail as a USP26 substrate linked USP26 to epithelial–mesenchymal transition and cancer cell invasion.","evidence":"DUB library screen, Co-IP, ubiquitination assay, migration/invasion assay","pmids":["30763716"],"confidence":"Medium","gaps":["In vivo relevance of USP26–Snail axis in metastasis not shown","Ubiquitin chain linkage type not specified"]},{"year":2020,"claim":"Placing USP26 downstream of RAC1B in a RAC1B→USP26→SMAD7 axis reinforced the TGF-β dampening model and revealed transcriptional regulation of USP26 in carcinoma cells.","evidence":"RNAi epistasis, rescue experiments, migration assay in mesenchymal carcinoma cells","pmids":["32545415"],"confidence":"Medium","gaps":["RAC1B-mediated transcriptional regulation of USP26 promoter not mapped","Generalizability beyond pancreatic carcinoma not tested"]},{"year":2021,"claim":"Demonstrating that USP26 localizes to the XY body and stabilizes TEX11 resolved the molecular mechanism underlying the meiotic pairing defect and XY aneuploidy in Usp26 knockout mice.","evidence":"KO mouse, immunofluorescence at XY body, Co-IP with TEX11, sperm FISH, offspring karyotyping","pmids":["33978233"],"confidence":"High","gaps":["Ubiquitin chain type on TEX11 removed by USP26 not specified","Whether other XY body proteins are USP26 substrates is unknown"]},{"year":2022,"claim":"Discovery of the RNF12→REX1→USP26 feed-forward loop, in which USP26 prevents RNF12 autoubiquitylation, revealed a self-amplifying circuit required for germ cell differentiation.","evidence":"Quantitative proteomics, reciprocal Co-IP, ubiquitination assay, in vitro germ cell differentiation","pmids":["35857630"],"confidence":"High","gaps":["In vivo validation of feed-forward loop in testis not completed","Stoichiometry and regulation of USP26–RNF12 complex uncharacterized"]},{"year":2022,"claim":"Identification of TAZ as a USP26 substrate in anaplastic thyroid cancer extended USP26's oncogenic roles to Hippo pathway regulation.","evidence":"Co-IP, ubiquitination assay, knockdown/rescue, gene expression of TEAD targets","pmids":["35397626"],"confidence":"Medium","gaps":["In vivo TAZ stabilization by USP26 not demonstrated","Whether USP26 affects upstream Hippo kinases unknown"]},{"year":2024,"claim":"Multiple studies identified PRKN (K129), SIRT1, SIRT2, BAG3, KLF6, and TRAF3 as USP26 substrates, and revealed post-translational (Tip60 acetylation at K134) and transcriptional (HIF-1α, HBx) regulation of USP26, greatly expanding its regulatory network.","evidence":"Co-IP, site-specific mutagenesis, K63-linkage-specific ubiquitination assay, ChIP, KO mouse tumor models, acetylation assay, IFN-β reporter","pmids":["38565942","39251623","39377219","38880224","39058724","38064851"],"confidence":"Medium","gaps":["Many substrate interactions characterized by single labs and need independent replication","Structural determinants of substrate selectivity still completely unknown","Relative contribution of acetylation vs. transcriptional induction to USP26 activity regulation not compared"]},{"year":null,"claim":"A structural model of USP26 explaining its unusually broad substrate specificity, its allosteric regulation by acetylation, and the basis for disease-associated mutations is lacking.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure available","No unbiased proteomics-based substrate identification across tissues","Relative physiological importance of individual substrates in different tissues not ranked"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,3,4,5,9,10,11,12,13,14,15,19]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,2,3,7,9,10]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,22]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[1,9]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,3,5,9,10,11,12,13,14,15,19]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,11,15,18]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[8,9,10]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[15]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1]}],"complexes":["RNF12-USP26 complex"],"partners":["AR","TEX11","SMAD7","CBX4","CBX6","RLIM","TRAF3","MDM2"],"other_free_text":[]},"mechanistic_narrative":"USP26 is an X-linked deubiquitinating enzyme with broad substrate range that functions in male meiosis, DNA damage repair, TGF-β signaling, and multiple oncogenic pathways. In the testis, USP26 localizes to the XY body during meiosis and stabilizes TEX11, ensuring proper sex chromosome pairing; its loss causes meiotic defects, XY aneuploidy, and male subfertility/sterility [PMID:33978233, PMID:31551464]. At DNA double-strand breaks, USP26 counteracts RNF168-dependent ubiquitin conjugates to limit RAP80-BRCA1 spreading and promote PALB2-dependent homologous recombination [PMID:26101254]; in signaling contexts it deubiquitinates and stabilizes diverse substrates including SMAD7 (attenuating TGF-β signaling) [PMID:28381482], CBX4/CBX6 (suppressing somatic reprogramming via PRC1) [PMID:28839133], AR [PMID:20501646], TAZ [PMID:35397626], SIRT1 [PMID:39251623], PRKN [PMID:38565942], BAG3 [PMID:38880224], and TRAF3 (suppressing type I interferon signaling by removing K63-linked ubiquitin) [PMID:39058724]. USP26 activity is itself regulated by Tip60-mediated acetylation at K134, which enhances substrate binding [PMID:38880224], and its transcription is induced by HIF-1α, HBx, TGF-β, and the RNF12-REX1 axis, establishing feed-forward regulatory circuits in germ cell differentiation and disease [PMID:39377219, PMID:39251623, PMID:35857630]."