{"gene":"TEX19","run_date":"2026-04-28T21:42:58","timeline":{"discoveries":[{"year":2008,"finding":"Tex19.1 knockout in mice causes activation of endogenous retroviruses (ERVs) during meiosis, defects in meiotic chromosome synapsis, persistence of DNA double-strand breaks, and loss of post-meiotic germ cells, establishing Tex19.1 as part of a germline mechanism repressing transposable elements to maintain genomic stability.","method":"Knockout mouse model, immunostaining, histological analysis, RT-PCR for retrovirus expression","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — clean KO with multiple defined cellular phenotypes, replicated by subsequent labs","pmids":["18802469"],"is_preprint":false},{"year":2007,"finding":"TEX19.1 protein localizes to the nucleus of mouse ES cells and inner cell mass cells, as determined by immunofluorescence.","method":"Immunofluorescence in mouse ES cells and ICM","journal":"Stem cells (Dayton, Ohio)","confidence":"Medium","confidence_rationale":"Tier 3 — direct localization experiment, single lab, single method","pmids":["18096721"],"is_preprint":false},{"year":2010,"finding":"TEX19.1 forms a stable protein complex with the E3 ubiquitin ligase UBR2 in mouse testes, and UBR2 binding metabolically stabilizes TEX19.1 protein during spermatogenesis; in Ubr2-deficient germ cells, Tex19.1 mRNA is present but protein is absent.","method":"Co-immunoprecipitation, western blotting, Ubr2 knockout mouse analysis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — reciprocal protein interaction confirmed in vivo, KO mouse showing absence of TEX19.1 protein, replicated across labs","pmids":["21103378"],"is_preprint":false},{"year":2013,"finding":"Tex19.1 suppresses LINE-1 retrotransposon activity in the hypomethylated mouse placenta; Tex19.1-/- placentas show derepressed retrotransposon mRNAs and upregulated LINE-1 ORF1 protein in trophectoderm-derived cells, and exhibit reduced spongiotrophoblast, glycogen trophoblast, and sinusoidal trophoblast giant cells causing intra-uterine growth retardation.","method":"Knockout mouse model, RT-PCR/qPCR for retrotransposon expression, immunostaining, histological analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — KO with multiple defined cellular and molecular phenotypes in placenta","pmids":["23364048"],"is_preprint":false},{"year":2017,"finding":"TEX19.1 directly interacts with the LINE-1-encoded protein L1-ORF1p, stimulates its polyubiquitylation and proteasomal degradation, and restricts L1 mobilization in pluripotent mouse embryonic stem cells; TEX19.1 acts at least in part by promoting UBR2 E3 ubiquitin ligase activity toward L1-ORF1p.","method":"Co-immunoprecipitation, in vitro ubiquitylation assay, retrotransposition reporter assay, western blotting, Tex19.1 KO ESCs","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 — direct interaction and in vitro ubiquitylation assay with functional retrotransposition readout, multiple orthogonal methods in single study","pmids":["28806172"],"is_preprint":false},{"year":2017,"finding":"Tex19.1 promotes Spo11-dependent meiotic recombination in mouse spermatocytes; Tex19.1-/- spermatocytes show reduced early recombination foci during leptotene/zygotene but not defects in upstream events (MEI4 foci or H3K4me3 at hotspots). Ubr2 mutant mice phenocopy these recombination defects, placing TEX19.1 and UBR2 in the same genetic pathway promoting meiotic recombination.","method":"Knockout mouse model, immunostaining for recombination foci (RAD51, DMC1), genetic epistasis with Ubr2 mutants, ChIP for H3K4me3","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with defined molecular phenotype, multiple orthogonal approaches","pmids":["28708824"],"is_preprint":false},{"year":2017,"finding":"TEX19 paralogs (TEX19.1 and TEX19.2) interact with PIWI proteins and the TEX19 VPTEL domain directly binds piRNAs in adult mouse testes, identifying TEX19 paralogs as members of the postnatal piRNA pathway for retrotransposon suppression.","method":"Immunoprecipitation, GST pulldown, mass spectrometry, Tex19 double knockout mouse model","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP and GST pulldown with MS validation, supported by DKO phenotype","pmids":["28254886"],"is_preprint":false},{"year":2009,"finding":"DAZL protein binds to the 3'UTR of Tex19.1 mRNA and represses Tex19.1 expression at the translational level in germ cells.","method":"Electrophoretic mobility shift assay (EMSA), luciferase translation assay in zebrafish embryos","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 2 — EMSA plus functional translation assay, but single lab","pmids":["19247806"],"is_preprint":false},{"year":2018,"finding":"A meiotic recombination-dependent checkpoint delays pachytene progression in Tex19.1-/- spermatocytes; autosomally synapsed Tex19.1-/- spermatocytes are enriched for early recombination foci and show skewed patterns of axis elongation, chromatin modifications, and histone H1t expression towards early pachytene substages. This delay is Spo11-dependent, as it does not occur in a Spo11 mutant background.","method":"Knockout mouse model, genetic epistasis with Spo11 