{"gene":"SND1","run_date":"2026-06-10T07:46:37","timeline":{"discoveries":[{"year":2014,"finding":"Crystal structure of the MTDH-SND1 complex was determined at high resolution, revealing that an 11-residue MTDH peptide motif occupies an extended groove between SND1's SN1 and SN2 domains, with two MTDH tryptophan residues nestled into two well-defined pockets in SND1. Mutagenesis of both tryptophan-binding pockets disrupted MTDH-SND1 interaction and impaired their roles in breast cancer and SND1 stability under stress.","method":"X-ray crystallography, mutagenesis, functional cancer cell assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure combined with mutagenesis and functional validation in cancer cells in a single rigorous study","pmids":["25242325"],"is_preprint":false},{"year":2014,"finding":"MTDH interacts with and stabilizes SND1; disrupting the MTDH-SND1 interaction (by silencing either protein or disrupting their binding) compromises tumor-initiating cell survival and tumorigenesis in multiple mouse mammary tumor models, establishing that MTDH supports cell survival under oncogenic/stress conditions through SND1 stabilization.","method":"Co-immunoprecipitation, mouse genetic tumor models, knockdown/disruption studies with in vivo xenograft/tumor assays","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus multiple mouse cancer models across oncogene subtypes, replicated in clinical breast cancer samples","pmids":["24981741"],"is_preprint":false},{"year":2011,"finding":"SND1 was identified as an MTDH-interacting protein by mass spectrometry-based screen and confirmed by co-immunoprecipitation. SND1 promotes lung metastasis, resistance to apoptosis, and regulates expression of metastasis- and chemoresistance-associated genes in breast cancer cells.","method":"Mass spectrometry pulldown, co-immunoprecipitation, loss-of-function (knockdown) with metastasis assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS identification confirmed by Co-IP, single lab, functional knockdown with defined metastasis phenotype","pmids":["21478147"],"is_preprint":false},{"year":2019,"finding":"SND1 functions as an m6A RNA reader: it binds m6A-modified hairpin in KSHV ORF50 RNA, stabilizes the ORF50 transcript, and is essential for KSHV lytic replication. RIP-seq and eCLIP characterization confirmed SND1 as a transcriptome-wide m6A reader.","method":"RIP-seq, eCLIP, RNA immunoprecipitation, m6A-modified RNA binding assays, SND1 depletion with viral replication readout","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal biochemical methods (RIP-seq, eCLIP, direct m6A-modified RNA binding), functional viral replication phenotype upon SND1 depletion","pmids":["31647415"],"is_preprint":false},{"year":2023,"finding":"SND1 binds the 5' end of SARS-CoV-2 negative-sense viral RNA and is required for viral RNA synthesis. SND1 interacts directly with the viral RNA-binding protein NSP9 and remodels NSP9 occupancy, altering covalent NSP9 linkage to initiating nucleotides at replication-transcription initiation sites.","method":"Biochemical fractionation of viral RNA-bound proteins, SND1 depletion with viral RNA synthesis and growth kinetics readout, Co-IP with NSP9, covalent RNA-protein linkage mapping","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (RNA binding, Co-IP, covalent linkage mapping, replication organelle imaging) in a single rigorous study","pmids":["37794589"],"is_preprint":false},{"year":2012,"finding":"SND1 promotes tumor angiogenesis in hepatocellular carcinoma through a linear pathway: SND1 activates NF-κB, which induces miR-221, which in turn induces angiogenic factors Angiogenin and CXCL16. Inhibition of any component in this cascade blocked SND1-induced angiogenesis.","method":"Stable SND1 overexpression/knockdown in HCC cells, CAM assay, HUVEC differentiation assay, reporter and pathway inhibitor experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistatic pathway dissection via stable gain/loss-of-function and inhibitor rescue, single lab, two orthogonal angiogenesis assays","pmids":["22396537"],"is_preprint":false},{"year":2015,"finding":"SND1 expression is transcriptionally activated by the TGFβ1/Smad2/Smad3 complex binding to Smad-specific recognition motifs (RD motifs) in the SND1 promoter. SND1 in turn promotes Smurf1 expression, leading to RhoA ubiquitination and degradation, disrupting F-actin organization and increasing breast cancer cell migration, invasion, and metastasis.","method":"Promoter analysis (luciferase, EMSA, ChIP), Smad complex gain/loss-of-function, RhoA ubiquitination assay, cell migration/invasion assays, in vivo metastasis models","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (EMSA, ChIP, ubiquitination assay, in vivo metastasis), single lab","pmids":["25596283"],"is_preprint":false},{"year":2017,"finding":"SND1 directly binds to conserved motifs (motifs 1 and 2) in the promoter regions of Smad2/3/4 genes, recruits the histone acetyltransferase GCN5 through its Tudor domain, increases H3K9 acetylation, and thereby activates Smad2/3/4 transcription to enhance TGFβ1 signaling and breast cancer metastasis.","method":"EMSA, GST pulldown (Tudor domain requirement), ChIP, loss-of-function assays, phospho-Smad readout","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — EMSA and GST pulldown identify domain and DNA binding, ChIP validates in-cell recruitment, single lab","pmids":["28263968"],"is_preprint":false},{"year":2013,"finding":"SND1 interacts with SAM68 (identified by mass spectrometry) and together they promote inclusion of CD44 variable exons in prostate cancer cells. SND1 recruits SAM68 and spliceosomal components to CD44 pre-mRNA; the effect of SND1 on CD44 splicing required SAM68 and intact SAM68-binding sites in the pre-mRNA.","method":"Mass spectrometry, co-immunoprecipitation, SAM68 knockdown epistasis, RT-PCR splicing assays, mutation of SAM68-binding sites in pre-mRNA","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, MS identification, epistatic SAM68 knockdown plus pre-mRNA mutation, single lab","pmids":["23995791"],"is_preprint":false},{"year":2016,"finding":"SND1 interacts with monoglyceride lipase (MGLL), identified by modified yeast two-hybrid and confirmed by co-immunoprecipitation; this interaction results in ubiquitination and proteasomal degradation of MGLL, suppressing its tumor-suppressive function in hepatocellular carcinoma.","method":"Yeast two-hybrid, co-immunoprecipitation, ubiquitination assay, MGLL overexpression rescue, in vivo xenograft","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP and ubiquitination assay, single lab","pmids":["26997225"],"is_preprint":false},{"year":2021,"finding":"The MTDH-SND1 complex suppresses antitumor T cell responses by binding to and destabilizing Tap1/Tap2 mRNAs, reducing antigen presentation machinery components. Pharmacological disruption of the MTDH-SND1 complex with compound C26-A6 enhanced tumor antigen presentation and CD8+ T cell infiltration.","method":"Genetic and pharmacological disruption of MTDH-SND1 complex, mRNA stability assays for Tap1/Tap2, in vivo immunological readouts (T cell infiltration, antigen presentation)","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic disruption plus pharmacological inhibitor in multiple preclinical models with mechanistic mRNA destabilization readout, replicated across approaches","pmids":["35121988"],"is_preprint":false},{"year":2021,"finding":"Genetic ablation of Mtdh in mice inhibits breast cancer development through disruption of the MTDH-SND1 interaction, establishing that the interaction is required to sustain breast cancer progression. Small-molecule inhibitors C26-A2 and C26-A6 disrupting this protein-protein interaction suppressed tumor growth, metastasis, and enhanced chemotherapy sensitivity.","method":"Genetically modified mice (Mtdh ablation), small-molecule compound screen against MTDH-SND1 PPI, in vitro and in vivo TNBC preclinical models","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — mouse genetic ablation plus orthogonal pharmacological disruption with multiple in vivo cancer models, replicated across studies","pmids":["35121987"],"is_preprint":false},{"year":2020,"finding":"SND1 is an ER membrane-associated protein: its N-terminal peptide associates with SEC61A anchored on the ER membrane. The SN domain of SND1 catches nascent MHC-I heavy chain and guides it to ER-associated degradation (ERAD), thereby impairing normal MHC-I assembly and antigen presentation, enabling immune evasion by tumor cells.","method":"Subcellular fractionation, co-immunoprecipitation (SND1-SEC61A, SND1-MHC-I heavy chain), ERAD pathway assays, SND1 deletion in syngeneic mouse tumor models with CD8+ T cell readout","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple Co-IPs, ER localization confirmed by fractionation, in vivo mouse models with OT-I transgenic validation, mechanistic ERAD pathway characterization","pmids":["32917674"],"is_preprint":false},{"year":2022,"finding":"Mitochondrion-localized SND1 (via N-terminal amino acids 1–63 as a mitochondrial targeting sequence imported via TOM70) interacts with PGAM5 in mitochondria, promoting PGAM5-DRP1 binding and mitophagy, which supports liver cancer cell proliferation and