},"prefetch_data":{"uniprot":{"accession":"Q9BXU7","full_name":"Ubiquitin carboxyl-terminal hydrolase 26","aliases":["Deubiquitinating enzyme 26","Ubiquitin thioesterase 26","Ubiquitin-specific-processing protease 26"],"length_aa":913,"mass_kda":104.0,"function":"Deubiquitinase regulating several biological processes through the deubiquitination of components of these processes (PubMed:20501646, PubMed:28839133). Involved in somatic cell reprogramming through the 'Lys-48'-linked deubiquitination and stabilization of CBX4 and CBX6, two components of the polycomb-repressive complex 1 (PRC1) (PubMed:28839133). Also deubiquitinates and probably stabilizes the androgen receptor (AR), regulating the androgen receptor signaling pathway (PubMed:20501646). May play a role in spermatogenesis (PubMed:34202084)","subcellular_location":"Nucleus; Cytoplasm, cytoskeleton, flagellum axoneme","url":"https://www.uniprot.org/uniprotkb/Q9BXU7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/USP26","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/USP26","total_profiled":1310},"omim":[{"mim_id":"305700","title":"SPERMATOGENIC FAILURE, X-LINKED, 1; SPGFX1","url":"https://www.omim.org/entry/305700"},{"mim_id":"301101","title":"SPERMATOGENIC FAILURE, X-LINKED, 6; SPGFX6","url":"https://www.omim.org/entry/301101"},{"mim_id":"300309","title":"UBIQUITIN-SPECIFIC PROTEASE 26; USP26","url":"https://www.omim.org/entry/300309"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Not detected","tissue_distribution":"Not detected","driving_tissues":[],"url":"https://www.proteinatlas.org/search/USP26"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9BXU7","domains":[{"cath_id":"2.30.29.180","chopping":"5-105","consensus_level":"medium","plddt":83.5377,"start":5,"end":105}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BXU7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BXU7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BXU7-F1-predicted_aligned_error_v6.png","plddt_mean":59.97},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=USP26","jax_strain_url":"https://www.jax.org/strain/search?query=USP26"},"sequence":{"accession":"Q9BXU7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BXU7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BXU7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BXU7"}},"corpus_meta":[{"pmid":"15562280","id":"PMC_15562280","title":"Possible role of USP26 in patients with severely impaired spermatogenesis.","date":"2005","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/15562280","citation_count":76,"is_preprint":false},{"pmid":"20501646","id":"PMC_20501646","title":"The deubiquitinating enzyme USP26 is a regulator of androgen receptor signaling.","date":"2010","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/20501646","citation_count":73,"is_preprint":false},{"pmid":"26101254","id":"PMC_26101254","title":"The de-ubiquitylating enzymes USP26 and USP37 regulate homologous recombination by counteracting RAP80.","date":"2015","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/26101254","citation_count":64,"is_preprint":false},{"pmid":"28381482","id":"PMC_28381482","title":"USP26 regulates TGF-β signaling by deubiquitinating and stabilizing SMAD7.","date":"2017","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/28381482","citation_count":61,"is_preprint":false},{"pmid":"30763716","id":"PMC_30763716","title":"USP26 promotes esophageal squamous cell carcinoma metastasis through stabilizing Snail.","date":"2019","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/30763716","citation_count":47,"is_preprint":false},{"pmid":"16888075","id":"PMC_16888075","title":"Haplotypes, mutations and male fertility: the story of the testis-specific ubiquitin protease USP26.","date":"2006","source":"Molecular human reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/16888075","citation_count":36,"is_preprint":false},{"pmid":"27089915","id":"PMC_27089915","title":"A Novel Missense Mutation in USP26 Gene Is Associated With Nonobstructive Azoospermia.","date":"2016","source":"Reproductive sciences (Thousand Oaks, Calif.)","url":"https://pubmed.ncbi.nlm.nih.gov/27089915","citation_count":33,"is_preprint":false},{"pmid":"18927127","id":"PMC_18927127","title":"USP26 gene variations in fertile and infertile men.","date":"2008","source":"Human reproduction (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/18927127","citation_count":32,"is_preprint":false},{"pmid":"17121659","id":"PMC_17121659","title":"Alterations of the USP26 gene in Caucasian men.","date":"2006","source":"International journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/17121659","citation_count":31,"is_preprint":false},{"pmid":"28839133","id":"PMC_28839133","title":"USP26 functions as a negative regulator of cellular reprogramming by stabilising PRC1 complex components.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28839133","citation_count":31,"is_preprint":false},{"pmid":"23779098","id":"PMC_23779098","title":"Ubiquitin-specific protease (USP26) gene alterations associated with male infertility and recurrent pregnancy loss (RPL) in Iranian infertile patients.","date":"2013","source":"Journal of assisted reproduction and genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23779098","citation_count":29,"is_preprint":false},{"pmid":"18958354","id":"PMC_18958354","title":"Association of USP26 haplotypes in men in Taiwan, China with severe spermatogenic defect.","date":"2008","source":"Asian journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/18958354","citation_count":28,"is_preprint":false},{"pmid":"35397626","id":"PMC_35397626","title":"USP26 promotes anaplastic thyroid cancer progression by stabilizing TAZ.