{"gene":"LUC7L2","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2021,"finding":"LUC7L2 represses OXPHOS and promotes glycolysis by multiple mechanisms: (1) splicing of glycolytic enzyme PFKM to suppress glycogen synthesis, (2) splicing of cystine/glutamate antiporter SLC7A11 (xCT) to suppress glutamate oxidation, and (3) secondary repression of mitochondrial respiratory supercomplex formation. Loss of LUC7L2 shifts energy metabolism from glycolysis to OXPHOS.","method":"Genetic loss-of-function (knockdown/knockout) combined with transcriptome and metabolic analyses; genome-scale screen for OXPHOS-increasing genes","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal mechanisms identified by KO with defined metabolic phenotypes, splicing targets validated, replicated finding consistent with parallel paper (PMID:33852859)","pmids":["33852893"],"is_preprint":false},{"year":2021,"finding":"LUC7L2 (and LUC7L3) crosslinks to weak 5' splice sites and to the 5' end of U1 snRNA, establishing an evolutionarily conserved role in 5' splice site selection. All three human LUC7 paralogs bind similar core but distinct regulatory splicing factors, mediated through their divergent arginine-serine-rich (RS) domains absent in yeast Luc7p. Knockdown of LUC7L2 upregulates spliceosomal factors and downregulates glycolysis genes.","method":"Protein interaction assays (co-IP/pulldown), RNA crosslinking studies, siRNA knockdown with RNA-seq for alternative splicing analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNA crosslinking to U1 snRNA and 5'SS established by direct binding assays; knockdown splicing phenotypes; replicated across labs with PMID:33852893 and PMID:39979239","pmids":["33852859"],"is_preprint":false},{"year":2021,"finding":"LUC7L2 directly binds intron 3 of MITA/STING precursor mRNA, inhibits its splicing, and promotes nonsense-mediated decay, leading to reduced MITA protein levels and dampened innate antiviral response. LUC7L2-deficient mice show resistance to lethal HSV-1 infection and reduced viral loads in brain. LUC7L2 is induced following HSV-1 infection, constituting a negative feedback loop.","method":"RNA-binding protein assay (direct binding to MITA pre-mRNA intron 3), LUC7L2 knockout mice with HSV-1 infection model, RNA splicing analysis, protein level measurement","journal":"Cell discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct RNA binding demonstrated, knockout mouse model with defined viral infection phenotype, mechanistic pathway from binding to NMD to protein downregulation established","pmids":["34155193"],"is_preprint":false},{"year":2024,"finding":"LUC7L2 mediates intron 7 retention of MLH1, reducing MLH1 expression and inhibiting mismatch repair (MMR), leading to temozolomide resistance in glioblastoma. Histone H3K9 lactylation activates LUC7L2 transcription by enrichment at its promoter (shown by CUT&Tag), which in turn drives MLH1 intron retention (shown by SLAM-seq and RNA-seq).","method":"CUT&Tag (H3K9 lactylation at LUC7L2 promoter), SLAM-seq, RNA-seq, multi-omics analysis; functional validation in TMZ-resistant GBM cells and in vivo","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple omics methods in single lab, clear mechanistic chain from H3K9la → LUC7L2 expression → MLH1 intron retention → MMR inhibition, but not independently replicated","pmids":["38477507"],"is_preprint":false},{"year":2025,"finding":"LUC7L2 (and LUC7L) specifically enhance splicing of 'right-handed' 5' splice sites with stronger consensus matching on the intron side of the /GU dinucleotide, while LUC7L3 enhances 'left-handed' 5'SS with stronger consensus upstream of the /GU. This 5'SS class-specific regulation was validated by splice site mutagenesis and by domain-swapping experiments between human LUC7 paralogs. The LUC7L2/LUC7L3 subfamilies evolved before the animal-plant split, and plant LUC7 orthologs show similar specificity.","method":"Splice site mutagenesis, domain-swapping between LUC7 paralogs, transcriptome analysis in human cell lines and leukemias with LUC7L2 copy number variation, Arabidopsis mutant analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of