tumor growth.","method":"Organelle subcellular isolation, immunoprecipitation-mass spectrometry, domain deletion (MTS mutants), Co-IP, in vitro and in vivo tumor models","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS confirmed by Co-IP, MTS domain deletion, organelle fractionation in multiple cell lines, single lab","pmids":["35433434"],"is_preprint":false},{"year":2007,"finding":"SND1 functions as a component of RISC and overexpression in colon cancer cells causes downregulation of APC protein without altering APC mRNA levels, and alters E-cadherin distribution from membrane to cytoplasm. Stable Snd1 overexpression in IEC6 cells promotes loss of contact inhibition and cell growth.","method":"Stable overexpression in intestinal epithelial cells, immunohistochemistry, Western blot (APC protein vs. mRNA), cell proliferation assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — stable overexpression with specific molecular (APC protein vs. mRNA, E-cadherin redistribution) and cellular phenotype readouts, single lab","pmids":["17909068"],"is_preprint":false},{"year":2012,"finding":"SND1-BRAF chromosomal rearrangement (7q32-7q34) produces a constitutively active SND1-BRAF fusion protein that hyperactivates the MAPK pathway (ERK), conferring resistance to c-Met inhibitor in gastric cancer cells. Combination with RAF or MEK inhibitor overcame resistance.","method":"Chromosomal rearrangement characterization, functional expression of SND1-BRAF fusion, ERK phosphorylation assays, inhibitor combination studies","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — fusion protein expressed and tested with pathway readout and pharmacological rescue, single lab","pmids":["22745804"],"is_preprint":false},{"year":2013,"finding":"SND1 interacts with and regulates processing of miR-17-92a cluster: SND1 binds pre-miR-92a and all mature miR-17-92a members (identified by RNA pulldown and mass spectrometry), and SND1 silencing resolves a hypoxia-induced block in miRNA processing, increasing mature miRNA levels.","method":"RNA pulldown, mass spectrometry, SND1 knockdown, miRNA processing Northern/qPCR assays under hypoxic conditions","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA pulldown with MS confirmation, knockdown epistasis on miRNA processing, single lab","pmids":["23770094"],"is_preprint":false},{"year":2010,"finding":"SND1 (SND p102) colocalizes with endoplasmic reticulum and Golgi markers by sucrose gradient fractionation, and under steatogenic conditions translocates to and associates specifically with low-density lipid droplets in hepatocytes, as confirmed by both gradient fractionation and confocal microscopy.","method":"Sucrose gradient fractionation, confocal microscopy, oleate treatment of HepG2 cells","journal":"Journal of physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal localization methods (fractionation + confocal), single lab, functional implication for lipid droplet targeting","pmids":["20414760"],"is_preprint":false},{"year":2015,"finding":"SND1 increases AT1R mRNA stability, resulting in elevated AT1R protein levels, which activates ERK and Smad2 and consequently the TGFβ signaling pathway, promoting EMT, migration, and invasion in hepatocellular carcinoma cells.","method":"mRNA stability assays, Western blot for ERK/Smad2 phosphorylation, SND1 overexpression/knockdown, migration/invasion assays","journal":"FEBS open bio","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — mRNA stability measured with multiple signaling readouts, single lab, no direct RNA binding confirmation shown in abstract","pmids":["24918049"],"is_preprint":false},{"year":2019,"finding":"SND1 acts upstream of SLUG to promote EMT: SND1 recruits acetyltransferases GCN5 and CBP/p300 to the SLUG promoter, increasing chromatin accessibility and activating SLUG transcription; SLUG then regulates N-CAD, VIM, E-CAD, and CLDN1 expression to promote EMT in ovarian cancer cells.","method":"ChIP, gene expression profiling, SND1 loss-of-function, co-activator recruitment assays, invasion/migration assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating co-activator recruitment to SLUG promoter, loss-of-function epistasis with SLUG, single lab","pmids":["30509125"],"is_preprint":false},{"year":2012,"finding":"The SND1 gene promoter is regulated by NF-κB, Sp1, and NF-Y transcription factors. EMSA and ChIP confirmed direct binding of these factors to specific sites in the SND1 proximal promoter; mutation of CCAAT/GC boxes and NF-κB elements substantially reduced SND1 promoter activity. TNF-α-induced upregulation of SND1 is mediated at least in part via NF-κB.","method":"EMSA, ChIP, luciferase reporter assays with deletion analysis and site-directed mutagenesis","journal":"Biochimie","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — EMSA and ChIP with mutagenesis validation, single lab, multiple orthogonal promoter assays","pmids":["23160072"],"is_preprint":false},{"year":2015,"finding":"SND1 occupies 645 gene promoters in HepG2 cells under basal conditions and 281 additional promoters upon TNFα treatment, as determined by ChIP-chip. SND1 deficiency compromises glycerolipid gene reprogramming and lipid phenotypic responses to TNFα.","method":"ChIP-chip, transcription factor binding site analysis, SND1 knockdown with lipid metabolism readout","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-chip with 21 individual gene validations, functional knockdown readout, single lab","pmids":["26323317"],"is_preprint":false},{"year":2017,"finding":"SREBP-2 directly binds to SRE and E-box motifs in the SND1 proximal promoter to activate SND1 transcription, as shown by ChIP and site-directed mutagenesis. SREBP-1c/1a binds the SRE element and represses SND1 transcription. SREBP-2 activating conditions (simvastatin, lipoprotein-deficient medium) increase SND1 mRNA and promoter activity.","method":"ChIP, luciferase reporter assays, site-directed mutagenesis, SREBP overexpression and siRNA knockdown","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — ChIP with mutagenesis and functional reporter validation, single lab","pmids":["29296233"],"is_preprint":false},{"year":2017,"finding":"SND1 localizes to stress granules under heat shock, and this recruitment requires intact microtubule cytoskeleton tracks; nocodazole-mediated microtubule depolymerization significantly impairs SND1 granule assembly during heat shock. SND1 granules co-localize with α-tubulin microtubules.","method":"Immunofluorescence live-cell imaging, nocodazole treatment, heat shock assay, co-localization analysis","journal":"Anatomical record","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct imaging plus pharmacological disruption of cytoskeleton with functional assembly readout, single lab","pmids":["28758359"],"is_preprint":false},{"year":2019,"finding":"PIM1 kinase directly binds and phosphorylates SND1; decreased SND1 expression leads to upregulation of senescence-associated secretory phenotype (SASP), and SND1 is involved in PIM1-mediated cellular senescence.","method":"Silver staining/LC-MS/MS identification of PIM1-interacting proteins, Co-IP, immunofluorescence, Western blot, cell proliferation assays","journal":"Medical science monitor","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and phosphorylation asserted but specific phosphorylation site or kinase assay not detailed in abstract; single lab, single approach","pmids":["31860636"],"is_preprint":false},{"year":2021,"finding":"SND1 Tudor domain interacts with ERG (an ETS-domain transcription factor overexpressed in prostate cancer); ERG promotes nuclear localization of the SND1/MTDH complex; forced nuclear localization of SND1 prominently increases its growth-promoting function; prostate-specific Snd1 deletion reduces cancer growth in PB-Cre/Ptenflox/flox/ERG mice.","method":"Co-immunoprecipitation (Tudor domain), domain-specific interaction mapping, nuclear localization forced-expression experiments, Snd1 conditional knockout mouse prostate cancer model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain-resolved Co-IP, conditional mouse KO cancer model, nuclear localization functional experiments, transcriptomic overlap, multiple orthogonal methods","pmids":["37973913"],"is_preprint":false},{"year":2022,"finding":"SND1 binds to the 3' UTR of GPX4 mRNA and stabilizes it; knockdown of SND1 in bladder cancer cells promotes ferroptosis by destabilizing GPX4 mRNA, overcoming cisplatin resistance.","method":"ChIP and dual-luciferase assay for SND1-GPX4 mRNA 3'UTR binding, RNA interference, ferroptosis assays (ROS, iron, GSH, MDA), GPX4 overexpression rescue","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA binding assay plus rescue experiments, single lab, two orthogonal assays","pmids":["36453257"],"is_preprint":false},{"year":2022,"finding":"SND1 destabilizes HSPA5 mRNA by binding to its 3'UTR, leading to reduced HSPA5 protein, which in turn reduces GPX4 expression (since HSPA5 protein directly stabilizes GPX4), ultimately promoting ferroptosis in osteoarthritis chondrocytes.","method":"RNA binding (3'UTR binding assay), mRNA stability assay, Co-IP for HSPA5-GPX4 interaction, SND1 knockdown in vivo (rat OA model), IL-1β-stimulated chondrocyte