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/35397626","citation_count":27,"is_preprint":false},{"pmid":"31551464","id":"PMC_31551464","title":"Usp26 mutation in mice leads to defective spermatogenesis depending on genetic background.","date":"2019","source":"Scientific 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infertility.","date":"2015","source":"Andrology","url":"https://pubmed.ncbi.nlm.nih.gov/25755145","citation_count":20,"is_preprint":false},{"pmid":"21147082","id":"PMC_21147082","title":"Association between ubiquitin-specific protease USP26 polymorphism and male infertility in Chinese men.","date":"2010","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21147082","citation_count":19,"is_preprint":false},{"pmid":"18377898","id":"PMC_18377898","title":"Sequence analysis of the X-linked USP26 gene in severe male factor infertility patients and fertile controls.","date":"2008","source":"Fertility and sterility","url":"https://pubmed.ncbi.nlm.nih.gov/18377898","citation_count":19,"is_preprint":false},{"pmid":"30887115","id":"PMC_30887115","title":"Ubiquitin-specific protease 26 (USP26) is not essential for mouse gametogenesis and fertility.","date":"2019","source":"Chromosoma","url":"https://pubmed.ncbi.nlm.nih.gov/30887115","citation_count":18,"is_preprint":false},{"pmid":"27810359","id":"PMC_27810359","title":"The testis-specific USP26 is a deubiquitinating enzyme of the ubiquitin ligase Mdm2.","date":"2016","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/27810359","citation_count":17,"is_preprint":false},{"pmid":"27726449","id":"PMC_27726449","title":"Single nucleotide polymorphisms of USP26 in azoospermic men.","date":"2016","source":"Systems biology in reproductive medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27726449","citation_count":16,"is_preprint":false},{"pmid":"34202084","id":"PMC_34202084","title":"Novel Mutations in X-Linked, USP26-Induced Asthenoteratozoospermia and Male Infertility.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/34202084","citation_count":15,"is_preprint":false},{"pmid":"38565942","id":"PMC_38565942","title":"USP26 promotes colorectal cancer tumorigenesis by restraining PRKN-mediated mitophagy.","date":"2024","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/38565942","citation_count":15,"is_preprint":false},{"pmid":"19503076","id":"PMC_19503076","title":"The expression of Usp26 gene in mouse testis and brain.","date":"2009","source":"Asian journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/19503076","citation_count":15,"is_preprint":false},{"pmid":"32235588","id":"PMC_32235588","title":"Preclinical Study Using ABT263 to Increase Enzalutamide Sensitivity to Suppress Prostate Cancer Progression Via Targeting BCL2/ROS/USP26 Axis Through Altering ARv7 Protein Degradation.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/32235588","citation_count":15,"is_preprint":false},{"pmid":"39377219","id":"PMC_39377219","title":"USP26 Combats Age-Related Declines in Self-Renewal and Multipotent Differentiation of BMSC by Maintaining Mitochondrial Homeostasis.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39377219","citation_count":14,"is_preprint":false},{"pmid":"32410375","id":"PMC_32410375","title":"Novel mutation in USP26 associated with azoospermia in a Sertoli cell-only syndrome patient.","date":"2020","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32410375","citation_count":11,"is_preprint":false},{"pmid":"29111204","id":"PMC_29111204","title":"The impacts of nineteen mutations on the enzymatic activity of USP26.","date":"2017","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/29111204","citation_count":11,"is_preprint":false},{"pmid":"32760222","id":"PMC_32760222","title":"Targeting deubiquitinating enzyme USP26 by microRNA-203 regulates Snail1's pro-metastatic functions in esophageal cancer.","date":"2020","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/32760222","citation_count":10,"is_preprint":false},{"pmid":"33064378","id":"PMC_33064378","title":"USP26 deubiquitinates androgen receptor (AR) in the maintenance of sperm maturation and spermatogenesis through the androgen receptor signaling pathway.","date":"2020","source":"Advances in clinical and experimental medicine : official organ Wroclaw Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/33064378","citation_count":10,"is_preprint":false},{"pmid":"39251623","id":"PMC_39251623","title":"USP26 as a hepatitis B virus-induced deubiquitinase primes hepatocellular carcinogenesis by epigenetic remodeling.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39251623","citation_count":9,"is_preprint":false},{"pmid":"38880224","id":"PMC_38880224","title":"Acetylation-dependent deubiquitinase USP26 stabilizes BAG3 to promote breast cancer progression.","date":"2024","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/38880224","citation_count":8,"is_preprint":false},{"pmid":"32545415","id":"PMC_32545415","title":"RAC1B Induces SMAD7 via USP26 to Suppress TGFβ1-Dependent Cell Migration in Mesenchymal-Subtype Carcinoma Cells.