mutant, immunostaining for recombination foci and chromatin modifications, histone H1t expression analysis","journal":"Chromosoma","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis in double mutant with defined molecular phenotype","pmids":["29907896"],"is_preprint":false},{"year":2020,"finding":"TEX19.1 inhibits UBR2-mediated N-end rule protein degradation in postnatal mouse oocytes, thereby maintaining acetylated SMC3 cohesin on meiotic chromosome axes; Tex19.1-/- oocytes show depletion of acetylated SMC3, defects in chiasmata maintenance, chromosome missegregation during meiosis I, and transmission of aneuploidies to offspring.","method":"Knockout mouse model, co-immunoprecipitation, chromosome spreads, immunostaining for cohesin subunits, aneuploidy assay in offspring, somatic cell UBR2 knockdown experiments","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — KO with multiple orthogonal phenotypes plus biochemical interaction and epistasis with UBR2","pmids":["32232464"],"is_preprint":false},{"year":2024,"finding":"TEX19 upregulates CDK4 protein levels in breast cancer cells by interfering with SKP2-mediated ubiquitination of CDK4; TEX19 knockdown combined with SKP2 overexpression destabilizes CDK4 protein and enhances its ubiquitination, and CDK4 knockdown rescues the pro-proliferative effects of TEX19 overexpression.","method":"Co-IP, CHX chase experiment, siRNA knockdown, western blotting, cell proliferation/migration assays, in vivo xenograft model","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP and functional rescue in cancer cell lines, single lab","pmids":["38867223"],"is_preprint":false},{"year":2023,"finding":"FOXA1 transcription factor binds to the TEX19 promoter and activates TEX19 expression, thereby promoting glycolysis and proliferation in lung adenocarcinoma cells; ChIP confirmed FOXA1 binding, and rescue assays showed FOXA1-driven effects depend on TEX19.","method":"Dual luciferase reporter assay, chromatin immunoprecipitation (ChIP), siRNA knockdown, Seahorse metabolic flux assay, rescue experiments","journal":"Molecular biotechnology","confidence":"Medium","confidence_rationale":"Tier 2-3 — ChIP and luciferase reporter confirm direct regulation, functional rescue shows dependency, single lab","pmids":["37606876"],"is_preprint":false}],"current_model":"TEX19.1 is a mammalian-specific protein that operates in germ cells and pluripotent cells to suppress retrotransposons (particularly LINE-1 and ERVs) via direct interaction with L1-ORF1p and promotion of its UBR2-mediated polyubiquitylation and degradation; it also interacts with PIWI proteins and piRNAs as part of the piRNA pathway, is itself stabilized by UBR2 binding during spermatogenesis, promotes Spo11-dependent meiotic recombination in spermatocytes, and maintains acetylated SMC3 cohesin in oocytes by inhibiting UBR2-mediated N-end rule degradation, thereby preventing age-related aneuploidy in the female germline."},"narrative":{"teleology":[{"year":2007,"claim":"Determining where TEX19.1 protein resides revealed its nuclear localization in pluripotent cells, suggesting a nuclear function in early embryonic and germ cell biology.","evidence":"Immunofluorescence in mouse ES cells and inner cell mass","pmids":["18096721"],"confidence":"Medium","gaps":["Single method (immunofluorescence) without biochemical fractionation","Localization in germ cells not yet examined","No functional data at this stage"]},{"year":2008,"claim":"The first loss-of-function study established that Tex19.1 is required to repress endogenous retroviruses in the germline and to support meiotic chromosome synapsis and post-meiotic germ cell survival, linking transposon control to meiotic fidelity.","evidence":"Tex19.1 knockout mouse with histology, immunostaining for synapsis markers, RT-PCR for ERV expression","pmids":["18802469"],"confidence":"High","gaps":["Molecular mechanism of transposon repression unknown","Whether synapsis defects are a direct or indirect consequence of transposon activation unclear","No biochemical interactors identified"]},{"year":2009,"claim":"Identification of DAZL as a translational repressor of Tex19.1 mRNA revealed a layer of post-transcriptional control over TEX19.1 protein levels in germ cells.","evidence":"EMSA showing DAZL binding to Tex19.1 3′UTR; luciferase translation assay in zebrafish embryos","pmids":["19247806"],"confidence":"Medium","gaps":["Translational repression demonstrated in heterologous system (zebrafish), not confirmed in mammalian germ cells","Physiological significance of DAZL-mediated Tex19.1 regulation not tested in vivo"]},{"year":2010,"claim":"Discovery that TEX19.1 forms a stable complex with the E3 ubiquitin ligase UBR2 and depends on UBR2 for protein stability identified the key enzymatic partner through which TEX19.1 acts.","evidence":"Co-immunoprecipitation and western blotting in mouse testes; Ubr2 knockout showing loss of TEX19.1 protein despite normal mRNA","pmids":["21103378"],"confidence":"High","gaps":["Substrates of the TEX19.1–UBR2 complex not yet identified","Whether TEX19.1 activates or redirects UBR2 catalytic activity unknown"]},{"year":2013,"claim":"Extension of