{"gene":"NSMCE1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2026,"finding":"The NSMCE1/NSMCE3 subcomplex of SMC5/6 is sufficient to inhibit HBV transcription in vitro, independently of the full holo-complex, as measured by a luciferase reporter in a cell-free expression system with purified subcomplexes.","method":"Cell-free transcription assay with purified NSMCE1/3 subcomplex and luciferase reporter","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution with purified subcomplex, single lab, single study","pmids":["41825673"],"is_preprint":false},{"year":2026,"finding":"NSMCE1/NSMCE3 overexpression causes degradation of HBx protein via a ubiquitin-independent proteasomal mechanism: the effect is blocked by a proteasome inhibitor but not by an E1 ubiquitin-activating enzyme inhibitor, and NSMCE1/3 interacts with the 20S proteasome without stimulating HBx ubiquitination.","method":"Cycloheximide chase, proteasome inhibitor treatment, E1 inhibitor treatment, Co-immunoprecipitation with 20S proteasome, ubiquitination assay","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, chase assay, inhibitor experiments) in a single lab study","pmids":["41825673"],"is_preprint":false},{"year":2026,"finding":"NSMCE1/NSMCE3 represses HBx expression at both the mRNA and protein level, and overexpression of NSMCE1/3 inhibits HBV proliferation in hepatoma cell lines, while knockdown of NSMCE3 promotes HBV proliferation.","method":"RT-PCR, cycloheximide chase, overexpression and knockdown in hepatoma cell lines with HBV proliferation readout","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with defined cellular phenotype, multiple readouts, single lab","pmids":["41825673"],"is_preprint":false},{"year":2019,"finding":"Nsmce1 overexpression in mouse hippocampal neuronal cells (HT-22) inhibits expression of AD marker genes App, Bace2, and Mapt, and promotes cell proliferation; knockdown of Nsmce1 has the opposite effects. Nsmce1 overexpression also increases alternative splicing complexity, with events enriched in the ubiquitin-mediated proteolysis pathway.","method":"Overexpression and knockdown in HT-22 cells, RT-PCR/qPCR for marker genes, cell proliferation assay, RNA-seq transcriptomics","journal":"Functional & integrative genomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — gain- and loss-of-function with gene expression and proliferation readouts, no pathway placement or direct molecular mechanism, single lab","pmids":["31792732"],"is_preprint":false}],"current_model":"NSMCE1 is a subunit of the SMC5/6 complex whose NSMCE1/NSMCE3 subcomplex is sufficient to inhibit HBV transcription in vitro and to promote ubiquitin-independent proteasomal degradation of the viral HBx protein through interaction with the 20S proteasome; in neuronal cells, NSMCE1 also participates in genome integrity maintenance and modulates ubiquitin-mediated proteolysis and alternative splicing pathways."},"narrative":{"mechanistic_narrative":"NSMCE1 is a subunit of the SMC5/6 genome-integrity complex that, together with NSMCE3, forms a subcomplex with antiviral activity against hepatitis B virus [PMID:41825673]. The purified NSMCE1/NSMCE3 subcomplex is sufficient to inhibit HBV transcription in a cell-free reporter assay, acting independently of the full holo-complex [PMID:41825673]. NSMCE1/NSMCE3 additionally drives degradation of the viral HBx protein through a ubiquitin-independent route: degradation requires proteasome activity but not E1 ubiquitin-activating enzyme function, and the subcomplex physically associates with the 20S proteasome without stimulating HBx ubiquitination [PMID:41825673]. Through these combined transcriptional and post-translational effects, NSMCE1/NSMCE3 represses HBx at the mRNA and protein level and restricts HBV proliferation in hepatoma cells, whereas NSMCE3 knockdown enhances viral proliferation [PMID:41825673]. In mouse hippocampal neuronal cells, Nsmce1 modulates expression of Alzheimer's disease marker genes and reshapes alternative splicing toward the ubiquitin-mediated proteolysis pathway [PMID:31792732]. Beyond these findings, the molecular basis of NSMCE1's contribution to the intact SMC5/6 complex has not been characterized in the available corpus.","teleology":[{"year":2019,"claim":"Established the first cellular phenotype for NSMCE1 outside canonical genome maintenance, linking it to neuronal gene-expression control and splicing regulation.","evidence":"Overexpression and knockdown in HT-22 hippocampal cells with marker-gene qPCR, proliferation assays, and RNA-seq","pmids":["31792732"],"confidence":"Low","gaps":["No direct molecular mechanism or pathway placement for the splicing/proteolysis effects","AD marker-gene changes are correlative, not mechanistically connected to NSMCE1 activity","Single lab, single cell line"]},{"year":2026,"claim":"Showed that the NSMCE1/NSMCE3 subcomplex alone is sufficient to repress HBV transcription, decoupling