splice sites and domain swapping validate model; confirmed across human cells, leukemia samples, and plant orthologs; multiple orthogonal methods","pmids":["39979239"],"is_preprint":false},{"year":2007,"finding":"LUC7L2 interacts with the disease modifier SCNM1 in a yeast two-hybrid screen; this interaction requires the acidic C-terminal domain of SCNM1. LUC7L2 co-localizes with U1-70K in nuclear speckles in mammalian cells, suggesting a function with SCNM1 in recognition of weak splice donor sites.","method":"Yeast two-hybrid screen, co-localization by immunofluorescence in mammalian cells","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid and co-localization by imaging; interaction domain mapping provides moderate mechanistic detail; not confirmed by Co-IP","pmids":["17656373"],"is_preprint":false},{"year":2024,"finding":"The second zinc finger (ZnF2) domain of yeast Luc7 (ortholog of LUC7L2) plays a role in splice site selection; humanization of ZnF2 to mirror LUC7L or LUC7L2 alters usage of nonconsensus 5' splice sites. Humanized Luc7 can suppress mutation of ATPase Prp28 (involved in U1 release and U6 exchange at the 5'SS), indicating the ZnF domain influences ATPase requirements for U1 snRNP release.","method":"Reporter assays, transcriptome analysis, yeast genetic interactions (suppressor assay), domain humanization in S. cerevisiae","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (suppressor of Prp28 mutation), reporter assays, and transcriptome analysis in yeast; single lab, multiple methods","pmids":["38719745"],"is_preprint":false},{"year":2021,"finding":"LUC7L2 knockdown in NPC radioresistant cells led to reduction of SQSTM1 (p62) expression and enhancement of autophagy, sensitizing cells to ionizing radiation. Immunoprecipitation identified SQSTM1 as a binding partner of LUC7L2.","method":"CRISPR/Cas9 genome-wide screen, immunoprecipitation (LUC7L2-SQSTM1), knockdown with autophagy flux assay and clonogenic survival after IR","journal":"Cell death discovery","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP identifying SQSTM1 as binding partner; functional link to autophagy via knockdown phenotype, but mechanism is not fully resolved and single lab","pmids":["34907164"],"is_preprint":false},{"year":2024,"finding":"LUC7L2 promotes liver cancer cell proliferation and DNA damage repair via RRAS. LUC7L2 enhances H3K4me3 and RNA Pol II occupancy on the RRAS promoter, increasing RRAS expression. The DNA damage repair enhancement by LUC7L2 was abolished by RRAS knockdown, indicating RRAS dependence. RRAS increases DNA damage repair via H3K36me3-dependent mechanisms.","method":"Overexpression and knockdown in liver cancer cells, ChIP (H3K4me3 and RNAPolII at RRAS promoter), xenograft transplantation, rescue experiment (LUC7L2 OE + RRAS KD)","journal":"Cells & development","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, ChIP showing promoter occupancy changes, rescue epistasis experiment; mechanism linking splicing factor to epigenetic regulation is atypical and not independently replicated","pmids":["39571735"],"is_preprint":false}],"current_model":"LUC7L2 is a U1 snRNP-associated RNA splicing factor that selectively enhances splicing of 'right-handed' 5' splice sites through its second zinc finger domain; it regulates cellular energy metabolism by promoting glycolysis and repressing OXPHOS via splicing of PFKM and SLC7A11; it dampens innate antiviral immunity by binding MITA/STING pre-mRNA intron 3 to promote intron retention and nonsense-mediated decay; and it can be transcriptionally activated by histone H3K9 lactylation to drive MLH1 intron retention and suppress mismatch repair."