model","journal":"Inflammation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA binding, protein-protein Co-IP, in vivo validation in OA model, single lab with multiple orthogonal methods","pmids":["35320827"],"is_preprint":false},{"year":2024,"finding":"KDM6A interacts with SND1 (interaction enhanced by KDM6A SUMOylation at K90); the KDM6A-SND1 complex protects nascent DNA by recruiting RPA and Ku70, preventing replication fork collapse. Loss of KDM6A or SND1 increases H3K9ac and H4K8ac but attenuates Ku70 and H3K4me3 at nascent DNA, enhancing genotoxin sensitivity.","method":"Co-IP, nascent DNA chromatin analysis (Ku70/RPA enrichment), histone modification ChIP, KDM6A mutation analysis, genotoxin sensitivity assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with mutation mapping plus chromatin analysis of nascent DNA, single lab, multiple orthogonal methods","pmids":["38850159"],"is_preprint":false},{"year":2024,"finding":"In vascular smooth muscle cells, ELK1 transcription factor binds the Snd1 promoter to activate its transcription upon PDGF stimulation. Upregulated SND1 then competes with myocardin for SRF binding and recruits KAT2B (histone acetyltransferase) to SRF target gene promoters, increasing histone acetylation and promoting SRF-driven transcription of proliferation- and migration-related genes, thereby inducing neointimal hyperplasia. SMC-specific Snd1 knockout mice showed reduced neointimal hyperplasia.","method":"ChIP, Co-IP (SND1-SRF interaction), chromatin accessibility/histone acetylation assays, SMC-specific conditional Snd1 knockout mice, wire-injury vascular model","journal":"Cellular and molecular life sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — SMC-specific KO mouse model with vascular phenotype, ChIP, Co-IP, and histone modification assays establishing the ELK1-SND1-SRF pathway in vivo and in vitro","pmids":["38279051"],"is_preprint":false},{"year":2025,"finding":"SND1 translational repression is mediated by the mTORC1/4E-BP1 pathway under sunitinib stress in endothelial cells. SND1 transcriptionally regulates UBE2N, an E2-conjugating enzyme mediating K63-linked ubiquitination; UBE2N, together with E3 ligases RNF8 and RNF168, mediates the DNA damage repair response that protects endothelial cells from sunitinib-induced dysfunction.","method":"Ribosome profiling (translational control mapping), mTORC1/4E-BP1 pathway modulation, SND1 OE/knockdown, UBE2N downstream identification, DNA damage repair assays, in vitro and in vivo vascular dysfunction models","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ribosome profiling plus mTORC1 pathway modulation, SND1-UBE2N transcriptional axis with DNA repair readout, in vivo validation, single lab","pmids":["39895626"],"is_preprint":false},{"year":2023,"finding":"SND1 binds to and stabilizes lncTCF7, and together SND1 and lncTCF7 are required for recruitment of the SWI/SNF chromatin remodeling complex to the TCF7 promoter to activate TCF7 transcription. The SND1-binding region maps to the 3'-end of lncTCF7.","method":"RNA pulldown, quantitative mass spectrometry, knockdown epistasis, ChIP (SND1, SWI/SNF recruitment), structural probing of lncTCF7 subdomains","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA pulldown with MS, ChIP, knockdown epistasis with two orthogonal methods, single lab","pmids":["39169000"],"is_preprint":false},{"year":2025,"finding":"USP37 is the deubiquitinase of SND1, stabilizing SND1 protein. CDK1 phosphorylates USP37 at threonine 631 (not serine 628), enhancing USP37 deubiquitinase activity and thereby stabilizing SND1 to drive colorectal cancer progression. Dacarbazine was identified as a pharmacological inhibitor of USP37 that disrupts SND1 stability.","method":"Proteomics, ubiquitinomics, interactomics (MS-based), CDK1 phosphorylation site mapping (T631 vs S628 mutagenesis), USP37 deubiquitinase activity assay, in vivo CRC models","journal":"Acta pharmaceutica sinica. B","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphorylation site mutagenesis (T631 vs S628), deubiquitinase activity assay, proteomics confirmation, single lab","pmids":["40486858"],"is_preprint":false},{"year":2021,"finding":"SPT6 interacts with SND1 to co-activate hTERT expression and promote colon cancer cell proliferation, stemness, and growth in vitro and in vivo. SPT6 was identified by pull-down/mass spectrometry as a protein binding the hTERT promoter.","method":"Pulldown/mass spectrometry, SPT6-SND1 interaction confirmed, hTERT promoter reporter assays, in vitro and xenograft in vivo models","journal":"Molecular oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — MS pulldown, functional co-activation, but interaction details (Co-IP validation) not detailed in abstract; single lab","pmids":["33305480"],"is_preprint":false},{"year":2023,"finding":"SNAI3-AS1 competitively binds SND1 and perturbs m6A-dependent recognition of Nrf2 mRNA 3'UTR by SND1, reducing Nrf2 mRNA stability and sensitizing glioma cells to ferroptosis.","method":"RNA pulldown, RIP, MeRIP, dual-luciferase reporter assay, gain/loss-of-function rescue experiments","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple RNA binding assays (pulldown, RIP, MeRIP) with functional rescue experiments, single lab","pmids":["37202791"],"is_preprint":false},{"year":2023,"finding":"SND1 co-activates HIF1α as a transcriptional co-activator, regulating downstream EZH2 transcription, and thereby promotes PyMT-induced breast tumor initiation and expansion of tumor-initiating cells.","method":"SND1 knockout in PyMT mouse model, histological and cytometric analysis, mechanistic co-activator assays (SND1-HIF1α interaction and EZH2 transcription readout)","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mouse KO tumor model with defined cellular phenotype, mechanistic HIF1α co-activation pathway established, single lab","pmids":["37622244"],"is_preprint":false},{"year":2022,"finding":"N-glycosylation of SND1 at Asn50 is required for its folding and stability; mutation of Asn50 destabilizes SND1 and leads to its ER-associated degradation, inhibiting glioma cell proliferation and metastasis.","method":"Site-directed mutagenesis of four N-glycosylation sites (N50, N168, N283, N416), Western blot, ERAD pathway assays, cell proliferation and invasion assays","journal":"Journal of immunology research","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — site-directed mutagenesis establishing site-specific glycosylation with functional and ERAD readout, single lab","pmids":["36213325"],"is_preprint":false},{"year":2024,"finding":"PIM1-catalyzed phosphorylation of SND1 at serine 426 strengthens SND1-SMARCA5 interaction; this interaction mediates SND1's regulation of chromatin dynamics and transcriptional activation of CUX1 oncogene, promoting ESCC progression. Disruption of S426 phosphorylation impaired SND1-SMARCA5 interaction and inhibited ESCC tumor growth in vivo.","method":"PIM1 phosphorylation assay (S426 site-directed mutagenesis), Co-IP (SND1-SMARCA5), ChIP (histone modification, RNA polymerase II), in vivo tumor models","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphorylation site mutagenesis, Co-IP, chromatin assays, in vivo model, single lab","pmids":["39725102"],"is_preprint":false},{"year":2025,"finding":"SREBF1 binds the SND1 gene promoter and activates its transcription; SND1 then forms a complex with MTDH that directly binds and degrades SESN2 mRNA, activating mTOR signaling and promoting prostate cancer progression. Disruption of the MTDH-SND1 interaction with C26-A6 inhibited SESN2 mRNA degradation.","method":"ChIP, dual-luciferase reporter assay, DNA pulldown, RIP-seq and RNA pulldown (SESN2 mRNA binding), pharmacological disruption (C26-A6), in vitro and xenograft models","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for promoter binding, RIP-seq for mRNA target, pharmacological disruption with rescue, single lab","pmids":["40775338"],"is_preprint":false},{"year":2021,"finding":"In SND1 knockout mice, dendritic cells show lower costimulatory molecule expression and IL-12 production and higher IL-10 production; adoptive transfer of SND1-KO DCs failed to protect against chlamydial challenge infection and showed reduced ability to promote Th1 responses. This establishes SND1 as required for normal DC function in promoting Th1/17 immunity.","method":"SND1 knockout mouse model, DC isolation and functional assays, DC-T cell co-culture, adoptive DC transfer, in vivo chlamydial lung infection model","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — SND1 KO mouse with defined immunological phenotype, multiple functional DC assays, adoptive transfer epistasis, single lab","pmids":["33635920"],"is_preprint":false},{"year":2023,"finding":"The SN domain of SND1 interacts with MHC-I heavy chain at K490-containing sites (as determined by structure-based virtual screening and docking analysis); EGC (-)-Epigallocatechin prevents SND1-MHC-I binding by altering the spatial conformation of SND1 at this site, restoring MHC-I surface presentation and CD8+ T cell responses.","method":"Structure-based virtual screening, molecular docking, EGC treatment with MHC-I surface expression readout, in vivo melanoma mouse model, CD8+ T cell functional assays","journal":"Cancer letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — docking-guided inhibitor and cell/in vivo functional readout but direct binding confirmation by biochemical assay not detailed; single lab","pmids":["38710299"],"is_preprint":false}],"current_model":"SND1 is a multifunctional nuclear/cytoplasmic/ER/mitochondrial protein that acts as: (1) a transcriptional co-activator recruiting histone acetyltransferases (GCN5, CBP/p300, KAT2B) to target promoters including Smad2/3/4, SLUG, SRF-target genes, and hTERT; (2) an RNA-binding protein and m6A reader that stabilizes or destabilizes specific mRNAs (e.g., AT1R, GPX4, Tap1/Tap2, SESN2) and modulates miRNA processing; (3) a structural component of RISC; (4) an ER membrane-associated protein (via SEC61A) that redirects nascent MHC-I heavy chain to ERAD to suppress antigen presentation; (5) a mitochondrially-imported protein (via N-terminal MTS/TOM70) that promotes PGAM5-mediated mitophagy; and (6) a scaffold that stabilizes its oncogenic partner MTDH (and the interaction surface is defined by crystal structure showing MTDH tryptophan residues in SND1's SN1/2 groove), with the MTDH-SND1 complex degrading tumor-suppressor mRNAs and driving breast and prostate cancer progression — all of which are regulated by post-translational modifications including PIM1/CDK1-mediated phosphorylation (S426), USP37-mediated deubiquitination, and N-glycosylation at Asn50."},"narrative":{"mechanistic_narrative":"SND1 is a multifunctional staphylococcal-nuclease-domain protein that couples RNA metabolism, chromatin-based transcriptional co-activation, and protein turnover to drive cancer progression and tissue remodeling [PMID:28263968, PMID:37973913]. As a transcriptional co-activator it binds defined promoter motifs and recruits histone acetyltransferases — GCN5 to Smad2/3/4 promoters via its Tudor domain to amplify TGF-β1 signaling [PMID:28263968], GCN5 and CBP/p300 to the SLUG promoter to drive EMT [PMID:30509125], and KAT2B to SRF target genes where it competes with myocardin to promote vascular smooth-muscle proliferation [PMID:38279051]; it likewise co-activates HIF1α/EZH2 in tumor-initiating cells [PMID:37622244]. As an RNA-binding protein and m6A reader it determines the fate of specific transcripts, stabilizing GPX4 and AT1R mRNAs and m6A-modified viral and Nrf2 RNAs while destabilizing HSPA5, with these activities controlling ferroptosis sensitivity and TGFβ/ERK signaling [PMID:31647415, PMID:24918049, PMID:36453257, PMID:35320827, PMID:37202791]. SND1 is most prominently a scaffold for the oncoprotein MTDH: an 11-residue MTDH motif inserts two tryptophan residues into pockets of the SND1 SN1/SN2 groove, and this interaction stabilizes SND1, is required to sustain breast cancer, and forms an MTDH-SND1 complex that destabilizes tumor-suppressor and antigen-presentation mRNAs (Tap1/Tap2, SESN2) [PMID:25242325, PMID:24981741, PMID:35121988, PMID:40775338]. SND1 additionally evades immune detection at the ER, where its N-terminus associates with SEC61A and its SN domain diverts nascent MHC-I heavy chain to ERAD [PMID:32917674], and it localizes to mitochondria via an N-terminal targeting sequence to promote PGAM5-dependent mitophagy [PMID:35433434]. SND1 activity and abundance are tuned by PIM1/CDK1-driven phosphorylation, USP37-mediated deubiquitination, and N-glycosylation at Asn50 [PMID:40486858, PMID:36213325, PMID:39725102]. Genetically, an SND1-BRAF fusion produces a constitutively active MAPK-driving oncoprotein [PMID:22745804], and SND1 is required for dendritic-cell-driven Th1 immunity in vivo [PMID:33635920].","teleology":[{"year":2007,"claim":"Established that SND1 overexpression has oncogenic potential and acts post-transcriptionally, by downregulating APC protein without changing its mRNA and redistributing E-cadherin in intestinal epithelial cells.","evidence":"stable overexpression in IEC6/colon cancer cells with APC protein-vs-mRNA Western blots and proliferation assays","pmids":["17909068"],"confidence":"Medium","gaps":["mechanism of APC protein loss without mRNA change not resolved","RISC component role asserted but not biochemically dissected"]},{"year":2011,"claim":"Identified SND1 as a physical MTDH partner and a driver of metastasis and chemoresistance, opening the MTDH-SND1 oncogenic axis.","evidence":"mass spectrometry pulldown and Co-IP with knockdown metastasis assays in breast cancer cells","pmids":["21478147"],"confidence":"Medium","gaps":["interaction interface unknown at this stage","downstream mRNA targets of the complex not yet defined"]},{"year":2012,"claim":"Mapped SND1 into discrete signaling and oncogenic outputs — an NF-κB/miR-221/angiogenic-factor cascade in HCC and a constitutively active SND1-BRAF fusion driving MAPK and inhibitor resistance.","evidence":"gain/loss-of-function with angiogenesis assays and pathway inhibitors; SND1-BRAF fusion expression with ERK readout and inhibitor combinations","pmids":["22396537","22745804"],"confidence":"Medium","gaps":["whether SND1 directly activates NF-κB or acts indirectly unresolved","SND1-BRAF fusion is a rearrangement-specific event, not general SND1 function"]},{"year":2012,"claim":"Defined how SND1 expression itself is controlled, showing its promoter is bound and regulated by NF-κB, Sp1 and NF-Y and induced by TNF-α.","evidence":"EMSA, ChIP, luciferase reporters with deletion and site-directed mutagenesis","pmids":["23160072"],"confidence":"Medium","gaps":["physiological stimuli engaging each factor not fully mapped"]},{"year":2013,"claim":"Revealed SND1 roles in RNA processing — promoting CD44 alternative splicing via SAM68 and binding/regulating miR-17-92a cluster processing under hypoxia.","evidence":"MS, Co-IP, SAM68 knockdown epistasis and pre-mRNA mutation; RNA pulldown/MS and knockdown miRNA processing assays","pmids":["23995791","23770094"],"confidence":"Medium","gaps":["direct RNA-binding determinants on SND1 not defined","generality of miRNA processing role beyond hypoxia unknown"]},{"year":2014,"claim":"Solved the structural and functional basis of the MTDH-SND1 interaction, showing two MTDH tryptophans dock into SN1/SN2 pockets and that MTDH stabilizes SND1 to sustain tumor-initiating cell survival in vivo.","evidence":"X-ray crystallography with pocket mutagenesis; Co-IP and multiple mouse mammary tumor models","pmids":["25242325","24981741"],"confidence":"High","gaps":["structure does not define the complex's RNA-degrading active mechanism","stabilization mechanism (which ubiquitin machinery is countered) not identified here"]},{"year":2015,"claim":"Established SND1 as a TGFβ-induced effector and an mRNA-stability regulator, being activated by Smad2/3 and in turn promoting Smurf1-mediated RhoA degradation and stabilizing AT1R mRNA to amplify TGFβ/ERK signaling.","evidence":"promoter ChIP/EMSA, RhoA ubiquitination, mRNA stability assays and metastasis models","pmids":["25596283","24918049"],"confidence":"Medium","gaps":["direct SND1 binding to AT1R mRNA not shown","feedforward loop with TGFβ not quantified in vivo"]},{"year":2015,"claim":"Defined SND1 as a chromatin-associated factor on a genome scale, occupying hundreds of promoters and reprogramming glycerolipid gene expression in response to TNFα.","evidence":"ChIP-chip with TNFα stimulation and lipid metabolism knockdown readouts","pmids":["26323317"],"confidence":"Medium","gaps":["direct vs indirect promoter occupancy not distinguished for all loci","co-activator partners at most promoters unidentified"]},{"year":2017,"claim":"Mechanistically defined SND1 as a Tudor-domain co-activator that recruits GCN5 to Smad2/3/4 promoters and increases H3K9 acetylation, linking its DNA binding to chromatin modification.","evidence":"EMSA, GST pulldown for Tudor requirement, ChIP and phospho-Smad readouts","pmids":["28263968"],"confidence":"Medium","gaps":["whether Tudor domain reads a histone or protein mark to recruit GCN5 not resolved"]},{"year":2017,"claim":"Connected SND1 to lipid/metabolic transcriptional control and stress-granule biology, showing SREBP-2 activates and SREBP-1 represses its promoter, and SND1 assembles into microtubule-dependent stress granules under heat shock.","evidence":"ChIP/reporter mutagenesis with SREBP modulation; live-cell imaging with nocodazole disruption","pmids":["29296233","28758359"],"confidence":"Medium","gaps":["functional consequence of stress-granule recruitment unknown","metabolic feedback between SREBP and SND1 not closed"]},{"year":2019,"claim":"Broadened the co-activator model to EMT by showing SND1 recruits GCN5 and CBP/p300 to the SLUG promoter, and linked SND1 to PIM1-mediated phosphorylation and senescence.","evidence":"ChIP, co-activator recruitment and invasion assays; LC-MS/MS, Co-IP and senescence (SASP) readouts","pmids":["30509125","31860636"],"confidence":"Medium","gaps":["PIM1 phosphorylation site not defined in this study (Low confidence)","SLUG co-activation generality across tumor types untested"]},{"year":2020,"claim":"Revealed an ER-membrane function for SND1: anchored via SEC61A, its SN domain diverts nascent MHC-I heavy chain to ERAD, providing a direct mechanism for tumor immune evasion.","evidence":"fractionation, Co-IP (SEC61A, MHC-I), ERAD assays and syngeneic mouse tumor models with CD8+ T-cell