this antiviral function from the full SMC5/6 holo-complex.","evidence":"Cell-free transcription assay with purified NSMCE1/3 subcomplex and luciferase reporter","pmids":["41825673"],"confidence":"Medium","gaps":["In vitro reconstitution only; not validated in chromatinized cellular HBV context","Mechanism of transcriptional repression unresolved","Single study, single lab"]},{"year":2026,"claim":"Defined a ubiquitin-independent proteasomal pathway by which NSMCE1/NSMCE3 degrades the viral HBx protein and restricts HBV proliferation.","evidence":"Cycloheximide chase, proteasome and E1 inhibitor treatments, 20S proteasome Co-IP and ubiquitination assays, plus gain/loss-of-function in hepatoma cells","pmids":["41825673"],"confidence":"Medium","gaps":["Structural basis of NSMCE1/3 binding to the 20S proteasome unknown","How HBx is targeted to the proteasome without ubiquitination is unresolved","Reciprocal validation of the 20S interaction not described"]},{"year":null,"claim":"How NSMCE1's antiviral and proteasome-directing activities relate to its role within the intact SMC5/6 complex and to genome integrity remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural or biochemical characterization of NSMCE1 within full SMC5/6 in this corpus","Connection between neuronal splicing/proteolysis role and antiviral role unestablished","No in vivo evidence for the antiviral mechanism"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,2]}],"localization":[],"pathway":[{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,1,2]}],"complexes":["SMC5/6 complex","NSMCE1/NSMCE3 subcomplex"],"partners":["NSMCE3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WV22","full_name":"Non-structural maintenance of chromosomes element 1 homolog","aliases":[],"length_aa":266,"mass_kda":30.9,"function":"RING-type zinc finger-containing E3 ubiquitin ligase that assembles with melanoma antigen protein (MAGE) to catalyze the direct transfer of ubiquitin from E2 ubiquitin-conjugating enzyme to a specific substrate. Within MAGE-RING ubiquitin ligase complex, MAGE stimulates and specifies ubiquitin ligase activity likely through recruitment and/or stabilization of the E2 ubiquitin-conjugating enzyme at the E3:substrate complex. Involved in maintenance of genome integrity, DNA damage response and DNA repair (PubMed:20864041, PubMed:29225034). NSMCE3/MAGEG1 and NSMCE1 ubiquitin ligase are components of SMC5-SMC6 complex and may positively regulate homologous recombination-mediated DNA repair (PubMed:18086888). MAGEF1-NSMCE1 ubiquitin ligase promotes proteasomal degradation of MMS19, a key component of the cytosolic iron-sulfur protein assembly (CIA) machinery. Down-regulation of MMS19 impairs the activity of several DNA repair and metabolism enzymes such as ERCC2/XPD, FANCJ, RTEL1 and POLD1 that require iron-sulfur clusters as cofactors (PubMed:29225034)","subcellular_location":"Nucleus; Chromosome, telomere","url":"https://www.uniprot.org/uniprotkb/Q8WV22/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/NSMCE1","classification":"Common Essential","n_dependent_lines":784,"n_total_lines":1208,"dependency_fraction":0.6490066225165563},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NSMCE1","total_profiled":1310},"omim":[{"mim_id":"617263","title":"NSE1 HOMOLOG, SMC5-SMC6 COMPLEX COMPONENT; NSMCE1","url":"https://www.omim.org/entry/617263"},{"mim_id":"617246","title":"NSE2 (MMS21) HOMOLOG, SMC5-SMC6 COMPLEX SUMO LIGASE; NSMCE2","url":"https://www.omim.org/entry/617246"},{"mim_id":"617241","title":"LUNG DISEASE, IMMUNODEFICIENCY, AND CHROMOSOME BREAKAGE SYNDROME; LICS","url":"https://www.omim.org/entry/617241"},{"mim_id":"612987","title":"NSE4 HOMOLOG A, SMC5-SMC6 COMPLEX COMPONENT; NSMCE4A","url":"https://www.omim.org/entry/612987"},{"mim_id":"608243","title":"NSE3 HOMOLOG, SMC5-SMC6 COMPLEX COMPONENT; NSMCE3","url":"https://www.omim.org/entry/608243"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NSMCE1"},"hgnc":{"alias_symbol":["NSE1"],"prev_symbol":[]},"alphafold":{"accession":"Q8WV22","domains":[{"cath_id":"3.90.1150.220","chopping":"14-95","consensus_level":"medium","plddt":92.0505,"start":14,"end":95},{"cath_id":"1.10.10.10","chopping":"103-185","consensus_level":"high","plddt":95.3284,"start":103,"end":185},{"cath_id":"3.30.40.10","chopping":"190-245","consensus_level":"medium","plddt":96.2995,"start":190,"end":245}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WV22","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WV22-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WV22-F1-predicted_aligned_error_v6.png","plddt_mean":89.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NSMCE1","jax_strain_url":"https://www.jax.org/strain/search?query=NSMCE1"},"sequence":{"accession":"Q8WV22","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WV22.