TEX19.1's retrotransposon-suppressive role to the placenta showed it functions outside the germline to restrain LINE-1 in hypomethylated somatic tissues, with loss causing trophoblast defects and intrauterine growth retardation.","evidence":"Tex19.1 knockout mouse placenta analysis with qPCR for retrotransposon mRNA, immunostaining for L1-ORF1p, histological quantification of trophoblast subtypes","pmids":["23364048"],"confidence":"High","gaps":["Whether placental phenotype is entirely caused by L1 derepression or partly transposon-independent not resolved","Mechanism of retrotransposon suppression in placenta not defined biochemically"]},{"year":2017,"claim":"Three concurrent studies resolved TEX19.1's molecular mechanism: it directly binds L1-ORF1p to stimulate UBR2-dependent polyubiquitylation and degradation of L1-ORF1p, restricting retrotransposition; it interacts with PIWI proteins and piRNAs as part of the postnatal piRNA pathway; and it promotes Spo11-dependent early meiotic recombination in a pathway genetically shared with UBR2.","evidence":"Co-IP, in vitro ubiquitylation assay, retrotransposition reporter in ESCs [PMID:28806172]; GST pulldown, mass spectrometry, Tex19 double KO [PMID:28254886]; immunostaining for RAD51/DMC1 foci, genetic epistasis with Ubr2 and Spo11 mutants [PMID:28708824]","pmids":["28806172","28254886","28708824"],"confidence":"High","gaps":["How TEX19.1 coordinates piRNA-pathway and UBR2-dependent mechanisms is unknown","Whether L1-ORF1p ubiquitylation is sufficient to explain all retrotransposon suppression not tested","How TEX19.1–UBR2 promotes recombination foci formation mechanistically unresolved"]},{"year":2018,"claim":"Demonstrating that a Spo11-dependent meiotic checkpoint delays pachytene progression in Tex19.1-null spermatocytes clarified that reduced recombination initiation triggers a surveillance mechanism rather than immediate apoptosis.","evidence":"Tex19.1 knockout and Tex19.1/Spo11 double mutant mice with immunostaining for recombination intermediates, chromatin modifications, and histone H1t staging","pmids":["29907896"],"confidence":"High","gaps":["Identity of the checkpoint sensor detecting reduced recombination intermediates unknown","Whether the checkpoint is ATR/ATM-dependent not tested"]},{"year":2020,"claim":"Revealing that TEX19.1 inhibits UBR2-mediated N-end rule degradation of acetylated SMC3 cohesin in oocytes uncovered a second, transposon-independent function: maintaining chromosome cohesion to prevent age-related aneuploidy.","evidence":"Tex19.1 knockout oocyte chromosome spreads showing depleted acetylated SMC3, chiasmata loss, meiosis I missegregation; co-IP of TEX19.1 with UBR2; aneuploidy transmission to offspring; UBR2 knockdown rescue in somatic cells","pmids":["32232464"],"confidence":"High","gaps":["Whether TEX19.1 directly shields acetylated SMC3 from UBR2 or acts indirectly not resolved","Relevance to human age-related aneuploidy not tested","Whether cohesin protection and retrotransposon suppression are coordinated or independent functions unknown"]},{"year":2023,"claim":"Identification of FOXA1 as a direct transcriptional activator of TEX19 in lung adenocarcinoma extended TEX19's relevance beyond the germline, showing that ectopic TEX19 expression promotes glycolysis and proliferation in somatic cancer cells.","evidence":"ChIP for FOXA1 at TEX19 promoter, dual luciferase reporter, Seahorse metabolic flux assay, rescue experiments in lung adenocarcinoma cell lines","pmids":["37606876"],"confidence":"Medium","gaps":["Downstream mechanism by which TEX19 promotes glycolysis not identified","Single-lab finding in cancer cell lines without in vivo validation"]},{"year":2024,"claim":"TEX19 was shown to stabilize CDK4 protein in breast cancer cells by interfering with SKP2-mediated ubiquitination, revealing a cancer-context mechanism of cell cycle promotion distinct from its germline UBR2-dependent functions.","evidence":"Co-IP of TEX19 with CDK4, CHX chase, siRNA knockdown and SKP2 overexpression epistasis, xenograft model","pmids":["38867223"],"confidence":"Medium","gaps":["Whether TEX19 directly competes with SKP2 for CDK4 binding or acts indirectly not established","Relevance to normal germline CDK4 regulation unknown","Single-lab study"]},{"year":null,"claim":"How TEX19 coordinates its dual roles in retrotransposon suppression (via L1-ORF1p degradation and piRNA pathway) and meiotic chromosome maintenance (via cohesin protection), and whether these functions are separable or mechanistically linked, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of TEX19.1 or TEX19.1–UBR2 complex available","Whether human TEX19 performs equivalent functions in human germ cells is untested","Separation-of-function mutations distinguishing transposon suppression from cohesin protection have not been generated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,9,10]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4,9,10]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5,8,9]}],"complexes":["TEX19.1–UBR2"],"partners":["UBR2","L1-ORF1P","PIWIL1","PIWIL2","CDK4","SMC3","DAZL"],"other_free_text":[]},"mechanistic_narrative":"TEX19 is a