},"narrative":{"mechanistic_narrative":"LUC7L2 is a U1 snRNP-associated splicing factor that controls 5' splice site selection and, through its splicing output, governs cellular energy metabolism, innate antiviral signaling, and DNA repair [PMID:33852893, PMID:33852859, PMID:39979239]. It crosslinks directly to weak 5' splice sites and to the 5' end of U1 snRNA, and its second zinc-finger (ZnF2) domain confers class-specific splice-site preference: LUC7L2 selectively enhances splicing of 'right-handed' 5' splice sites bearing stronger consensus on the intronic side of the /GU dinucleotide, a specificity validated by splice-site mutagenesis and paralog domain swapping and conserved from animals to plants [PMID:33852859, PMID:39979239]. ZnF2 acts at the step of U1 snRNP release, influencing the ATPase (Prp28) requirement for U1 displacement and U6 exchange at the 5' splice site [PMID:38719745]. Through this activity LUC7L2 represses oxidative phosphorylation and promotes glycolysis, in part by directing splicing of the glycolytic enzyme PFKM and the cystine/glutamate antiporter SLC7A11, with its loss shifting metabolism toward OXPHOS [PMID:33852893]. LUC7L2 also dampens innate antiviral immunity by binding intron 3 of MITA/STING pre-mRNA, inhibiting its splicing and triggering nonsense-mediated decay to lower MITA protein, such that LUC7L2-deficient mice resist lethal HSV-1 infection [PMID:34155193]. In glioblastoma, LUC7L2 is transcriptionally activated by histone H3K9 lactylation at its promoter and drives MLH1 intron 7 retention to suppress mismatch repair and confer temozolomide resistance [PMID:38477507].","teleology":[{"year":2007,"claim":"Established the first physical and spatial context for LUC7L2 as a splicing-associated factor, linking it to recognition of weak splice donor sites.","evidence":"Yeast two-hybrid screen identifying SCNM1 interaction and immunofluorescence co-localization with U1-70K in nuclear speckles","pmids":["17656373"],"confidence":"Medium","gaps":["Interaction not confirmed by Co-IP in mammalian cells","No direct demonstration of splice-site activity at this stage","Functional consequence of the SCNM1 interaction not defined"]},{"year":2021,"claim":"Defined LUC7L2 as a direct 5' splice site recognition factor and revealed its broad control over energy metabolism, answering what the protein binds and what its splicing output does to cell physiology.","evidence":"RNA crosslinking to U1 snRNA and weak 5'SS, co-IP of LUC7 paralog interactomes, and loss-of-function with RNA-seq and metabolic profiling (including a genome-scale OXPHOS screen) identifying PFKM and SLC7A11 splicing targets","pmids":["33852859","33852893"],"confidence":"High","gaps":["Structural basis of weak 5'SS recognition not resolved","How splicing changes mechanistically rewire respiratory supercomplex assembly not detailed"]},{"year":2021,"claim":"Extended LUC7L2 function beyond metabolism to innate immunity, showing that its splicing activity can silence a target gene by coupling intron retention to NMD.","evidence":"Direct RNA-binding assay to MITA pre-mRNA intron 3, splicing/NMD analysis, and LUC7L2-knockout mice in an HSV-1 infection model","pmids":["34155193"],"confidence":"High","gaps":["Determinants directing LUC7L2 to MITA intron 3 specifically not mapped","Whether the same mechanism applies to other immune transcripts unknown"]},{"year":2024,"claim":"Connected LUC7L2 to a metabolic-epigenetic input and a DNA-repair output, showing how its expression is induced and how it can suppress mismatch repair.","evidence":"CUT&Tag for H3K9 lactylation at the LUC7L2 promoter, SLAM-seq and RNA-seq for MLH1 intron retention, with functional validation in TMZ-resistant glioblastoma in vivo","pmids":["38477507"],"confidence":"Medium","gaps":["Single-lab study not independently replicated","Direct LUC7L2 binding to MLH1 pre-mRNA not demonstrated"]},{"year":2024,"claim":"Provided the mechanistic step at which the LUC7 zinc-finger acts, placing ZnF2 at the point of U1 snRNP release during 5'SS selection.","evidence":"Domain humanization of yeast Luc7 ZnF2, reporter assays, transcriptome analysis, and genetic suppression of a Prp28 ATPase mutation in S. cerevisiae","pmids":["38719745"],"confidence":"Medium","gaps":["Single-organism (yeast) genetics; direct biochemical demonstration in human spliceosomes absent","Structural details of ZnF2-5'SS contact not resolved"]},{"year":2025,"claim":"Resolved the precise sequence logic of LUC7 paralog specificity, distinguishing LUC7L2/LUC7L 'right-handed' from LUC7L3 'left-handed' 5'SS preference and tracing its deep evolutionary conservation.","evidence":"Splice-site