readout","pmids":["32917674"],"confidence":"High","gaps":["selectivity determinants for MHC-I substrate engagement not defined","balance between ER and nuclear pools not quantified"]},{"year":2021,"claim":"Validated the MTDH-SND1 interaction as a therapeutic target across breast cancer and immune evasion, showing complex disruption destabilizes Tap1/Tap2 mRNA, enhances antigen presentation, and that small molecules suppress tumor growth.","evidence":"Mtdh genetic ablation mice, PPI small-molecule inhibitors (C26-A2/A6), mRNA stability and T-cell infiltration readouts","pmids":["35121987","35121988"],"confidence":"High","gaps":["nuclease/destabilization catalytic step within the complex not biochemically isolated","full mRNA target spectrum of the complex unmapped"]},{"year":2021,"claim":"Established prostate-cancer-specific control of SND1 localization, showing ERG binds the SND1 Tudor domain to drive nuclear localization of the SND1/MTDH complex and growth, and that SND1 supports dendritic-cell Th1 immunity in vivo.","evidence":"domain Co-IP, forced-nuclear-localization experiments, conditional Snd1 knockout prostate model; SND1-KO DC functional and adoptive-transfer assays","pmids":["37973913","33635920"],"confidence":"High","gaps":["how nuclear vs cytoplasmic partitioning is normally regulated unresolved","molecular basis of SND1's DC function not defined"]},{"year":2022,"claim":"Defined SND1 as a regulator of ferroptosis through opposing mRNA-fate decisions — stabilizing GPX4 to confer cisplatin resistance and destabilizing HSPA5 to promote ferroptosis — and uncovered mitochondrial and glycosylation-dependent functions.","evidence":"3'UTR binding/luciferase and ferroptosis rescue assays; mitochondrial fractionation/IP-MS with PGAM5; Asn50 glycosylation mutagenesis with ERAD readout","pmids":["36453257","35320827","35433434","36213325"],"confidence":"Medium","gaps":["context determining stabilization vs destabilization of bound transcripts unknown","mitochondrial import and ER/nuclear roles not reconciled into one regulatory logic"]},{"year":2023,"claim":"Extended SND1's RNA-reader role to viral and stress RNAs and to lncRNA-guided chromatin remodeling, including m6A-dependent Nrf2 regulation, NSP9-dependent SARS-CoV-2 replication, lncTCF7-directed SWI/SNF recruitment, and HIF1α co-activation.","evidence":"RIP/MeRIP/RNA pulldown and rescue; viral RNA binding, Co-IP and covalent-linkage mapping; RNA pulldown/MS and ChIP; PyMT Snd1-KO tumor model","pmids":["37202791","37794589","39169000","37622244"],"confidence":"Medium","gaps":["whether m6A reading and protein-scaffolding use the same SND1 surface unknown","physiological RNA target hierarchy not established"]},{"year":2024,"claim":"Defined SND1 functions in genome protection and vascular remodeling and refined its post-translational control, including KDM6A-dependent fork protection, ELK1-driven SND1/SRF/KAT2B vascular signaling, and PIM1-S426 phosphorylation strengthening SND1-SMARCA5 chromatin activity.","evidence":"Co-IP and nascent-DNA chromatin analysis; SMC-specific Snd1 KO with wire-injury model, ChIP/Co-IP; PIM1 S426 mutagenesis with Co-IP, ChIP and tumor models","pmids":["38850159","38279051","39725102"],"confidence":"Medium","gaps":["how SND1 partitions between fork protection and transcriptional roles unknown","ordering of phosphorylation events relative to partner choice undefined"]},{"year":2025,"claim":"Integrated SND1 into translational and degradative control loops, showing mTORC1/4E-BP1 represses SND1 translation while SND1 transcriptionally drives a UBE2N DNA-repair program, and that USP37 (CDK1-activated) deubiquitinates and stabilizes SND1, and SREBF1-induced SND1 forms an MTDH complex degrading SESN2 mRNA to activate mTOR.","evidence":"ribosome profiling and mTORC1 modulation with DNA-repair readouts; proteomics, CDK1 T631 site mapping and DUB activity assays; ChIP/RIP-seq with C26-A6 disruption","pmids":["39895626","40486858","40775338"],"confidence":"Medium","gaps":["feedback between SND1-mTOR signaling and its own translational repression not closed","in vivo relevance of USP37-SND1 axis beyond CRC untested"]},{"year":null,"claim":"How SND1 selects between stabilizing versus destabilizing bound mRNAs, and how its activities are partitioned across nuclear chromatin, cytoplasmic RNA, ER membrane, and mitochondria within a single cell, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["no unifying biochemical model linking the SN-domain nuclease/scaffold and Tudor reader functions","regulatory logic governing subcellular partitioning undefined","catalytic step of MTDH-SND1 mRNA degradation not reconstituted"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[3,26,27,34]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[7,19,20]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[7,19,29,35]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,8,31]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[7]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[12,17,36]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7,25,28]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[13]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[17]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[14,23]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[17]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[3,26,27,34]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7,19,29]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,1,10,11,15]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10,12,39]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,7,18,38]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[28,30]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[21,22]}],"complexes":["MTDH-SND1 complex","RISC"],"partners":["MTDH","SEC61A","GCN5","PGAM5","SAM68","ERG","SMARCA5","KDM6A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7KZF4","full_name":"Staphylococcal nuclease domain-containing protein 1","aliases":["100 kDa coactivator","EBNA2 coactivator p100","Tudor domain-containing protein 11","p100 co-activator"],"length_aa":910,"mass_kda":102.0,"function":"Endonuclease that mediates miRNA decay of both protein-free and AGO2-loaded miRNAs (PubMed:18453631, PubMed:28546213). As part of its function in miRNA decay, regulates mRNAs involved in G1-to-S phase transition (PubMed:28546213). Functions as a bridging factor between STAT6 and the basal transcription factor (PubMed:12234934). Plays a role in PIM1 regulation of MYB activity (PubMed:9809063). Functions as a transcriptional coactivator for STAT5 (By similarity) (Microbial infection) Functions as a transcriptional coactivator for the Epstein-Barr virus nuclear antigen 2 (EBNA2) (Microbial infection) Promotes SARS-CoV-2 RNA synthesis by binding to negative-sense RNA and the viral protein nsp9","subcellular_location":"Cytoplasm; Nucleus; Melanosome","url":"https://www.uniprot.org/uniprotkb/Q7KZF4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SND1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"G3BP2","stoichiometry":0.2},{"gene":"NPM1","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"RPS16","stoichiometry":0.2},{"gene":"SRP19","stoichiometry":0.2},{"gene":"SRP68","stoichiometry":0.2},{"gene":"SRP9","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SND1","total_profiled":1310},"omim":[{"mim_id":"610028","title":"POLY(ADP-RIBOSE) POLYMERASE FAMILY, MEMBER 14; PARP14","url":"https://www.omim.org/entry/610028"},{"mim_id":"602181","title":"STAPHYLOCOCCAL NUCLEASE DOMAIN- AND TUDOR DOMAIN-CONTAINING PROTEIN 1; SND1","url":"https://www.omim.org/entry/602181"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Cytosol","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SND1"},"hgnc":{"alias_symbol":["TDRD11","p100","TSN"],"prev_symbol":[]},"alphafold":{"accession":"Q7KZF4","domains":[{"cath_id":"2.40.50.90","chopping":"18-171","consensus_level":"high","plddt":92.8984,"start":18,"end":171},{"cath_id":"2.40.50.90","chopping":"182-232_240-325","consensus_level":"high","plddt":94.4519,"start":182,"end":325},{"cath_id":"2.40.50.90","chopping":"337-377_393-493","consensus_level":"high","plddt":91.4431,"start":337,"end":493},{"cath_id":"2.40.50.90","chopping":"504-657","consensus_level":"high","plddt":90.8319,"start":504,"end":657},{"cath_id":"2.40.50.90","chopping":"682-892","consensus_level":"medium","plddt":93.4084,"start":682,"end":892}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7KZF4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7KZF4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7KZF4-F1-predicted_aligned_error_v6.png","plddt_mean":89.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SND1","jax_strain_url":"https://www.jax.org/strain/search?query=SND1"},"sequence":{"accession":"Q7KZF4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7KZF4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7KZF4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7KZF4"}},"corpus_meta":[{"pmid":"32645525","id":"PMC_32645525","title":"A 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\"year\": 2014,\n      \"finding\": \"Crystal structure of the MTDH-SND1 complex was determined at high resolution, revealing that an 11-residue MTDH peptide motif occupies an extended groove between SND1's SN1 and SN2 domains, with two MTDH tryptophan residues nestled into two well-defined pockets in SND1. Mutagenesis of both tryptophan-binding pockets disrupted MTDH-SND1 interaction and impaired their roles in breast cancer and SND1 stability under stress.