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/32545415","citation_count":8,"is_preprint":false},{"pmid":"35857630","id":"PMC_35857630","title":"An RNF12-USP26 amplification loop drives germ cell specification and is disrupted by disease-associated mutations.","date":"2022","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/35857630","citation_count":7,"is_preprint":false},{"pmid":"38064851","id":"PMC_38064851","title":"Machine learning-based classification of deubiquitinase USP26 and its cell proliferation inhibition through stabilizing KLF6 in cervical cancer.","date":"2023","source":"Computers in biology and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38064851","citation_count":6,"is_preprint":false},{"pmid":"35074940","id":"PMC_35074940","title":"The association between mutations in ubiquitin-specific protease 26 (USP26) and male infertility: a systematic review and meta-analysis.","date":"2022","source":"Asian journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/35074940","citation_count":5,"is_preprint":false},{"pmid":"22568204","id":"PMC_22568204","title":"[Polymorphism of Usp26 correlates with idiopathic male infertility].","date":"2012","source":"Zhonghua nan ke xue = National journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/22568204","citation_count":5,"is_preprint":false},{"pmid":"20180409","id":"PMC_20180409","title":"[Mutation of the USP26 gene in spermatogenesis dysfunction].","date":"2010","source":"Zhonghua nan ke xue = National journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/20180409","citation_count":4,"is_preprint":false},{"pmid":"34031897","id":"PMC_34031897","title":"USP26: a genetic risk factor for sperm X-Y aneuploidy.","date":"2021","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/34031897","citation_count":4,"is_preprint":false},{"pmid":"41417635","id":"PMC_41417635","title":"Activating the Osteoblastic USP26 Pathway Alleviates Multi-Organ Fibrosis by Decreasing Insulin Resistance.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41417635","citation_count":1,"is_preprint":false},{"pmid":"39058724","id":"PMC_39058724","title":"USP26 suppresses type I interferon signaling by targeting TRAF3 for deubiquitination.","date":"2024","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/39058724","citation_count":1,"is_preprint":false},{"pmid":"41423141","id":"PMC_41423141","title":"A novel candidate missense variant in the catalytic domain of USP26 associated with asthenoteratozoospermia.","date":"2025","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/41423141","citation_count":1,"is_preprint":false},{"pmid":"41125405","id":"PMC_41125405","title":"USP26 Promotes Cell Proliferation of Gastric Cancer by Stabilizing c-Myc.","date":"2025","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/41125405","citation_count":0,"is_preprint":false},{"pmid":"41687771","id":"PMC_41687771","title":"Osteoblastic USP26 regulates B lymphopoiesis by endogenous tryptophan metabolites.","date":"2026","source":"Journal of advanced research","url":"https://pubmed.ncbi.nlm.nih.gov/41687771","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.11.675685","title":"Active maintenance of meiosis-specific chromosome structures in <i>C. elegans</i> by the deubiquitinase DUO-1","date":"2025-09-12","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.11.675685","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23199,"output_tokens":5516,"usd":0.076169},"stage2":{"model":"claude-opus-4-6","input_tokens":9113,"output_tokens":3162,"usd":0.186922},"total_usd":0.263091,"stage1_batch_id":"msgbatch_01BparvgRZ9S2LMidvaoo86K","stage2_batch_id":"msgbatch_01NkBfv9SVZWthhS7j6mU6G3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"USP26 is a nuclear protein that binds to androgen receptor (AR) via three nuclear receptor interaction motifs, modulates AR ubiquitination, and counteracts hormone-induced AR ubiquitination, thereby stabilizing AR and contributing to AR transcriptional activity. USP26 assembles with AR and other cofactors in subnuclear foci.\",\n      \"method\": \"shRNA library screen, co-immunoprecipitation, ubiquitination assay, immunofluorescence, nuclear fractionation\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ubiquitination assay, nuclear localization with functional consequence, replicated by multiple subsequent studies\",\n      \"pmids\": [\"20501646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"USP26 is recruited to DNA double-strand breaks (DSBs) where it removes RNF168-induced ubiquitin conjugates, limiting the spreading of RAP80-BRCA1 from DSBs, and promoting the association of BRCA1 with PALB2 to facilitate homologous recombination (HR). Depletion of USP26 disrupts HR execution, an effect alleviated by simultaneous depletion of RAP80.\",\n      \"method\": \"Genetic screen, siRNA depletion, laser micro-irradiation/DSB induction, immunofluorescence, epistasis (double knockdown), HR reporter assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with defined phenotypic readout, multiple orthogonal methods, clear pathway placement\",\n      \"pmids\": [\"26101254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"USP26 deubiquitinates and stabilizes SMAD7, acting as a negative regulator of TGF-β signaling. TGF-β rapidly induces USP26 expression, and USP26 in turn limits ubiquitin-mediated turnover of SMAD7; knockdown of USP26 destabilizes SMAD7, leading to TGF-β receptor stabilization and enhanced p-SMAD2 levels.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, ubiquitination assay, western blot, cycloheximide chase\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ubiquitination assay, loss-of-function with defined signaling phenotype, moderate evidence\",\n      \"pmids\": [\"28381482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"USP26 negatively regulates somatic cell reprogramming by removing K48-linked polyubiquitination from CBX4 and CBX6 (PRC1 complex components), stabilizing them. Accumulated CBX4 and CBX6 repress pluripotency genes Sox2 and Nanog through PRC1-mediated H2A ubiquitination at their promoters.\",\n      \"method\": \"Overexpression, knockdown, co-immunoprecipitation, ubiquitination assay (K48-linkage specific), reprogramming efficiency assay, ChIP\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including linkage-specific ubiquitination assay, functional reprogramming readout, defined pathway placement\",\n      \"pmids\": [\"28839133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP26 deubiquitinates and stabilizes Snail (SNAI1), an EMT transcription factor, promoting cancer cell migration and invasion. Identified via DUB library screen.