mutagenesis, paralog domain-swapping, transcriptome analysis across human cells and leukemias with LUC7L2 copy-number variation, and Arabidopsis ortholog analysis","pmids":["39979239"],"confidence":"High","gaps":["Co-crystal/structural basis of asymmetric consensus recognition not determined","Quantitative contribution of each paralog to genome-wide 5'SS choice not fully mapped"]},{"year":null,"claim":"How LUC7L2's single 5'SS-selection activity is integrated across its distinct metabolic, immune, and DNA-repair target sets — and the structural basis of its splice-site discrimination — remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of LUC7L2 bound to a 5'SS or U1 snRNA","Reported epigenetic/promoter-occupancy roles (RRAS, MLH1) sit awkwardly with a core splicing function and need orthogonal validation","SQSTM1 binding and autophagy link rest on a single Co-IP and knockdown phenotype"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[1,2,4]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,1,4]}],"localization":[{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,4]}],"complexes":["U1 snRNP"],"partners":["U1 SNRNA","LUC7L3","LUC7L","SCNM1","U1-70K","SQSTM1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y383","full_name":"Putative RNA-binding protein Luc7-like 2","aliases":[],"length_aa":392,"mass_kda":46.5,"function":"May bind to RNA via its Arg/Ser-rich domain","subcellular_location":"Nucleus speckle; Nucleus, nucleoplasm","url":"https://www.uniprot.org/uniprotkb/Q9Y383/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LUC7L2","classification":"Not Classified","n_dependent_lines":264,"n_total_lines":1208,"dependency_fraction":0.2185430463576159},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2},{"gene":"SCYL1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/LUC7L2","total_profiled":1310},"omim":[{"mim_id":"613056","title":"LUC7-LIKE 2 PRE-mRNA SPLICING FACTOR; LUC7L2","url":"https://www.omim.org/entry/613056"},{"mim_id":"608095","title":"SODIUM CHANNEL MODIFIER 1; SCNM1","url":"https://www.omim.org/entry/608095"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LUC7L2"},"hgnc":{"alias_symbol":["CGI-74","CGI-59","H_NH0792N18.3","FLJ10657","LUC7B2","hLuc7B2"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y383","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y383","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y383-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y383-F1-predicted_aligned_error_v6.png","plddt_mean":66.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LUC7L2","jax_strain_url":"https://www.jax.org/strain/search?query=LUC7L2"},"sequence":{"accession":"Q9Y383","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y383.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y383/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y383"}},"corpus_meta":[{"pmid":"38477507","id":"PMC_38477507","title":"Histone H3K9 Lactylation Confers Temozolomide Resistance in Glioblastoma via LUC7L2-Mediated MLH1 Intron Retention.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/38477507","citation_count":133,"is_preprint":false},{"pmid":"31093808","id":"PMC_31093808","title":"Genetic abnormalities and pathophysiology of MDS.","date":"2019","source":"International journal of clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31093808","citation_count":80,"is_preprint":false},{"pmid":"33852893","id":"PMC_33852893","title":"Loss of LUC7L2 and U1 snRNP subunits shifts energy metabolism from glycolysis to OXPHOS.","date":"2021","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/33852893","citation_count":77,"is_preprint":false},{"pmid":"31766606","id":"PMC_31766606","title":"Mutations in Splicing Factor Genes in Myeloid Malignancies: Significance and Impact on Clinical 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haematology","url":"https://pubmed.ncbi.nlm.nih.gov/26728869","citation_count":25,"is_preprint":false},{"pmid":"24612202","id":"PMC_24612202","title":"Hydrochlorothiazide-induced hyperuricaemia in the pharmacogenomic evaluation of antihypertensive responses study.","date":"2014","source":"Journal of internal medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24612202","citation_count":24,"is_preprint":false},{"pmid":"37024492","id":"PMC_37024492","title":"Mapping the landscape of genetic dependencies in chordoma.