\",\n      \"method\": \"X-ray crystallography, mutagenesis, functional cancer cell assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure combined with mutagenesis and functional validation in cancer cells in a single rigorous study\",\n      \"pmids\": [\"25242325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MTDH interacts with and stabilizes SND1; disrupting the MTDH-SND1 interaction (by silencing either protein or disrupting their binding) compromises tumor-initiating cell survival and tumorigenesis in multiple mouse mammary tumor models, establishing that MTDH supports cell survival under oncogenic/stress conditions through SND1 stabilization.\",\n      \"method\": \"Co-immunoprecipitation, mouse genetic tumor models, knockdown/disruption studies with in vivo xenograft/tumor assays\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus multiple mouse cancer models across oncogene subtypes, replicated in clinical breast cancer samples\",\n      \"pmids\": [\"24981741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SND1 was identified as an MTDH-interacting protein by mass spectrometry-based screen and confirmed by co-immunoprecipitation. SND1 promotes lung metastasis, resistance to apoptosis, and regulates expression of metastasis- and chemoresistance-associated genes in breast cancer cells.\",\n      \"method\": \"Mass spectrometry pulldown, co-immunoprecipitation, loss-of-function (knockdown) with metastasis assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification confirmed by Co-IP, single lab, functional knockdown with defined metastasis phenotype\",\n      \"pmids\": [\"21478147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SND1 functions as an m6A RNA reader: it binds m6A-modified hairpin in KSHV ORF50 RNA, stabilizes the ORF50 transcript, and is essential for KSHV lytic replication. RIP-seq and eCLIP characterization confirmed SND1 as a transcriptome-wide m6A reader.\",\n      \"method\": \"RIP-seq, eCLIP, RNA immunoprecipitation, m6A-modified RNA binding assays, SND1 depletion with viral replication readout\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal biochemical methods (RIP-seq, eCLIP, direct m6A-modified RNA binding), functional viral replication phenotype upon SND1 depletion\",\n      \"pmids\": [\"31647415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SND1 binds the 5' end of SARS-CoV-2 negative-sense viral RNA and is required for viral RNA synthesis. SND1 interacts directly with the viral RNA-binding protein NSP9 and remodels NSP9 occupancy, altering covalent NSP9 linkage to initiating nucleotides at replication-transcription initiation sites.\",\n      \"method\": \"Biochemical fractionation of viral RNA-bound proteins, SND1 depletion with viral RNA synthesis and growth kinetics readout, Co-IP with NSP9, covalent RNA-protein linkage mapping\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (RNA binding, Co-IP, covalent linkage mapping, replication organelle imaging) in a single rigorous study\",\n      \"pmids\": [\"37794589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SND1 promotes tumor angiogenesis in hepatocellular carcinoma through a linear pathway: SND1 activates NF-κB, which induces miR-221, which in turn induces angiogenic factors Angiogenin and CXCL16. Inhibition of any component in this cascade blocked SND1-induced angiogenesis.\",\n      \"method\": \"Stable SND1 overexpression/knockdown in HCC cells, CAM assay, HUVEC differentiation assay, reporter and pathway inhibitor experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistatic pathway dissection via stable gain/loss-of-function and inhibitor rescue, single lab, two orthogonal angiogenesis assays\",\n      \"pmids\": [\"22396537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SND1 expression is transcriptionally activated by the TGFβ1/Smad2/Smad3 complex binding to Smad-specific recognition motifs (RD motifs) in the SND1 promoter. SND1 in turn promotes Smurf1 expression, leading to RhoA ubiquitination and degradation, disrupting F-actin organization and increasing breast cancer cell migration, invasion, and metastasis.\",\n      \"method\": \"Promoter analysis (luciferase, EMSA, ChIP), Smad complex gain/loss-of-function, RhoA ubiquitination assay, cell migration/invasion assays, in vivo metastasis models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (EMSA, ChIP, ubiquitination assay, in vivo metastasis), single lab\",\n      \"pmids\": [\"25596283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SND1 directly binds to conserved motifs (motifs 1 and 2) in the promoter regions of Smad2/3/4 genes, recruits the histone acetyltransferase GCN5 through its Tudor domain, increases H3K9 acetylation, and thereby activates Smad2/3/4 transcription to enhance TGFβ1 signaling and breast cancer metastasis.\",\n      \"method\": \"EMSA, GST pulldown (Tudor domain requirement), ChIP, loss-of-function assays, phospho-Smad readout\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — EMSA and GST pulldown identify domain and DNA binding, ChIP validates in-cell recruitment, single lab\",\n      \"pmids\": [\"28263968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SND1 interacts with SAM68 (identified by mass spectrometry) and together they promote inclusion of CD44 variable exons in prostate cancer cells. SND1 recruits SAM68 and spliceosomal components to CD44 pre-mRNA; the effect of SND1 on CD44 splicing required SAM68 and intact SAM68-binding sites in the pre-mRNA.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, SAM68 knockdown epistasis, RT-PCR splicing assays, mutation of SAM68-binding sites in pre-mRNA\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, MS identification, epistatic SAM68 knockdown plus pre-mRNA mutation, single lab\",\n      \"pmids\": [\"23995791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SND1 interacts with monoglyceride lipase (MGLL), identified by modified yeast two-hybrid and confirmed by co-immunoprecipitation; this interaction results in ubiquitination and proteasomal degradation of MGLL, suppressing its tumor-suppressive function in hepatocellular carcinoma.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, ubiquitination assay, MGLL overexpression rescue, in vivo xenograft\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP and ubiquitination assay, single lab\",\n      \"pmids\": [\"26997225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The MTDH-SND1 complex suppresses antitumor T cell responses by binding to and destabilizing Tap1/Tap2 mRNAs, reducing antigen presentation machinery components. Pharmacological disruption of the MTDH-SND1 complex with compound C26-A6 enhanced tumor antigen presentation and CD8+ T cell infiltration.\",\n      \"method\": \"Genetic and pharmacological disruption of MTDH-SND1 complex, mRNA stability assays for Tap1/Tap2, in vivo immunological readouts (T cell infiltration, antigen presentation)\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic disruption plus pharmacological inhibitor in multiple preclinical models with mechanistic mRNA destabilization readout, replicated across approaches\",\n      \"pmids\": [\"35121988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Genetic ablation of Mtdh in mice inhibits breast cancer development through disruption of the MTDH-SND1 interaction, establishing that the interaction is required to sustain breast cancer progression. Small-molecule inhibitors C26-A2 and C26-A6 disrupting this protein-protein interaction suppressed tumor growth, metastasis, and enhanced chemotherapy sensitivity.\",\n      \"method\": \"Genetically modified mice (Mtdh ablation), small-molecule compound screen against MTDH-SND1 PPI, in vitro and in vivo TNBC preclinical models\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mouse genetic ablation plus orthogonal pharmacological disruption with multiple in vivo cancer models, replicated across studies\",\n      \"pmids\": [\"35121987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SND1 is an ER membrane-associated protein: its N-terminal peptide associates with SEC61A anchored on the ER membrane. The SN domain of SND1 catches nascent MHC-I heavy chain and guides it to ER-associated degradation (ERAD), thereby impairing normal MHC-I assembly and antigen presentation, enabling immune evasion by tumor cells.\",\n      \"method\": \"Subcellular fractionation, co-immunoprecipitation (SND1-SEC61A, SND1-MHC-I heavy chain), ERAD pathway assays, SND1 deletion in syngeneic mouse tumor models with CD8+ T cell readout\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple Co-IPs, ER localization confirmed by fractionation, in vivo mouse models with OT-I transgenic validation, mechanistic ERAD pathway characterization\",\n      \"pmids\": [\"32917674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Mitochondrion-localized SND1 (via N-terminal amino acids 1–63 as a mitochondrial targeting sequence imported via TOM70) interacts with PGAM5 in mitochondria, promoting PGAM5-DRP1 binding and mitophagy, which supports liver cancer cell proliferation and tumor growth.