\",\n      \"method\": \"DUB library screen, co-immunoprecipitation, ubiquitination assay, cycloheximide chase, migration/invasion assay\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and ubiquitination assay with functional cellular readout, single lab\",\n      \"pmids\": [\"30763716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"USP26 binds to Mdm2 through its coiled-coil C-terminal domain, deubiquitinates Mdm2, and stabilizes it. USP26 itself can be ubiquitinated by HeLa cell extract and has a defined half-life in HEK293 cells.\",\n      \"method\": \"Co-transfection, co-immunoprecipitation, cell-free ubiquitination assay, half-life determination (cycloheximide chase)\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro ubiquitination assay and Co-IP, single lab, moderate evidence\",\n      \"pmids\": [\"27810359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The USP26 R344W missense mutation reduces binding affinity and deubiquitinating activity of USP26 toward AR, eliminating USP26's inhibitory effect on AR transcriptional activity in HeLa and TM4 cells.\",\n      \"method\": \"Immunoprecipitation, ubiquitination assay, luciferase reporter assay, site-directed mutagenesis\",\n      \"journal\": \"Reproductive sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro deubiquitination assay with mutagenesis and functional reporter assay, single lab\",\n      \"pmids\": [\"27089915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The USP26 Q156H mutant loses deubiquitinase enzymatic activity, while 18 other tested USP26 variants retain wild-type activity. Artificially constructed truncation mutants (E174# and E189# split constructs) also lose activity, demonstrating requirement for intact protein.\",\n      \"method\": \"Site-directed mutagenesis, USP cleavage assay (Ub-Met-β-gal and GST-Ub52 substrates)\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic assay with mutagenesis, single lab\",\n      \"pmids\": [\"29111204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Usp26 mutation in mice (backcrossed to DBA/2 background) causes sterility or subfertility with atrophic testes, reduced spermatid numbers, malformed sperm head morphology, unsynapsed chromosomes in pachynema, and defective chiasma formation in diplonema, leading to apoptosis of metaphase spermatocytes.\",\n      \"method\": \"Mouse knockout (gene targeting), histology, cytological analysis of spermatocytes, fertility assessment\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO mouse model with multiple defined cellular phenotypes, background-dependent effect characterized\",\n      \"pmids\": [\"31551464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP26 protein localizes at the XY body during male meiosis, and USP26 knockout in male mice results in incomplete sex chromosome pairing by destabilizing TEX11, leading to XY aneuploid spermatozoa and elevated rates of 41,XXY offspring.\",\n      \"method\": \"Knockout mouse model, immunofluorescence (XY body localization), co-immunoprecipitation/interaction with TEX11, sperm FISH for aneuploidy, offspring karyotyping\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment tied to functional consequence, genetic KO with defined molecular mechanism (TEX11 destabilization), clinical validation\",\n      \"pmids\": [\"33978233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP26 is a downstream target of RNF12 (RLIM): RNF12 relieves REX1-mediated repression of Usp26 transcription, leading to increased USP26 abundance. USP26 then forms a complex with RNF12 and prevents RNF12 autoubiquitylation and proteasomal degradation, establishing a transcriptional feed-forward amplification loop required for germ cell differentiation and gametogenesis gene expression.\",\n      \"method\": \"Global quantitative proteomics, co-immunoprecipitation, ubiquitination assay, transcriptional reporter assay, in vitro germ cell differentiation, genetic interaction studies with TOKAS/infertility variants\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — proteomics discovery, reciprocal Co-IP, ubiquitination assay, in vitro functional validation, multiple orthogonal methods\",\n      \"pmids\": [\"35857630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP26 deubiquitinates and stabilizes TAZ (a Hippo pathway effector) in anaplastic thyroid cancer cells, in a deubiquitylation activity-dependent manner, regulating expression of TAZ/TEAD target genes (CTGF, ANKRD1, CYR61) and promoting cancer cell proliferation, migration, and invasion.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, knockdown/rescue experiments, gene expression analysis, functional assays (proliferation, migration, invasion)\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and ubiquitination assay with activity-dependent rescue, single lab\",\n      \"pmids\": [\"35397626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP26 directly interacts with PRKN (Parkin), deubiquitinates it at the K129 site, and reduces its activity, thereby restraining PRKN-mediated mitophagy and promoting colorectal cancer tumorigenesis. A K129R mutation on PRKN diminishes its activation and ability to mediate mitophagy.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (site-specific mutagenesis K129R), mitophagy assay, knockdown/overexpression with tumor growth readout\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — site-specific mutagenesis with functional readout, Co-IP, single lab\",\n      \"pmids\": [\"38565942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HBV-encoded protein HBx induces USP26 expression by binding to the USP26 promoter. USP26 then associates with SIRT1 and stabilizes it by deubiquitination, promoting cell proliferation and impeding apoptosis to drive hepatocellular carcinoma tumorigenesis.