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37024492","citation_count":22,"is_preprint":false},{"pmid":"31680297","id":"PMC_31680297","title":"Distinct and convergent consequences of splice factor mutations in myelodysplastic syndromes.","date":"2019","source":"American journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/31680297","citation_count":20,"is_preprint":false},{"pmid":"34155193","id":"PMC_34155193","title":"The RNA-binding protein LUC7L2 mediates MITA/STING intron retention to negatively regulate innate antiviral response.","date":"2021","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/34155193","citation_count":19,"is_preprint":false},{"pmid":"35084368","id":"PMC_35084368","title":"The significance of CUX1 and chromosome 7 in myeloid malignancies.","date":"2022","source":"Current opinion in hematology","url":"https://pubmed.ncbi.nlm.nih.gov/35084368","citation_count":17,"is_preprint":false},{"pmid":"34907164","id":"PMC_34907164","title":"CRISPR/Cas9 genome-wide screening identifies LUC7L2 that promotes radioresistance via autophagy in nasopharyngeal carcinoma cells.","date":"2021","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/34907164","citation_count":15,"is_preprint":false},{"pmid":"39979239","id":"PMC_39979239","title":"LUC7 proteins define two major classes of 5' splice sites in animals and plants.","date":"2025","source":"Nature 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research","url":"https://pubmed.ncbi.nlm.nih.gov/41964082","citation_count":0,"is_preprint":false},{"pmid":"41814313","id":"PMC_41814313","title":"Novel LUC7L::NUTM1 fusion in PDGFRA-rearranged myeloproliferative neoplasm with eosinophilia: a case report.","date":"2026","source":"World journal of surgical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41814313","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15911,"output_tokens":2705,"usd":0.044154,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9951,"output_tokens":2877,"usd":0.06084,"stage2_stop_reason":"end_turn"},"total_usd":0.104994,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"LUC7L2 represses OXPHOS and promotes glycolysis by multiple mechanisms: (1) splicing of glycolytic enzyme PFKM to suppress glycogen synthesis, (2) splicing of cystine/glutamate antiporter SLC7A11 (xCT) to suppress glutamate oxidation, and (3) secondary repression of mitochondrial respiratory supercomplex formation. Loss of LUC7L2 shifts energy metabolism from glycolysis to OXPHOS.\",\n      \"method\": \"Genetic loss-of-function (knockdown/knockout) combined with transcriptome and metabolic analyses; genome-scale screen for OXPHOS-increasing genes\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal mechanisms identified by KO with defined metabolic phenotypes, splicing targets validated, replicated finding consistent with parallel paper (PMID:33852859)\",\n      \"pmids\": [\"33852893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LUC7L2 (and LUC7L3) crosslinks to weak 5' splice sites and to the 5' end of U1 snRNA, establishing an evolutionarily conserved role in 5' splice site selection. All three human LUC7 paralogs bind similar core but distinct regulatory splicing factors, mediated through their divergent arginine-serine-rich (RS) domains absent in yeast Luc7p. Knockdown of LUC7L2 upregulates spliceosomal factors and downregulates glycolysis genes.\",\n      \"method\": \"Protein interaction assays (co-IP/pulldown), RNA crosslinking studies, siRNA knockdown with RNA-seq for alternative splicing analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNA crosslinking to U1 snRNA and 5'SS established by direct binding assays; knockdown splicing phenotypes; replicated across labs with PMID:33852893 and PMID:39979239\",\n      \"pmids\": [\"33852859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LUC7L2 directly binds intron 3 of MITA/STING precursor mRNA, inhibits its splicing, and promotes nonsense-mediated decay, leading to reduced MITA protein levels and dampened innate antiviral response. LUC7L2-deficient mice show resistance to lethal HSV-1 infection and reduced viral loads in brain. LUC7L2 is induced following HSV-1 infection, constituting a negative feedback loop.