\",\n      \"method\": \"Organelle subcellular isolation, immunoprecipitation-mass spectrometry, domain deletion (MTS mutants), Co-IP, in vitro and in vivo tumor models\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS confirmed by Co-IP, MTS domain deletion, organelle fractionation in multiple cell lines, single lab\",\n      \"pmids\": [\"35433434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SND1 functions as a component of RISC and overexpression in colon cancer cells causes downregulation of APC protein without altering APC mRNA levels, and alters E-cadherin distribution from membrane to cytoplasm. Stable Snd1 overexpression in IEC6 cells promotes loss of contact inhibition and cell growth.\",\n      \"method\": \"Stable overexpression in intestinal epithelial cells, immunohistochemistry, Western blot (APC protein vs. mRNA), cell proliferation assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — stable overexpression with specific molecular (APC protein vs. mRNA, E-cadherin redistribution) and cellular phenotype readouts, single lab\",\n      \"pmids\": [\"17909068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SND1-BRAF chromosomal rearrangement (7q32-7q34) produces a constitutively active SND1-BRAF fusion protein that hyperactivates the MAPK pathway (ERK), conferring resistance to c-Met inhibitor in gastric cancer cells. Combination with RAF or MEK inhibitor overcame resistance.\",\n      \"method\": \"Chromosomal rearrangement characterization, functional expression of SND1-BRAF fusion, ERK phosphorylation assays, inhibitor combination studies\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — fusion protein expressed and tested with pathway readout and pharmacological rescue, single lab\",\n      \"pmids\": [\"22745804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SND1 interacts with and regulates processing of miR-17-92a cluster: SND1 binds pre-miR-92a and all mature miR-17-92a members (identified by RNA pulldown and mass spectrometry), and SND1 silencing resolves a hypoxia-induced block in miRNA processing, increasing mature miRNA levels.\",\n      \"method\": \"RNA pulldown, mass spectrometry, SND1 knockdown, miRNA processing Northern/qPCR assays under hypoxic conditions\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA pulldown with MS confirmation, knockdown epistasis on miRNA processing, single lab\",\n      \"pmids\": [\"23770094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SND1 (SND p102) colocalizes with endoplasmic reticulum and Golgi markers by sucrose gradient fractionation, and under steatogenic conditions translocates to and associates specifically with low-density lipid droplets in hepatocytes, as confirmed by both gradient fractionation and confocal microscopy.\",\n      \"method\": \"Sucrose gradient fractionation, confocal microscopy, oleate treatment of HepG2 cells\",\n      \"journal\": \"Journal of physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal localization methods (fractionation + confocal), single lab, functional implication for lipid droplet targeting\",\n      \"pmids\": [\"20414760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SND1 increases AT1R mRNA stability, resulting in elevated AT1R protein levels, which activates ERK and Smad2 and consequently the TGFβ signaling pathway, promoting EMT, migration, and invasion in hepatocellular carcinoma cells.\",\n      \"method\": \"mRNA stability assays, Western blot for ERK/Smad2 phosphorylation, SND1 overexpression/knockdown, migration/invasion assays\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — mRNA stability measured with multiple signaling readouts, single lab, no direct RNA binding confirmation shown in abstract\",\n      \"pmids\": [\"24918049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SND1 acts upstream of SLUG to promote EMT: SND1 recruits acetyltransferases GCN5 and CBP/p300 to the SLUG promoter, increasing chromatin accessibility and activating SLUG transcription; SLUG then regulates N-CAD, VIM, E-CAD, and CLDN1 expression to promote EMT in ovarian cancer cells.\",\n      \"method\": \"ChIP, gene expression profiling, SND1 loss-of-function, co-activator recruitment assays, invasion/migration assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating co-activator recruitment to SLUG promoter, loss-of-function epistasis with SLUG, single lab\",\n      \"pmids\": [\"30509125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The SND1 gene promoter is regulated by NF-κB, Sp1, and NF-Y transcription factors. EMSA and ChIP confirmed direct binding of these factors to specific sites in the SND1 proximal promoter; mutation of CCAAT/GC boxes and NF-κB elements substantially reduced SND1 promoter activity. TNF-α-induced upregulation of SND1 is mediated at least in part via NF-κB.\",\n      \"method\": \"EMSA, ChIP, luciferase reporter assays with deletion analysis and site-directed mutagenesis\",\n      \"journal\": \"Biochimie\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — EMSA and ChIP with mutagenesis validation, single lab, multiple orthogonal promoter assays\",\n      \"pmids\": [\"23160072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SND1 occupies 645 gene promoters in HepG2 cells under basal conditions and 281 additional promoters upon TNFα treatment, as determined by ChIP-chip. SND1 deficiency compromises glycerolipid gene reprogramming and lipid phenotypic responses to TNFα.\",\n      \"method\": \"ChIP-chip, transcription factor binding site analysis, SND1 knockdown with lipid metabolism readout\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-chip with 21 individual gene validations, functional knockdown readout, single lab\",\n      \"pmids\": [\"26323317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SREBP-2 directly binds to SRE and E-box motifs in the SND1 proximal promoter to activate SND1 transcription, as shown by ChIP and site-directed mutagenesis. SREBP-1c/1a binds the SRE element and represses SND1 transcription. SREBP-2 activating conditions (simvastatin, lipoprotein-deficient medium) increase SND1 mRNA and promoter activity.\",\n      \"method\": \"ChIP, luciferase reporter assays, site-directed mutagenesis, SREBP overexpression and siRNA knockdown\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP with mutagenesis and functional reporter validation, single lab\",\n      \"pmids\": [\"29296233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SND1 localizes to stress granules under heat shock, and this recruitment requires intact microtubule cytoskeleton tracks; nocodazole-mediated microtubule depolymerization significantly impairs SND1 granule assembly during heat shock. SND1 granules co-localize with α-tubulin microtubules.\",\n      \"method\": \"Immunofluorescence live-cell imaging, nocodazole treatment, heat shock assay, co-localization analysis\",\n      \"journal\": \"Anatomical record\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct imaging plus pharmacological disruption of cytoskeleton with functional assembly readout, single lab\",\n      \"pmids\": [\"28758359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PIM1 kinase directly binds and phosphorylates SND1; decreased SND1 expression leads to upregulation of senescence-associated secretory phenotype (SASP), and SND1 is involved in PIM1-mediated cellular senescence.\",\n      \"method\": \"Silver staining/LC-MS/MS identification of PIM1-interacting proteins, Co-IP, immunofluorescence, Western blot, cell proliferation assays\",\n      \"journal\": \"Medical science monitor\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and phosphorylation asserted but specific phosphorylation site or kinase assay not detailed in abstract; single lab, single approach\",\n      \"pmids\": [\"31860636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SND1 Tudor domain interacts with ERG (an ETS-domain transcription factor overexpressed in prostate cancer); ERG promotes nuclear localization of the SND1/MTDH complex; forced nuclear localization of SND1 prominently increases its growth-promoting function; prostate-specific Snd1 deletion reduces cancer growth in PB-Cre/Ptenflox/flox/ERG mice.\",\n      \"method\": \"Co-immunoprecipitation (Tudor domain), domain-specific interaction mapping, nuclear localization forced-expression experiments, Snd1 conditional knockout mouse prostate cancer model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain-resolved Co-IP, conditional mouse KO cancer model, nuclear localization functional experiments, transcriptomic overlap, multiple orthogonal methods\",\n      \"pmids\": [\"37973913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SND1 binds to the 3' UTR of GPX4 mRNA and stabilizes it; knockdown of SND1 in bladder cancer cells promotes ferroptosis by destabilizing GPX4 mRNA, overcoming cisplatin resistance.