\",\n      \"method\": \"sgRNA library screen, Usp26 knockout mouse model (HCC tumorigenesis), co-immunoprecipitation, ubiquitination assay, ChIP (HBx on USP26 promoter)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — CRISPR screen, genetically engineered mouse model, ChIP, Co-IP and ubiquitination assay, multiple orthogonal methods\",\n      \"pmids\": [\"39251623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP26 deubiquitinates and stabilizes BAG3 (co-chaperone). The lysine acetyltransferase Tip60 acetylates USP26 at K134, enhancing USP26's binding affinity to BAG3 and promoting BAG3 deubiquitination and protein stability, thereby driving breast cancer progression.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, acetylation assay, site-directed mutagenesis (K134), in vivo tumor model, structure-based virtual screening\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ubiquitination/acetylation assays with mutagenesis, in vivo validation, single lab\",\n      \"pmids\": [\"38880224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP26 physically interacts with TRAF3 and removes K63-linked polyubiquitination from TRAF3, thereby suppressing TRAF3-mediated activation of the MAVS/TBK-1/IRF3 (type I interferon) signaling pathway during antiviral response.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K63-linkage specific), siRNA knockdown, IFN-β reporter assay, viral replication assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — linkage-specific ubiquitination assay, Co-IP, functional antiviral signaling readout, single lab\",\n      \"pmids\": [\"39058724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP26 deubiquitinates and stabilizes SIRT2; decreased USP26 expression leads to SIRT2 degradation via ubiquitination, causing mitochondrial dysfunction, BMSC senescence, and age-related decline in self-renewal and multipotency. HIF-1α transcriptionally upregulates USP26 by binding to -191 to -198 bp and -262 to -269 bp regions of the USP26 promoter.\",\n      \"method\": \"Knockdown/overexpression, co-immunoprecipitation, ubiquitination assay, ChIP (HIF-1α on USP26 promoter), mitochondrial function assay, BMSC differentiation assay\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ubiquitination assay, ChIP with functional cellular readout, single lab\",\n      \"pmids\": [\"39377219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP26 co-immunoprecipitates with androgen receptor (AR) in Leydig cells (TM3), influences AR deubiquitination, and upregulates CCND1 and SPATA46 (cell cycle and spermatogenesis factors) while decreasing TP73 expression, promoting Leydig cell G1-G2 transition and proliferation through the AR signaling pathway.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, western blot, flow cytometry (cell cycle), overexpression/inhibition plasmids\",\n      \"journal\": \"Advances in clinical and experimental medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP and partial mechanistic follow-up, single lab\",\n      \"pmids\": [\"33064378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RAC1B upregulates SMAD7 protein by promoting USP26 transcription; USP26 in turn deubiquitinates SMAD7, stabilizing it and suppressing TGF-β1-induced ALK5 signaling and cell migration in mesenchymal-type carcinoma cells.\",\n      \"method\": \"RNAi knockdown, overexpression/rescue, western blot, transcriptional reporter assay, cell migration assay\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis (RAC1B-USP26-SMAD7 axis), rescue experiments, functional migration readout, single lab\",\n      \"pmids\": [\"32545415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP26 interacts with and deubiquitinates KLF6, prolonging KLF6 protein stability. The functional interaction domain was mapped to amino acids 285-913 of USP26. Wild-type but not catalytic mutant USP26 attenuates KLF6 ubiquitination; USP26 overexpression inhibits HeLa cell proliferation and migration.\",\n      \"method\": \"DUB library screen, co-immunoprecipitation (domain mapping), ubiquitination assay, cycloheximide chase, shRNA knockdown, functional cellular assays\",\n      \"journal\": \"Computers in biology and medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain-mapped Co-IP, ubiquitination assay with catalytic mutant, functional readout, single lab\",\n      \"pmids\": [\"38064851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP26 deubiquitinates and stabilizes c-Myc by suppressing its polyubiquitination and degradation, promoting aerobic glycolysis and cell proliferation in gastric cancer.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, shRNA knockdown, functional proliferation/glycolysis assay\",\n      \"journal\": \"DNA and cell biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP and ubiquitination assay, single lab, no mutagenesis or structural validation\",\n      \"pmids\": [\"41125405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In osteoblasts, USP26 loss leads to ubiquitin-mediated degradation of IL4I1 (interleukin-4-induced protein 1), reducing production of the tryptophan metabolite indole-3-acetic acid (IAA) and compromising B lymphopoiesis; USP26 deficiency in osteoblasts also decreases H3K18 lactylation at the KSRP promoter, reducing FSTL1 mRNA alternative splicing and elevating FSTL1, causing insulin resistance and multi-organ fibrosis.