\",\n      \"method\": \"RNA-binding protein assay (direct binding to MITA pre-mRNA intron 3), LUC7L2 knockout mice with HSV-1 infection model, RNA splicing analysis, protein level measurement\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct RNA binding demonstrated, knockout mouse model with defined viral infection phenotype, mechanistic pathway from binding to NMD to protein downregulation established\",\n      \"pmids\": [\"34155193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LUC7L2 mediates intron 7 retention of MLH1, reducing MLH1 expression and inhibiting mismatch repair (MMR), leading to temozolomide resistance in glioblastoma. Histone H3K9 lactylation activates LUC7L2 transcription by enrichment at its promoter (shown by CUT&Tag), which in turn drives MLH1 intron retention (shown by SLAM-seq and RNA-seq).\",\n      \"method\": \"CUT&Tag (H3K9 lactylation at LUC7L2 promoter), SLAM-seq, RNA-seq, multi-omics analysis; functional validation in TMZ-resistant GBM cells and in vivo\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple omics methods in single lab, clear mechanistic chain from H3K9la → LUC7L2 expression → MLH1 intron retention → MMR inhibition, but not independently replicated\",\n      \"pmids\": [\"38477507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LUC7L2 (and LUC7L) specifically enhance splicing of 'right-handed' 5' splice sites with stronger consensus matching on the intron side of the /GU dinucleotide, while LUC7L3 enhances 'left-handed' 5'SS with stronger consensus upstream of the /GU. This 5'SS class-specific regulation was validated by splice site mutagenesis and by domain-swapping experiments between human LUC7 paralogs. The LUC7L2/LUC7L3 subfamilies evolved before the animal-plant split, and plant LUC7 orthologs show similar specificity.\",\n      \"method\": \"Splice site mutagenesis, domain-swapping between LUC7 paralogs, transcriptome analysis in human cell lines and leukemias with LUC7L2 copy number variation, Arabidopsis mutant analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of splice sites and domain swapping validate model; confirmed across human cells, leukemia samples, and plant orthologs; multiple orthogonal methods\",\n      \"pmids\": [\"39979239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"LUC7L2 interacts with the disease modifier SCNM1 in a yeast two-hybrid screen; this interaction requires the acidic C-terminal domain of SCNM1. LUC7L2 co-localizes with U1-70K in nuclear speckles in mammalian cells, suggesting a function with SCNM1 in recognition of weak splice donor sites.\",\n      \"method\": \"Yeast two-hybrid screen, co-localization by immunofluorescence in mammalian cells\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid and co-localization by imaging; interaction domain mapping provides moderate mechanistic detail; not confirmed by Co-IP\",\n      \"pmids\": [\"17656373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The second zinc finger (ZnF2) domain of yeast Luc7 (ortholog of LUC7L2) plays a role in splice site selection; humanization of ZnF2 to mirror LUC7L or LUC7L2 alters usage of nonconsensus 5' splice sites. Humanized Luc7 can suppress mutation of ATPase Prp28 (involved in U1 release and U6 exchange at the 5'SS), indicating the ZnF domain influences ATPase requirements for U1 snRNP release.\",\n      \"method\": \"Reporter assays, transcriptome analysis, yeast genetic interactions (suppressor assay), domain humanization in S. cerevisiae\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (suppressor of Prp28 mutation), reporter assays, and transcriptome analysis in yeast; single lab, multiple methods\",\n      \"pmids\": [\"38719745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LUC7L2 knockdown in NPC radioresistant cells led to reduction of SQSTM1 (p62) expression and enhancement of autophagy, sensitizing cells to ionizing radiation. Immunoprecipitation identified SQSTM1 as a binding partner of LUC7L2.