mammalian germline and pluripotent cell protein that safeguards genome integrity by suppressing retrotransposon mobilization and regulating meiotic chromosome dynamics through modulation of UBR2 E3 ubiquitin ligase activity. TEX19.1 directly binds LINE-1-encoded ORF1p and stimulates its UBR2-dependent polyubiquitylation and proteasomal degradation, restricting L1 retrotransposition in embryonic stem cells and preventing transposable element derepression in placenta and meiotic germ cells [PMID:28806172, PMID:23364048, PMID:18802469]. TEX19 paralogs also interact with PIWI proteins and directly bind piRNAs, placing them in the postnatal piRNA pathway for retrotransposon silencing [PMID:28254886]. In addition to transposon defense, TEX19.1 promotes Spo11-dependent meiotic recombination in spermatocytes and maintains acetylated SMC3 cohesin on oocyte chromosome axes by inhibiting UBR2-mediated N-end rule degradation, with its loss causing chiasmata defects, chromosome missegregation, and aneuploidy transmitted to offspring [PMID:28708824, PMID:32232464]."},"prefetch_data":{"uniprot":{"accession":"Q8NA77","full_name":"Testis-expressed protein 19","aliases":[],"length_aa":164,"mass_kda":18.5,"function":"Required during spermatogenesis and placenta development, participating in the repression of retrotransposable elements and prevent their mobilization. Collaborates with the Piwi-interacting RNA (piRNA) pathway, which mediates the repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins. Interacts with Piwi proteins and directly binds piRNAs, a class of 24 to 30 nucleotide RNAs that are generated by a Dicer-independent mechanism and are primarily derived from transposons and other repeated sequence elements. Also during spermatogenesis, promotes, with UBR2, SPO11-dependent recombination foci to accumulate and drive robust homologous chromosome synapsis (By similarity). Interacts with LINE-1 retrotransposon encoded LIRE1, stimulates LIRE1 polyubiquitination, mediated by UBR2, and degradation, inhibiting LINE-1 retrotransposon mobilization (PubMed:28806172)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q8NA77/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TEX19","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TEX19","total_profiled":1310},"omim":[{"mim_id":"615647","title":"TESTIS-EXPRESSED GENE 19; TEX19","url":"https://www.omim.org/entry/615647"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"testis","ntpm":30.0}],"url":"https://www.proteinatlas.org/search/TEX19"},"hgnc":{"alias_symbol":["FLJ35767"],"prev_symbol":[]},"alphafold":{"accession":"Q8NA77","domains":[{"cath_id":"-","chopping":"6-43","consensus_level":"high","plddt":73.0203,"start":6,"end":43}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NA77","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NA77-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NA77-F1-predicted_aligned_error_v6.png","plddt_mean":56.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TEX19","jax_strain_url":"https://www.jax.org/strain/search?query=TEX19"},"sequence":{"accession":"Q8NA77","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NA77.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NA77/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NA77"}},"corpus_meta":[{"pmid":"18802469","id":"PMC_18802469","title":"Deletion of the pluripotency-associated Tex19.1 gene causes activation of endogenous retroviruses and defective spermatogenesis in mice.","date":"2008","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18802469","citation_count":60,"is_preprint":false},{"pmid":"28806172","id":"PMC_28806172","title":"Mobilization of LINE-1 retrotransposons is restricted by Tex19.1 in mouse embryonic stem cells.","date":"2017","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/28806172","citation_count":37,"is_preprint":false},{"pmid":"18096721","id":"PMC_18096721","title":"Tex19, a mammalian-specific protein with a restricted expression in pluripotent stem cells and germ line.","date":"2007","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/18096721","citation_count":37,"is_preprint":false},{"pmid":"21103378","id":"PMC_21103378","title":"The ubiquitin ligase Ubr2, a recognition E3 component of the N-end rule pathway, stabilizes Tex19.1 during spermatogenesis.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21103378","citation_count":32,"is_preprint":false},{"pmid":"23364048","id":"PMC_23364048","title":"The genome-defence gene Tex19.1 suppresses LINE-1 retrotransposons in the placenta and prevents intra-uterine growth retardation in mice.","date":"2013","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23364048","citation_count":30,"is_preprint":false},{"pmid":"28708824","id":"PMC_28708824","title":"Tex19.1 promotes Spo11-dependent meiotic recombination in mouse spermatocytes.","date":"2017","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28708824","citation_count":22,"is_preprint":false},{"pmid":"23674551","id":"PMC_23674551","title":"The mammalian-specific Tex19.1 gene plays an essential role in spermatogenesis and placenta-supported development.","date":"2013","source":"Human reproduction (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/23674551","citation_count":17,"is_preprint":false},{"pmid":"19247806","id":"PMC_19247806","title":"DAZL binds to 3'UTR of Tex19.1 mRNAs and regulates Tex19.1 expression.","date":"2009","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/19247806","citation_count":16,"is_preprint":false},{"pmid":"31843525","id":"PMC_31843525","title":"TEX19 promotes ovarian carcinoma progression and is a potential target for epitope vaccine immunotherapy.","date":"2019","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31843525","citation_count":11,"is_preprint":false},{"pmid":"29907896","id":"PMC_29907896","title":"Defects in meiotic recombination delay progression through pachytene in Tex19.1-/- mouse spermatocytes.","date":"2018","source":"Chromosoma","url":"https://pubmed.ncbi.nlm.nih.gov/29907896","citation_count":10,"is_preprint":false},{"pmid":"32232464","id":"PMC_32232464","title":"Tex19.1 inhibits the N-end rule pathway and maintains acetylated SMC3 cohesin and sister chromatid cohesion in oocytes.","date":"2020","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/32232464","citation_count":10,"is_preprint":false},{"pmid":"28254886","id":"PMC_28254886","title":"Tex19 paralogs are new members of the piRNA pathway controlling retrotransposon suppression.","date":"2017","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/28254886","citation_count":9,"is_preprint":false},{"pmid":"37606876","id":"PMC_37606876","title":"Transcription Factor FOXA1 Facilitates Glycolysis and Proliferation of Lung Adenocarcinoma via Activation of TEX19.","date":"2023","source":"Molecular biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/37606876","citation_count":7,"is_preprint":false},{"pmid":"34036740","id":"PMC_34036740","title":"In silico modeling of the interaction between TEX19 and LIRE1, and analysis of TEX19 gene missense SNPs.","date":"2021","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34036740","citation_count":5,"is_preprint":false},{"pmid":"38867223","id":"PMC_38867223","title":"TEX19 increases the levels of CDK4 and promotes breast cancer by disrupting SKP2-mediated CDK4 ubiquitination.","date":"2024","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/38867223","citation_count":4,"is_preprint":false},{"pmid":"26459560","id":"PMC_26459560","title":"Tex19 and Sectm1 concordant molecular phylogenies support co-evolution of both eutherian-specific genes.","date":"2015","source":"BMC evolutionary biology","url":"https://pubmed.ncbi.nlm.nih.gov/26459560","citation_count":3,"is_preprint":false},{"pmid":"40897289","id":"PMC_40897289","title":"Patients with colon cancer exhibited greater TEX19 expression, controlled in vitro by epigenetic inhibitors.","date":"2025","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/40897289","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10449,"output_tokens":2852,"usd":0.037063},"stage2":{"model":"claude-opus-4-6","input_tokens":6194,"output_tokens":2884,"usd":0.154605},"total_usd":0.191668,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"Tex19.1 knockout in mice causes activation of endogenous retroviruses (ERVs) during meiosis, defects in meiotic chromosome synapsis, persistence of DNA double-strand breaks, and loss of post-meiotic germ cells, establishing Tex19.1 as part of a germline mechanism repressing transposable elements to maintain genomic stability.\",\n      \"method\": \"Knockout mouse model, immunostaining, histological analysis, RT-PCR for retrovirus expression\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple defined cellular phenotypes, replicated by subsequent labs\",\n      \"pmids\": [\"18802469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TEX19.1 protein localizes to the nucleus of mouse ES cells and inner cell mass cells, as determined by immunofluorescence.\",\n      \"method\": \"Immunofluorescence in mouse ES cells and ICM\",\n      \"journal\": \"Stem cells (Dayton, Ohio)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct localization experiment, single lab, single method\",\n      \"pmids\": [\"18096721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TEX19.1 forms a stable protein complex with the E3 ubiquitin ligase UBR2 in mouse testes, and UBR2 binding metabolically stabilizes TEX19.1 protein during spermatogenesis; in Ubr2-deficient germ cells, Tex19.1 mRNA is present but protein is absent.\",\n      \"method\": \"Co-immunoprecipitation, western blotting, Ubr2 knockout mouse analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal protein interaction confirmed in vivo, KO mouse showing absence of TEX19.1 protein, replicated across labs\",\n      \"pmids\": [\"21103378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Tex19.1 suppresses LINE-1 retrotransposon activity in the hypomethylated mouse placenta; Tex19.1-/- placentas show derepressed retrotransposon mRNAs and upregulated LINE-1 ORF1 protein in trophectoderm-derived cells, and exhibit reduced spongiotrophoblast, glycogen trophoblast, and sinusoidal trophoblast giant cells causing intra-uterine growth retardation.