\",\n      \"method\": \"Osteoblast-specific conditional Usp26 knockout, transcriptomics, targeted metabolomics, in vivo/in vitro supplementation experiments, engineered exosome delivery\",\n      \"journal\": \"Journal of advanced research / Advanced science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — conditional KO with multiple phenotypes but mechanistic links (IL4I1 ubiquitination, H3K18LA) need more direct biochemical validation\",\n      \"pmids\": [\"41687771\", \"41417635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"USP26 protein is expressed and co-localizes with androgen receptor predominantly in Leydig cell nuclei in human testis, with additional expression in spermatogonia, primary spermatocytes, round spermatids, and Sertoli cells, consistent with a role in regulating AR during spermatogenesis.\",\n      \"method\": \"Immunofluorescence co-localization, immunohistochemistry on human testis tissue arrays, multiplex qRT-PCR\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct protein localization by immunofluorescence with functional implication (AR co-localization), moderate evidence\",\n      \"pmids\": [\"24922532\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"USP26 is an X-linked deubiquitinating enzyme that stabilizes multiple substrate proteins — including androgen receptor (AR), SMAD7, Snail, CBX4/CBX6 (PRC1 components), TAZ, PRKN, SIRT1, SIRT2, BAG3, KLF6, c-Myc, Mdm2, TEX11, and TRAF3 — by removing their ubiquitin chains, thereby regulating AR transcriptional signaling, TGF-β pathway amplitude, homologous recombination at DNA double-strand breaks (by counteracting RAP80-BRCA1 spreading), meiotic sex chromosome pairing (localizing to the XY body and stabilizing TEX11), cellular reprogramming (via PRC1), and innate antiviral immunity (by removing K63-linked ubiquitin from TRAF3), with its own activity regulated by Tip60-mediated K134 acetylation and transcriptional induction by HIF-1α and HBx.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"USP26 is an X-linked deubiquitinating enzyme with broad substrate range that functions in male meiosis, DNA damage repair, TGF-β signaling, and multiple oncogenic pathways. In the testis, USP26 localizes to the XY body during meiosis and stabilizes TEX11, ensuring proper sex chromosome pairing; its loss causes meiotic defects, XY aneuploidy, and male subfertility/sterility [PMID:33978233, PMID:31551464]. At DNA double-strand breaks, USP26 counteracts RNF168-dependent ubiquitin conjugates to limit RAP80-BRCA1 spreading and promote PALB2-dependent homologous recombination [PMID:26101254]; in signaling contexts it deubiquitinates and stabilizes diverse substrates including SMAD7 (attenuating TGF-β signaling) [PMID:28381482], CBX4/CBX6 (suppressing somatic reprogramming via PRC1) [PMID:28839133], AR [PMID:20501646], TAZ [PMID:35397626], SIRT1 [PMID:39251623], PRKN [PMID:38565942], BAG3 [PMID:38880224], and TRAF3 (suppressing type I interferon signaling by removing K63-linked ubiquitin) [PMID:39058724]. USP26 activity is itself regulated by Tip60-mediated acetylation at K134, which enhances substrate binding [PMID:38880224], and its transcription is induced by HIF-1α, HBx, TGF-β, and the RNF12-REX1 axis, establishing feed-forward regulatory circuits in germ cell differentiation and disease [PMID:39377219, PMID:39251623, PMID:35857630].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Identifying USP26 as a nuclear DUB that directly binds and deubiquitinates AR established its first known enzymatic substrate and placed it within androgen signaling in the testis.\",\n      \"evidence\": \"shRNA screen, Co-IP, ubiquitination assay in mammalian cells\",\n      \"pmids\": [\"20501646\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No in vivo confirmation of AR stabilization by USP26\", \"Structural basis of NR-box–AR interaction not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating USP26–AR co-localization in Leydig cell nuclei of human testis confirmed physiological relevance of the USP26–AR interaction identified in cell lines.\",\n      \"evidence\": \"Immunofluorescence co-localization and immunohistochemistry on human testis tissue arrays\",\n      \"pmids\": [\"24922532\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional readout in primary human tissue\", \"Expression in other testicular cell types not linked to specific substrates\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealing that USP26 counteracts RNF168-induced ubiquitin at DSBs to restrict RAP80-BRCA1 spreading and promote HR expanded USP26 function beyond hormone signaling into the DNA damage response.\",\n      \"evidence\": \"Genetic screen, laser micro-irradiation, epistasis with RAP80 depletion, HR reporter assay\",\n      \"pmids\": [\"26101254\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct deubiquitination of specific histone marks at DSBs not demonstrated biochemically\", \"Contribution relative to other DSB-associated DUBs not quantified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of Mdm2 as a USP26 substrate and characterization of the R344W mutation's impact on AR deubiquitination began defining USP26's substrate diversity and catalytic requirements.\",\n      \"evidence\": \"Co-IP, cell-free ubiquitination assay, site-directed mutagenesis with reporter assays\",\n      \"pmids\": [\"27810359\", \"27089915\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mdm2 stabilization not tested in vivo\", \"Functional consequence of R344W on spermatogenesis not established in animal model\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Discovery that USP26 stabilizes SMAD7 to dampen TGF-β signaling, stabilizes CBX4/CBX6 to suppress reprogramming, and that Q156H abolishes catalytic activity established USP26 as a multi-pathway regulator and refined enzymatic mechanism.