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WV22/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WV22"}},"corpus_meta":[{"pmid":"33663605","id":"PMC_33663605","title":"Genome-wide epistasis analysis for Alzheimer's disease and implications for genetic risk prediction.","date":"2021","source":"Alzheimer's research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33663605","citation_count":40,"is_preprint":false},{"pmid":"36280825","id":"PMC_36280825","title":"Role of a lipid metabolism-related lncRNA signature in risk stratification and immune microenvironment for colon cancer.","date":"2022","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/36280825","citation_count":17,"is_preprint":false},{"pmid":"32931559","id":"PMC_32931559","title":"Whole genome sequencing identifies allelic ratio distortion in sperm involving genes related to spermatogenesis in a swine model.","date":"2020","source":"DNA research : an international journal for rapid publication of reports on genes and genomes","url":"https://pubmed.ncbi.nlm.nih.gov/32931559","citation_count":14,"is_preprint":false},{"pmid":"37659689","id":"PMC_37659689","title":"4D-DIA quantitative proteomics revealed the core mechanism of diabetic retinopathy after berberine treatment.","date":"2023","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37659689","citation_count":12,"is_preprint":false},{"pmid":"33754896","id":"PMC_33754896","title":"Identification of hub ubiquitin ligase genes affecting Alzheimer's disease by analyzing transcriptome data from multiple brain regions.","date":"2021","source":"Science progress","url":"https://pubmed.ncbi.nlm.nih.gov/33754896","citation_count":11,"is_preprint":false},{"pmid":"31792732","id":"PMC_31792732","title":"A transcriptomic analysis of Nsmce1 overexpression in mouse hippocampal neuronal cell by RNA sequencing.","date":"2019","source":"Functional & integrative genomics","url":"https://pubmed.ncbi.nlm.nih.gov/31792732","citation_count":7,"is_preprint":false},{"pmid":"39611166","id":"PMC_39611166","title":"Novel genomic variants influencing methotrexate delayed clearance in pediatric patients with acute lymphoblastic leukemia.","date":"2024","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39611166","citation_count":4,"is_preprint":false},{"pmid":"41825673","id":"PMC_41825673","title":"Mechanism insights into the role of Smc5/6 in HBV inhibition.","date":"2026","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/41825673","citation_count":0,"is_preprint":false},{"pmid":"41111109","id":"PMC_41111109","title":"Assessing SMC Complex Function in Replication Fork Progression with DNA Fiber Assays.","date":"2026","source":"Methods in molecular biology (Clifton, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/41111109","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7268,"output_tokens":1075,"usd":0.018964,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7589,"output_tokens":1683,"usd":0.04001,"stage2_stop_reason":"end_turn"},"total_usd":0.058974,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2026,\n      \"finding\": \"The NSMCE1/NSMCE3 subcomplex of SMC5/6 is sufficient to inhibit HBV transcription in vitro, independently of the full holo-complex, as measured by a luciferase reporter in a cell-free expression system with purified subcomplexes.\",\n      \"method\": \"Cell-free transcription assay with purified NSMCE1/3 subcomplex and luciferase reporter\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution with purified subcomplex, single lab, single study\",\n      \"pmids\": [\"41825673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NSMCE1/NSMCE3 overexpression causes degradation of HBx protein via a ubiquitin-independent proteasomal mechanism: the effect is blocked by a proteasome inhibitor but not by an E1 ubiquitin-activating enzyme inhibitor, and NSMCE1/3 interacts with the 20S proteasome without stimulating HBx ubiquitination.\",\n      \"method\": \"Cycloheximide chase, proteasome inhibitor treatment, E1 inhibitor treatment, Co-immunoprecipitation with 20S proteasome, ubiquitination assay\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, chase assay, inhibitor experiments) in a single lab study\",\n      \"pmids\": [\"41825673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NSMCE1/NSMCE3 represses HBx expression at both the mRNA and protein level, and overexpression of NSMCE1/3 inhibits HBV proliferation in hepatoma cell lines, while knockdown of NSMCE3 promotes HBV proliferation.\",\n      \"method\": \"RT-PCR, cycloheximide chase, overexpression and knockdown in hepatoma cell lines with HBV proliferation readout\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with defined cellular phenotype, multiple readouts, single lab\",\n      \"pmids\": [\"41825673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Nsmce1 overexpression in mouse hippocampal neuronal cells (HT-22) inhibits expression of AD marker genes App, Bace2, and Mapt, and promotes cell proliferation; knockdown of Nsmce1 has the opposite effects. Nsmce1 overexpression also increases alternative splicing complexity, with events enriched in the ubiquitin-mediated proteolysis pathway.