\",\n      \"method\": \"CRISPR/Cas9 genome-wide screen, immunoprecipitation (LUC7L2-SQSTM1), knockdown with autophagy flux assay and clonogenic survival after IR\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP identifying SQSTM1 as binding partner; functional link to autophagy via knockdown phenotype, but mechanism is not fully resolved and single lab\",\n      \"pmids\": [\"34907164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LUC7L2 promotes liver cancer cell proliferation and DNA damage repair via RRAS. LUC7L2 enhances H3K4me3 and RNA Pol II occupancy on the RRAS promoter, increasing RRAS expression. The DNA damage repair enhancement by LUC7L2 was abolished by RRAS knockdown, indicating RRAS dependence. RRAS increases DNA damage repair via H3K36me3-dependent mechanisms.\",\n      \"method\": \"Overexpression and knockdown in liver cancer cells, ChIP (H3K4me3 and RNAPolII at RRAS promoter), xenograft transplantation, rescue experiment (LUC7L2 OE + RRAS KD)\",\n      \"journal\": \"Cells & development\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, ChIP showing promoter occupancy changes, rescue epistasis experiment; mechanism linking splicing factor to epigenetic regulation is atypical and not independently replicated\",\n      \"pmids\": [\"39571735\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LUC7L2 is a U1 snRNP-associated RNA splicing factor that selectively enhances splicing of 'right-handed' 5' splice sites through its second zinc finger domain; it regulates cellular energy metabolism by promoting glycolysis and repressing OXPHOS via splicing of PFKM and SLC7A11; it dampens innate antiviral immunity by binding MITA/STING pre-mRNA intron 3 to promote intron retention and nonsense-mediated decay; and it can be transcriptionally activated by histone H3K9 lactylation to drive MLH1 intron retention and suppress mismatch repair.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LUC7L2 is a U1 snRNP-associated splicing factor that controls 5' splice site selection and, through its splicing output, governs cellular energy metabolism, innate antiviral signaling, and DNA repair [#0, #1, #4]. It crosslinks directly to weak 5' splice sites and to the 5' end of U1 snRNA, and its second zinc-finger (ZnF2) domain confers class-specific splice-site preference: LUC7L2 selectively enhances splicing of 'right-handed' 5' splice sites bearing stronger consensus on the intronic side of the /GU dinucleotide, a specificity validated by splice-site mutagenesis and paralog domain swapping and conserved from animals to plants [#1, #4]. ZnF2 acts at the step of U1 snRNP release, influencing the ATPase (Prp28) requirement for U1 displacement and U6 exchange at the 5' splice site [#6]. Through this activity LUC7L2 represses oxidative phosphorylation and promotes glycolysis, in part by directing splicing of the glycolytic enzyme PFKM and the cystine/glutamate antiporter SLC7A11, with its loss shifting metabolism toward OXPHOS [#0]. LUC7L2 also dampens innate antiviral immunity by binding intron 3 of MITA/STING pre-mRNA, inhibiting its splicing and triggering nonsense-mediated decay to lower MITA protein, such that LUC7L2-deficient mice resist lethal HSV-1 infection [#2]. In glioblastoma, LUC7L2 is transcriptionally activated by histone H3K9 lactylation at its promoter and drives MLH1 intron 7 retention to suppress mismatch repair and confer temozolomide resistance [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established the first physical and spatial context for LUC7L2 as a splicing-associated factor, linking it to recognition of weak splice donor sites.\",\n      \"evidence\": \"Yeast two-hybrid screen identifying SCNM1 interaction and immunofluorescence co-localization with U1-70K in nuclear speckles\",\n      \"pmids\": [\"17656373\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Interaction not confirmed by Co-IP in mammalian cells\",\n        \"No direct demonstration of splice-site activity at this stage\",\n        \"Functional consequence of the SCNM1 interaction not defined\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined LUC7L2 as a direct 5' splice site recognition factor and revealed its broad control over energy metabolism, answering what the protein binds and what its splicing output does to cell physiology.