\",\n      \"evidence\": \"Co-IP, K48-linkage-specific ubiquitination assay, reprogramming efficiency assay, ChIP, in vitro cleavage assay with mutagenesis\",\n      \"pmids\": [\"28381482\", \"28839133\", \"29111204\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for substrate selectivity among diverse targets unknown\", \"In vivo TGF-β regulation by USP26 not tested in knockout model\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Usp26 knockout mice revealed essential roles in meiotic chromosome synapsis and chiasma formation, providing the first genetic evidence that USP26 is required for male fertility.\",\n      \"evidence\": \"Gene-targeted mouse (DBA/2 background), histology, cytological analysis of spermatocytes\",\n      \"pmids\": [\"31551464\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular substrate mediating synapsis defect not identified in this study\", \"Background-dependent penetrance mechanism unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of Snail as a USP26 substrate linked USP26 to epithelial–mesenchymal transition and cancer cell invasion.\",\n      \"evidence\": \"DUB library screen, Co-IP, ubiquitination assay, migration/invasion assay\",\n      \"pmids\": [\"30763716\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of USP26–Snail axis in metastasis not shown\", \"Ubiquitin chain linkage type not specified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placing USP26 downstream of RAC1B in a RAC1B→USP26→SMAD7 axis reinforced the TGF-β dampening model and revealed transcriptional regulation of USP26 in carcinoma cells.\",\n      \"evidence\": \"RNAi epistasis, rescue experiments, migration assay in mesenchymal carcinoma cells\",\n      \"pmids\": [\"32545415\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RAC1B-mediated transcriptional regulation of USP26 promoter not mapped\", \"Generalizability beyond pancreatic carcinoma not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating that USP26 localizes to the XY body and stabilizes TEX11 resolved the molecular mechanism underlying the meiotic pairing defect and XY aneuploidy in Usp26 knockout mice.\",\n      \"evidence\": \"KO mouse, immunofluorescence at XY body, Co-IP with TEX11, sperm FISH, offspring karyotyping\",\n      \"pmids\": [\"33978233\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin chain type on TEX11 removed by USP26 not specified\", \"Whether other XY body proteins are USP26 substrates is unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Discovery of the RNF12→REX1→USP26 feed-forward loop, in which USP26 prevents RNF12 autoubiquitylation, revealed a self-amplifying circuit required for germ cell differentiation.\",\n      \"evidence\": \"Quantitative proteomics, reciprocal Co-IP, ubiquitination assay, in vitro germ cell differentiation\",\n      \"pmids\": [\"35857630\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo validation of feed-forward loop in testis not completed\", \"Stoichiometry and regulation of USP26–RNF12 complex uncharacterized\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of TAZ as a USP26 substrate in anaplastic thyroid cancer extended USP26's oncogenic roles to Hippo pathway regulation.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, knockdown/rescue, gene expression of TEAD targets\",\n      \"pmids\": [\"35397626\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo TAZ stabilization by USP26 not demonstrated\", \"Whether USP26 affects upstream Hippo kinases unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Multiple studies identified PRKN (K129), SIRT1, SIRT2, BAG3, KLF6, and TRAF3 as USP26 substrates, and revealed post-translational (Tip60 acetylation at K134) and transcriptional (HIF-1α, HBx) regulation of USP26, greatly expanding its regulatory network.\",\n      \"evidence\": \"Co-IP, site-specific mutagenesis, K63-linkage-specific ubiquitination assay, ChIP, KO mouse tumor models, acetylation assay, IFN-β reporter\",\n      \"pmids\": [\"38565942\", \"39251623\", \"39377219\", \"38880224\", \"39058724\", \"38064851\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Many substrate interactions characterized by single labs and need independent replication\", \"Structural determinants of substrate selectivity still completely unknown\", \"Relative contribution of acetylation vs. transcriptional induction to USP26 activity regulation not compared\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A structural model of USP26 explaining its unusually broad substrate specificity, its allosteric regulation by acetylation, and the basis for disease-associated mutations is lacking.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal or cryo-EM structure available\", \"No unbiased proteomics-based substrate identification across tissues\", \"Relative physiological importance of individual substrates in different tissues not ranked\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 5, 9, 10, 11, 12, 13, 14, 15, 19]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 2, 3, 7, 9, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 22]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [1, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 3, 5, 9, 10, 11, 12, 13, 14, 15, 19]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 11, 15, 18]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [8, 9, 10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\n      \"RNF12-USP26 complex\"\n    ],\n    \"partners\": [\n      \"AR\",\n      \"TEX11\",\n      \"SMAD7\",\n      \"CBX4\",\n      \"CBX6\",\n      \"RLIM\",\n      \"TRAF3\",\n      \"MDM2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}