\",\n      \"method\": \"Knockout mouse model, RT-PCR/qPCR for retrotransposon expression, immunostaining, histological analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO with multiple defined cellular and molecular phenotypes in placenta\",\n      \"pmids\": [\"23364048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TEX19.1 directly interacts with the LINE-1-encoded protein L1-ORF1p, stimulates its polyubiquitylation and proteasomal degradation, and restricts L1 mobilization in pluripotent mouse embryonic stem cells; TEX19.1 acts at least in part by promoting UBR2 E3 ubiquitin ligase activity toward L1-ORF1p.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitylation assay, retrotransposition reporter assay, western blotting, Tex19.1 KO ESCs\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct interaction and in vitro ubiquitylation assay with functional retrotransposition readout, multiple orthogonal methods in single study\",\n      \"pmids\": [\"28806172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Tex19.1 promotes Spo11-dependent meiotic recombination in mouse spermatocytes; Tex19.1-/- spermatocytes show reduced early recombination foci during leptotene/zygotene but not defects in upstream events (MEI4 foci or H3K4me3 at hotspots). Ubr2 mutant mice phenocopy these recombination defects, placing TEX19.1 and UBR2 in the same genetic pathway promoting meiotic recombination.\",\n      \"method\": \"Knockout mouse model, immunostaining for recombination foci (RAD51, DMC1), genetic epistasis with Ubr2 mutants, ChIP for H3K4me3\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with defined molecular phenotype, multiple orthogonal approaches\",\n      \"pmids\": [\"28708824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TEX19 paralogs (TEX19.1 and TEX19.2) interact with PIWI proteins and the TEX19 VPTEL domain directly binds piRNAs in adult mouse testes, identifying TEX19 paralogs as members of the postnatal piRNA pathway for retrotransposon suppression.\",\n      \"method\": \"Immunoprecipitation, GST pulldown, mass spectrometry, Tex19 double knockout mouse model\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and GST pulldown with MS validation, supported by DKO phenotype\",\n      \"pmids\": [\"28254886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DAZL protein binds to the 3'UTR of Tex19.1 mRNA and represses Tex19.1 expression at the translational level in germ cells.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA), luciferase translation assay in zebrafish embryos\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — EMSA plus functional translation assay, but single lab\",\n      \"pmids\": [\"19247806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A meiotic recombination-dependent checkpoint delays pachytene progression in Tex19.1-/- spermatocytes; autosomally synapsed Tex19.1-/- spermatocytes are enriched for early recombination foci and show skewed patterns of axis elongation, chromatin modifications, and histone H1t expression towards early pachytene substages. This delay is Spo11-dependent, as it does not occur in a Spo11 mutant background.\",\n      \"method\": \"Knockout mouse model, genetic epistasis with Spo11 mutant, immunostaining for recombination foci and chromatin modifications, histone H1t expression analysis\",\n      \"journal\": \"Chromosoma\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in double mutant with defined molecular phenotype\",\n      \"pmids\": [\"29907896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TEX19.1 inhibits UBR2-mediated N-end rule protein degradation in postnatal mouse oocytes, thereby maintaining acetylated SMC3 cohesin on meiotic chromosome axes; Tex19.1-/- oocytes show depletion of acetylated SMC3, defects in chiasmata maintenance, chromosome missegregation during meiosis I, and transmission of aneuploidies to offspring.\",\n      \"method\": \"Knockout mouse model, co-immunoprecipitation, chromosome spreads, immunostaining for cohesin subunits, aneuploidy assay in offspring, somatic cell UBR2 knockdown experiments\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO with multiple orthogonal phenotypes plus biochemical interaction and epistasis with UBR2\",\n      \"pmids\": [\"32232464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TEX19 upregulates CDK4 protein levels in breast cancer cells by interfering with SKP2-mediated ubiquitination of CDK4; TEX19 knockdown combined with SKP2 overexpression destabilizes CDK4 protein and enhances its ubiquitination, and CDK4 knockdown rescues the pro-proliferative effects of TEX19 overexpression.\",\n      \"method\": \"Co-IP, CHX chase experiment, siRNA knockdown, western blotting, cell proliferation/migration assays, in vivo xenograft model\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP and functional rescue in cancer cell lines, single lab\",\n      \"pmids\": [\"38867223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FOXA1 transcription factor binds to the TEX19 promoter and activates TEX19 expression, thereby promoting glycolysis and proliferation in lung adenocarcinoma cells; ChIP confirmed FOXA1 binding, and rescue assays showed FOXA1-driven effects depend on TEX19.