\",\n      \"evidence\": \"RNA crosslinking to U1 snRNA and weak 5'SS, co-IP of LUC7 paralog interactomes, and loss-of-function with RNA-seq and metabolic profiling (including a genome-scale OXPHOS screen) identifying PFKM and SLC7A11 splicing targets\",\n      \"pmids\": [\"33852859\", \"33852893\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Structural basis of weak 5'SS recognition not resolved\",\n        \"How splicing changes mechanistically rewire respiratory supercomplex assembly not detailed\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended LUC7L2 function beyond metabolism to innate immunity, showing that its splicing activity can silence a target gene by coupling intron retention to NMD.\",\n      \"evidence\": \"Direct RNA-binding assay to MITA pre-mRNA intron 3, splicing/NMD analysis, and LUC7L2-knockout mice in an HSV-1 infection model\",\n      \"pmids\": [\"34155193\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Determinants directing LUC7L2 to MITA intron 3 specifically not mapped\",\n        \"Whether the same mechanism applies to other immune transcripts unknown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected LUC7L2 to a metabolic-epigenetic input and a DNA-repair output, showing how its expression is induced and how it can suppress mismatch repair.\",\n      \"evidence\": \"CUT&Tag for H3K9 lactylation at the LUC7L2 promoter, SLAM-seq and RNA-seq for MLH1 intron retention, with functional validation in TMZ-resistant glioblastoma in vivo\",\n      \"pmids\": [\"38477507\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Single-lab study not independently replicated\",\n        \"Direct LUC7L2 binding to MLH1 pre-mRNA not demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided the mechanistic step at which the LUC7 zinc-finger acts, placing ZnF2 at the point of U1 snRNP release during 5'SS selection.\",\n      \"evidence\": \"Domain humanization of yeast Luc7 ZnF2, reporter assays, transcriptome analysis, and genetic suppression of a Prp28 ATPase mutation in S. cerevisiae\",\n      \"pmids\": [\"38719745\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Single-organism (yeast) genetics; direct biochemical demonstration in human spliceosomes absent\",\n        \"Structural details of ZnF2-5'SS contact not resolved\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the precise sequence logic of LUC7 paralog specificity, distinguishing LUC7L2/LUC7L 'right-handed' from LUC7L3 'left-handed' 5'SS preference and tracing its deep evolutionary conservation.\",\n      \"evidence\": \"Splice-site mutagenesis, paralog domain-swapping, transcriptome analysis across human cells and leukemias with LUC7L2 copy-number variation, and Arabidopsis ortholog analysis\",\n      \"pmids\": [\"39979239\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Co-crystal/structural basis of asymmetric consensus recognition not determined\",\n        \"Quantitative contribution of each paralog to genome-wide 5'SS choice not fully mapped\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LUC7L2's single 5'SS-selection activity is integrated across its distinct metabolic, immune, and DNA-repair target sets — and the structural basis of its splice-site discrimination — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"No high-resolution structure of LUC7L2 bound to a 5'SS or U1 snRNA\",\n        \"Reported epigenetic/promoter-occupancy roles (RRAS, MLH1) sit awkwardly with a core splicing function and need orthogonal validation\",\n        \"SQSTM1 binding and autophagy link rest on a single Co-IP and knockdown phenotype\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1, 2, 4]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"complexes\": [\n      \"U1 snRNP\"\n    ],\n    \"partners\": [\n      \"U1 snRNA\",\n      \"LUC7L3\",\n      \"LUC7L\",\n      \"SCNM1\",\n      \"U1-70K\",\n      \"SQSTM1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}