\",\n      \"method\": \"Overexpression and knockdown in HT-22 cells, RT-PCR/qPCR for marker genes, cell proliferation assay, RNA-seq transcriptomics\",\n      \"journal\": \"Functional & integrative genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — gain- and loss-of-function with gene expression and proliferation readouts, no pathway placement or direct molecular mechanism, single lab\",\n      \"pmids\": [\"31792732\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NSMCE1 is a subunit of the SMC5/6 complex whose NSMCE1/NSMCE3 subcomplex is sufficient to inhibit HBV transcription in vitro and to promote ubiquitin-independent proteasomal degradation of the viral HBx protein through interaction with the 20S proteasome; in neuronal cells, NSMCE1 also participates in genome integrity maintenance and modulates ubiquitin-mediated proteolysis and alternative splicing pathways.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NSMCE1 is a subunit of the SMC5/6 genome-integrity complex that, together with NSMCE3, forms a subcomplex with antiviral activity against hepatitis B virus [#0, #2]. The purified NSMCE1/NSMCE3 subcomplex is sufficient to inhibit HBV transcription in a cell-free reporter assay, acting independently of the full holo-complex [#0]. NSMCE1/NSMCE3 additionally drives degradation of the viral HBx protein through a ubiquitin-independent route: degradation requires proteasome activity but not E1 ubiquitin-activating enzyme function, and the subcomplex physically associates with the 20S proteasome without stimulating HBx ubiquitination [#1]. Through these combined transcriptional and post-translational effects, NSMCE1/NSMCE3 represses HBx at the mRNA and protein level and restricts HBV proliferation in hepatoma cells, whereas NSMCE3 knockdown enhances viral proliferation [#2]. In mouse hippocampal neuronal cells, Nsmce1 modulates expression of Alzheimer's disease marker genes and reshapes alternative splicing toward the ubiquitin-mediated proteolysis pathway [#3]. Beyond these findings, the molecular basis of NSMCE1's contribution to the intact SMC5/6 complex has not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Established the first cellular phenotype for NSMCE1 outside canonical genome maintenance, linking it to neuronal gene-expression control and splicing regulation.\",\n      \"evidence\": \"Overexpression and knockdown in HT-22 hippocampal cells with marker-gene qPCR, proliferation assays, and RNA-seq\",\n      \"pmids\": [\"31792732\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct molecular mechanism or pathway placement for the splicing/proteolysis effects\",\n        \"AD marker-gene changes are correlative, not mechanistically connected to NSMCE1 activity\",\n        \"Single lab, single cell line\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed that the NSMCE1/NSMCE3 subcomplex alone is sufficient to repress HBV transcription, decoupling this antiviral function from the full SMC5/6 holo-complex.\",\n      \"evidence\": \"Cell-free transcription assay with purified NSMCE1/3 subcomplex and luciferase reporter\",\n      \"pmids\": [\"41825673\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"In vitro reconstitution only; not validated in chromatinized cellular HBV context\",\n        \"Mechanism of transcriptional repression unresolved\",\n        \"Single study, single lab\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined a ubiquitin-independent proteasomal pathway by which NSMCE1/NSMCE3 degrades the viral HBx protein and restricts HBV proliferation.\",\n      \"evidence\": \"Cycloheximide chase, proteasome and E1 inhibitor treatments, 20S proteasome Co-IP and ubiquitination assays, plus gain/loss-of-function in hepatoma cells\",\n      \"pmids\": [\"41825673\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis of NSMCE1/3 binding to the 20S proteasome unknown\",\n        \"How HBx is targeted to the proteasome without ubiquitination is unresolved\",\n        \"Reciprocal validation of the 20S interaction not described\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NSMCE1's antiviral and proteasome-directing activities relate to its role within the intact SMC5/6 complex and to genome integrity remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural or biochemical characterization of NSMCE1 within full SMC5/6 in this corpus\",\n        \"Connection between neuronal splicing/proteolysis role and antiviral role unestablished\",\n        \"No in vivo evidence for the antiviral mechanism\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"complexes\": [\"SMC5/6 complex\", \"NSMCE1/NSMCE3 subcomplex\"],\n    \"partners\": [\"NSMCE3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"loss","faith_supported":5,"faith_total":5,"faith_pct":100.0}}