\",\n      \"method\": \"Dual luciferase reporter assay, chromatin immunoprecipitation (ChIP), siRNA knockdown, Seahorse metabolic flux assay, rescue experiments\",\n      \"journal\": \"Molecular biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — ChIP and luciferase reporter confirm direct regulation, functional rescue shows dependency, single lab\",\n      \"pmids\": [\"37606876\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TEX19.1 is a mammalian-specific protein that operates in germ cells and pluripotent cells to suppress retrotransposons (particularly LINE-1 and ERVs) via direct interaction with L1-ORF1p and promotion of its UBR2-mediated polyubiquitylation and degradation; it also interacts with PIWI proteins and piRNAs as part of the piRNA pathway, is itself stabilized by UBR2 binding during spermatogenesis, promotes Spo11-dependent meiotic recombination in spermatocytes, and maintains acetylated SMC3 cohesin in oocytes by inhibiting UBR2-mediated N-end rule degradation, thereby preventing age-related aneuploidy in the female germline.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TEX19 is a mammalian germline and pluripotent cell protein that safeguards genome integrity by suppressing retrotransposon mobilization and regulating meiotic chromosome dynamics through modulation of UBR2 E3 ubiquitin ligase activity. TEX19.1 directly binds LINE-1-encoded ORF1p and stimulates its UBR2-dependent polyubiquitylation and proteasomal degradation, restricting L1 retrotransposition in embryonic stem cells and preventing transposable element derepression in placenta and meiotic germ cells [PMID:28806172, PMID:23364048, PMID:18802469]. TEX19 paralogs also interact with PIWI proteins and directly bind piRNAs, placing them in the postnatal piRNA pathway for retrotransposon silencing [PMID:28254886]. In addition to transposon defense, TEX19.1 promotes Spo11-dependent meiotic recombination in spermatocytes and maintains acetylated SMC3 cohesin on oocyte chromosome axes by inhibiting UBR2-mediated N-end rule degradation, with its loss causing chiasmata defects, chromosome missegregation, and aneuploidy transmitted to offspring [PMID:28708824, PMID:32232464].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Determining where TEX19.1 protein resides revealed its nuclear localization in pluripotent cells, suggesting a nuclear function in early embryonic and germ cell biology.\",\n      \"evidence\": \"Immunofluorescence in mouse ES cells and inner cell mass\",\n      \"pmids\": [\"18096721\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single method (immunofluorescence) without biochemical fractionation\", \"Localization in germ cells not yet examined\", \"No functional data at this stage\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The first loss-of-function study established that Tex19.1 is required to repress endogenous retroviruses in the germline and to support meiotic chromosome synapsis and post-meiotic germ cell survival, linking transposon control to meiotic fidelity.\",\n      \"evidence\": \"Tex19.1 knockout mouse with histology, immunostaining for synapsis markers, RT-PCR for ERV expression\",\n      \"pmids\": [\"18802469\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of transposon repression unknown\", \"Whether synapsis defects are a direct or indirect consequence of transposon activation unclear\", \"No biochemical interactors identified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identification of DAZL as a translational repressor of Tex19.1 mRNA revealed a layer of post-transcriptional control over TEX19.1 protein levels in germ cells.\",\n      \"evidence\": \"EMSA showing DAZL binding to Tex19.1 3′UTR; luciferase translation assay in zebrafish embryos\",\n      \"pmids\": [\"19247806\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Translational repression demonstrated in heterologous system (zebrafish), not confirmed in mammalian germ cells\", \"Physiological significance of DAZL-mediated Tex19.1 regulation not tested in vivo\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Discovery that TEX19.1 forms a stable complex with the E3 ubiquitin ligase UBR2 and depends on UBR2 for protein stability identified the key enzymatic partner through which TEX19.1 acts.\",\n      \"evidence\": \"Co-immunoprecipitation and western blotting in mouse testes; Ubr2 knockout showing loss of TEX19.1 protein despite normal mRNA\",\n      \"pmids\": [\"21103378\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrates of the TEX19.1–UBR2 complex not yet identified\", \"Whether TEX19.1 activates or redirects UBR2 catalytic activity unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extension of TEX19.1's retrotransposon-suppressive role to the placenta showed it functions outside the germline to restrain LINE-1 in hypomethylated somatic tissues, with loss causing trophoblast defects and intrauterine growth retardation.