Affinage

LUC7L2

Putative RNA-binding protein Luc7-like 2 · UniProt Q9Y383

Length
392 aa
Mass
46.5 kDa
Annotated
2026-06-10
27 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2007 Medium

    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

    PMID:17656373

    Open questions at the time
    • 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
  2. 2021 High

    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

    PMID:33852859 PMID:33852893

    Open questions at the time
    • Structural basis of weak 5'SS recognition not resolved
    • How splicing changes mechanistically rewire respiratory supercomplex assembly not detailed
  3. 2021 High

    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

    PMID:34155193

    Open questions at the time
    • Determinants directing LUC7L2 to MITA intron 3 specifically not mapped
    • Whether the same mechanism applies to other immune transcripts unknown
  4. 2024 Medium

    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

    PMID:38477507

    Open questions at the time
    • Single-lab study not independently replicated
    • Direct LUC7L2 binding to MLH1 pre-mRNA not demonstrated
  5. 2024 Medium

    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

    PMID:38719745

    Open questions at the time
    • Single-organism (yeast) genetics; direct biochemical demonstration in human spliceosomes absent
    • Structural details of ZnF2-5'SS contact not resolved
  6. 2025 High

    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

    PMID:39979239

    Open questions at the time
    • Co-crystal/structural basis of asymmetric consensus recognition not determined
    • Quantitative contribution of each paralog to genome-wide 5'SS choice not fully mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 3 GO:0140098 catalytic activity, acting on RNA 3
Localization
GO:0005654 nucleoplasm 1
Pathway
R-HSA-8953854 Metabolism of RNA 3
Partners
LUC7LLUC7L3SCNM1SQSTM1U1 SNRNAU1-70K
Complex memberships
U1 snRNP

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 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. Genetic loss-of-function (knockdown/knockout) combined with transcriptome and metabolic analyses; genome-scale screen for OXPHOS-increasing genes Molecular cell High 33852893
2021 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. Protein interaction assays (co-IP/pulldown), RNA crosslinking studies, siRNA knockdown with RNA-seq for alternative splicing analysis Cell reports High 33852859
2021 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. 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 Cell discovery High 34155193
2024 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). CUT&Tag (H3K9 lactylation at LUC7L2 promoter), SLAM-seq, RNA-seq, multi-omics analysis; functional validation in TMZ-resistant GBM cells and in vivo Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 38477507
2025 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. Splice site mutagenesis, domain-swapping between LUC7 paralogs, transcriptome analysis in human cell lines and leukemias with LUC7L2 copy number variation, Arabidopsis mutant analysis Nature communications High 39979239
2007 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. Yeast two-hybrid screen, co-localization by immunofluorescence in mammalian cells Human molecular genetics Medium 17656373
2024 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. Reporter assays, transcriptome analysis, yeast genetic interactions (suppressor assay), domain humanization in S. cerevisiae RNA (New York, N.Y.) Medium 38719745
2021 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. CRISPR/Cas9 genome-wide screen, immunoprecipitation (LUC7L2-SQSTM1), knockdown with autophagy flux assay and clonogenic survival after IR Cell death discovery Low 34907164
2024 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. Overexpression and knockdown in liver cancer cells, ChIP (H3K4me3 and RNAPolII at RRAS promoter), xenograft transplantation, rescue experiment (LUC7L2 OE + RRAS KD) Cells & development Low 39571735

Source papers

Stage 0 corpus · 27 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2024 Histone H3K9 Lactylation Confers Temozolomide Resistance in Glioblastoma via LUC7L2-Mediated MLH1 Intron Retention. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 133 38477507
2019 Genetic abnormalities and pathophysiology of MDS. International journal of clinical oncology 80 31093808
2021 Loss of LUC7L2 and U1 snRNP subunits shifts energy metabolism from glycolysis to OXPHOS. Molecular cell 77 33852893
2019 Mutations in Splicing Factor Genes in Myeloid Malignancies: Significance and Impact on Clinical Features. Cancers 68 31766606
2021 Functional analyses of human LUC7-like proteins involved in splicing regulation and myeloid neoplasms. Cell reports 47 33852859
2007 Evidence for a direct role of the disease modifier SCNM1 in splicing. Human molecular genetics 37 17656373
2016 Concurrent detection of targeted copy number variants and mutations using a myeloid malignancy next generation sequencing panel allows comprehensive genetic analysis using a single testing strategy. British journal of haematology 25 26728869
2014 Hydrochlorothiazide-induced hyperuricaemia in the pharmacogenomic evaluation of antihypertensive responses study. Journal of internal medicine 24 24612202
2023 Mapping the landscape of genetic dependencies in chordoma. Nature communications 22 37024492
2019 Distinct and convergent consequences of splice factor mutations in myelodysplastic syndromes. American journal of hematology 20 31680297
2021 The RNA-binding protein LUC7L2 mediates MITA/STING intron retention to negatively regulate innate antiviral response. Cell discovery 19 34155193
2022 The significance of CUX1 and chromosome 7 in myeloid malignancies. Current opinion in hematology 17 35084368
2021 CRISPR/Cas9 genome-wide screening identifies LUC7L2 that promotes radioresistance via autophagy in nasopharyngeal carcinoma cells. Cell death discovery 15 34907164
2025 LUC7 proteins define two major classes of 5' splice sites in animals and plants. Nature communications 10 39979239
2024 Biological relevance of alternative splicing in hematologic malignancies. Molecular medicine (Cambridge, Mass.) 8 38760666
2023 A molecular study of pediatric pilomyxoid and pilocytic astrocytomas: Genome-wide copy number screening, retrospective analysis of clinicopathological features and long-term clinical outcome. Frontiers in oncology 8 36860324
2022 Cytogenetic and Genetic Abnormalities with Diagnostic Value in Myelodysplastic Syndromes (MDS): Focus on the Pre-Messenger RNA Splicing Process. Diagnostics (Basel, Switzerland) 8 35885562
2025 Inhibition of lactylation by LRP1 expression increases the risk of intervertebral disc degeneration: A multi-omics summary-based Mendelian randomization analysis. Medicine 3 40988222
2024 A Gene Cluster of Mitochondrial Complexes Contributes to the Cognitive Decline of COVID-19 Infection. Molecular neurobiology 3 39271627
2024 Functional analysis of the zinc finger modules of the Saccharomyces cerevisiae splicing factor Luc7. RNA (New York, N.Y.) 2 38719745
2019 [Genetic defects of chromosome 5q and 7q in myeloid neoplasms]. [Rinsho ketsueki] The Japanese journal of clinical hematology 2 31391370
2026 Novel LUC7L::NUTM1 fusion in PDGFRA-rearranged myeloproliferative neoplasm with eosinophilia: a case report. World journal of surgical oncology 0 41814313
2026 The molecular landscape of the C1498 murine acute myeloid leukemia cell line. Biomarker research 0 41964082
2026 CircRAD18 promotes glioblastoma proliferation, migration and invasion via the miR‑1231/LUC7L2 axis. International journal of molecular medicine 0 42138196
2025 Genomic Insights into Blood Pressure Regulation: Exploring Ion Channel and Transporter Gene Variations in Jordanian Hypertensive Individuals. Medicina (Kaunas, Lithuania) 0 39859138
2024 Functional Analysis of the Zinc Finger Modules of the S. cerevisiae Splicing Factor Luc7. bioRxiv : the preprint server for biology 0 38352541
2024 LUC7L2 accelerates the growth of liver cancer cells by enhancing DNA damage repair via RRAS. Cells & development 0 39571735

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