\",\n      \"evidence\": \"Tex19.1 knockout mouse placenta analysis with qPCR for retrotransposon mRNA, immunostaining for L1-ORF1p, histological quantification of trophoblast subtypes\",\n      \"pmids\": [\"23364048\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether placental phenotype is entirely caused by L1 derepression or partly transposon-independent not resolved\", \"Mechanism of retrotransposon suppression in placenta not defined biochemically\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Three concurrent studies resolved TEX19.1's molecular mechanism: it directly binds L1-ORF1p to stimulate UBR2-dependent polyubiquitylation and degradation of L1-ORF1p, restricting retrotransposition; it interacts with PIWI proteins and piRNAs as part of the postnatal piRNA pathway; and it promotes Spo11-dependent early meiotic recombination in a pathway genetically shared with UBR2.\",\n      \"evidence\": \"Co-IP, in vitro ubiquitylation assay, retrotransposition reporter in ESCs [PMID:28806172]; GST pulldown, mass spectrometry, Tex19 double KO [PMID:28254886]; immunostaining for RAD51/DMC1 foci, genetic epistasis with Ubr2 and Spo11 mutants [PMID:28708824]\",\n      \"pmids\": [\"28806172\", \"28254886\", \"28708824\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TEX19.1 coordinates piRNA-pathway and UBR2-dependent mechanisms is unknown\", \"Whether L1-ORF1p ubiquitylation is sufficient to explain all retrotransposon suppression not tested\", \"How TEX19.1–UBR2 promotes recombination foci formation mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrating that a Spo11-dependent meiotic checkpoint delays pachytene progression in Tex19.1-null spermatocytes clarified that reduced recombination initiation triggers a surveillance mechanism rather than immediate apoptosis.\",\n      \"evidence\": \"Tex19.1 knockout and Tex19.1/Spo11 double mutant mice with immunostaining for recombination intermediates, chromatin modifications, and histone H1t staging\",\n      \"pmids\": [\"29907896\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the checkpoint sensor detecting reduced recombination intermediates unknown\", \"Whether the checkpoint is ATR/ATM-dependent not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealing that TEX19.1 inhibits UBR2-mediated N-end rule degradation of acetylated SMC3 cohesin in oocytes uncovered a second, transposon-independent function: maintaining chromosome cohesion to prevent age-related aneuploidy.\",\n      \"evidence\": \"Tex19.1 knockout oocyte chromosome spreads showing depleted acetylated SMC3, chiasmata loss, meiosis I missegregation; co-IP of TEX19.1 with UBR2; aneuploidy transmission to offspring; UBR2 knockdown rescue in somatic cells\",\n      \"pmids\": [\"32232464\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TEX19.1 directly shields acetylated SMC3 from UBR2 or acts indirectly not resolved\", \"Relevance to human age-related aneuploidy not tested\", \"Whether cohesin protection and retrotransposon suppression are coordinated or independent functions unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of FOXA1 as a direct transcriptional activator of TEX19 in lung adenocarcinoma extended TEX19's relevance beyond the germline, showing that ectopic TEX19 expression promotes glycolysis and proliferation in somatic cancer cells.\",\n      \"evidence\": \"ChIP for FOXA1 at TEX19 promoter, dual luciferase reporter, Seahorse metabolic flux assay, rescue experiments in lung adenocarcinoma cell lines\",\n      \"pmids\": [\"37606876\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream mechanism by which TEX19 promotes glycolysis not identified\", \"Single-lab finding in cancer cell lines without in vivo validation\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"TEX19 was shown to stabilize CDK4 protein in breast cancer cells by interfering with SKP2-mediated ubiquitination, revealing a cancer-context mechanism of cell cycle promotion distinct from its germline UBR2-dependent functions.\",\n      \"evidence\": \"Co-IP of TEX19 with CDK4, CHX chase, siRNA knockdown and SKP2 overexpression epistasis, xenograft model\",\n      \"pmids\": [\"38867223\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TEX19 directly competes with SKP2 for CDK4 binding or acts indirectly not established\", \"Relevance to normal germline CDK4 regulation unknown\", \"Single-lab study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TEX19 coordinates its dual roles in retrotransposon suppression (via L1-ORF1p degradation and piRNA pathway) and meiotic chromosome maintenance (via cohesin protection), and whether these functions are separable or mechanistically linked, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of TEX19.1 or TEX19.1–UBR2 complex available\", \"Whether human TEX19 performs equivalent functions in human germ cells is untested\", \"Separation-of-function mutations distinguishing transposon suppression from cohesin protection have not been generated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 9, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 9, 10]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5, 8, 9]}\n    ],\n    \"complexes\": [\n      \"TEX19.1–UBR2\"\n    ],\n    \"partners\": [\n      \"UBR2\",\n      \"L1-ORF1p\",\n      \"PIWIL1\",\n      \"PIWIL2\",\n      \"CDK4\",\n      \"SMC3\",\n      \"DAZL\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}