\",\n      \"method\": \"ChIP and dual-luciferase assay for SND1-GPX4 mRNA 3'UTR binding, RNA interference, ferroptosis assays (ROS, iron, GSH, MDA), GPX4 overexpression rescue\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA binding assay plus rescue experiments, single lab, two orthogonal assays\",\n      \"pmids\": [\"36453257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SND1 destabilizes HSPA5 mRNA by binding to its 3'UTR, leading to reduced HSPA5 protein, which in turn reduces GPX4 expression (since HSPA5 protein directly stabilizes GPX4), ultimately promoting ferroptosis in osteoarthritis chondrocytes.\",\n      \"method\": \"RNA binding (3'UTR binding assay), mRNA stability assay, Co-IP for HSPA5-GPX4 interaction, SND1 knockdown in vivo (rat OA model), IL-1β-stimulated chondrocyte model\",\n      \"journal\": \"Inflammation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA binding, protein-protein Co-IP, in vivo validation in OA model, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"35320827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KDM6A interacts with SND1 (interaction enhanced by KDM6A SUMOylation at K90); the KDM6A-SND1 complex protects nascent DNA by recruiting RPA and Ku70, preventing replication fork collapse. Loss of KDM6A or SND1 increases H3K9ac and H4K8ac but attenuates Ku70 and H3K4me3 at nascent DNA, enhancing genotoxin sensitivity.\",\n      \"method\": \"Co-IP, nascent DNA chromatin analysis (Ku70/RPA enrichment), histone modification ChIP, KDM6A mutation analysis, genotoxin sensitivity assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with mutation mapping plus chromatin analysis of nascent DNA, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38850159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In vascular smooth muscle cells, ELK1 transcription factor binds the Snd1 promoter to activate its transcription upon PDGF stimulation. Upregulated SND1 then competes with myocardin for SRF binding and recruits KAT2B (histone acetyltransferase) to SRF target gene promoters, increasing histone acetylation and promoting SRF-driven transcription of proliferation- and migration-related genes, thereby inducing neointimal hyperplasia. SMC-specific Snd1 knockout mice showed reduced neointimal hyperplasia.\",\n      \"method\": \"ChIP, Co-IP (SND1-SRF interaction), chromatin accessibility/histone acetylation assays, SMC-specific conditional Snd1 knockout mice, wire-injury vascular model\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — SMC-specific KO mouse model with vascular phenotype, ChIP, Co-IP, and histone modification assays establishing the ELK1-SND1-SRF pathway in vivo and in vitro\",\n      \"pmids\": [\"38279051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SND1 translational repression is mediated by the mTORC1/4E-BP1 pathway under sunitinib stress in endothelial cells. SND1 transcriptionally regulates UBE2N, an E2-conjugating enzyme mediating K63-linked ubiquitination; UBE2N, together with E3 ligases RNF8 and RNF168, mediates the DNA damage repair response that protects endothelial cells from sunitinib-induced dysfunction.\",\n      \"method\": \"Ribosome profiling (translational control mapping), mTORC1/4E-BP1 pathway modulation, SND1 OE/knockdown, UBE2N downstream identification, DNA damage repair assays, in vitro and in vivo vascular dysfunction models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ribosome profiling plus mTORC1 pathway modulation, SND1-UBE2N transcriptional axis with DNA repair readout, in vivo validation, single lab\",\n      \"pmids\": [\"39895626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SND1 binds to and stabilizes lncTCF7, and together SND1 and lncTCF7 are required for recruitment of the SWI/SNF chromatin remodeling complex to the TCF7 promoter to activate TCF7 transcription. The SND1-binding region maps to the 3'-end of lncTCF7.\",\n      \"method\": \"RNA pulldown, quantitative mass spectrometry, knockdown epistasis, ChIP (SND1, SWI/SNF recruitment), structural probing of lncTCF7 subdomains\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA pulldown with MS, ChIP, knockdown epistasis with two orthogonal methods, single lab\",\n      \"pmids\": [\"39169000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP37 is the deubiquitinase of SND1, stabilizing SND1 protein. CDK1 phosphorylates USP37 at threonine 631 (not serine 628), enhancing USP37 deubiquitinase activity and thereby stabilizing SND1 to drive colorectal cancer progression. Dacarbazine was identified as a pharmacological inhibitor of USP37 that disrupts SND1 stability.\",\n      \"method\": \"Proteomics, ubiquitinomics, interactomics (MS-based), CDK1 phosphorylation site mapping (T631 vs S628 mutagenesis), USP37 deubiquitinase activity assay, in vivo CRC models\",\n      \"journal\": \"Acta pharmaceutica sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation site mutagenesis (T631 vs S628), deubiquitinase activity assay, proteomics confirmation, single lab\",\n      \"pmids\": [\"40486858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SPT6 interacts with SND1 to co-activate hTERT expression and promote colon cancer cell proliferation, stemness, and growth in vitro and in vivo. SPT6 was identified by pull-down/mass spectrometry as a protein binding the hTERT promoter.\",\n      \"method\": \"Pulldown/mass spectrometry, SPT6-SND1 interaction confirmed, hTERT promoter reporter assays, in vitro and xenograft in vivo models\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — MS pulldown, functional co-activation, but interaction details (Co-IP validation) not detailed in abstract; single lab\",\n      \"pmids\": [\"33305480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SNAI3-AS1 competitively binds SND1 and perturbs m6A-dependent recognition of Nrf2 mRNA 3'UTR by SND1, reducing Nrf2 mRNA stability and sensitizing glioma cells to ferroptosis.\",\n      \"method\": \"RNA pulldown, RIP, MeRIP, dual-luciferase reporter assay, gain/loss-of-function rescue experiments\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple RNA binding assays (pulldown, RIP, MeRIP) with functional rescue experiments, single lab\",\n      \"pmids\": [\"37202791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SND1 co-activates HIF1α as a transcriptional co-activator, regulating downstream EZH2 transcription, and thereby promotes PyMT-induced breast tumor initiation and expansion of tumor-initiating cells.\",\n      \"method\": \"SND1 knockout in PyMT mouse model, histological and cytometric analysis, mechanistic co-activator assays (SND1-HIF1α interaction and EZH2 transcription readout)\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mouse KO tumor model with defined cellular phenotype, mechanistic HIF1α co-activation pathway established, single lab\",\n      \"pmids\": [\"37622244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"N-glycosylation of SND1 at Asn50 is required for its folding and stability; mutation of Asn50 destabilizes SND1 and leads to its ER-associated degradation, inhibiting glioma cell proliferation and metastasis.\",\n      \"method\": \"Site-directed mutagenesis of four N-glycosylation sites (N50, N168, N283, N416), Western blot, ERAD pathway assays, cell proliferation and invasion assays\",\n      \"journal\": \"Journal of immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-directed mutagenesis establishing site-specific glycosylation with functional and ERAD readout, single lab\",\n      \"pmids\": [\"36213325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PIM1-catalyzed phosphorylation of SND1 at serine 426 strengthens SND1-SMARCA5 interaction; this interaction mediates SND1's regulation of chromatin dynamics and transcriptional activation of CUX1 oncogene, promoting ESCC progression. Disruption of S426 phosphorylation impaired SND1-SMARCA5 interaction and inhibited ESCC tumor growth in vivo.\",\n      \"method\": \"PIM1 phosphorylation assay (S426 site-directed mutagenesis), Co-IP (SND1-SMARCA5), ChIP (histone modification, RNA polymerase II), in vivo tumor models\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation site mutagenesis, Co-IP, chromatin assays, in vivo model, single lab\",\n      \"pmids\": [\"39725102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SREBF1 binds the SND1 gene promoter and activates its transcription; SND1 then forms a complex with MTDH that directly binds and degrades SESN2 mRNA, activating mTOR signaling and promoting prostate cancer progression. Disruption of the MTDH-SND1 interaction with C26-A6 inhibited SESN2 mRNA degradation.\",\n      \"method\": \"ChIP, dual-luciferase reporter assay, DNA pulldown, RIP-seq and RNA pulldown (SESN2 mRNA binding), pharmacological disruption (C26-A6), in vitro and xenograft models\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for promoter binding, RIP-seq for mRNA target, pharmacological disruption with rescue, single lab\",\n      \"pmids\": [\"40775338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In SND1 knockout mice, dendritic cells show lower costimulatory molecule expression and IL-12 production and higher IL-10 production; adoptive transfer of SND1-KO DCs failed to protect against chlamydial challenge infection and showed reduced ability to promote Th1 responses. This establishes SND1 as required for normal DC function in promoting Th1/17 immunity.\",\n      \"method\": \"SND1 knockout mouse model, DC isolation and functional assays, DC-T cell co-culture, adoptive DC transfer, in vivo chlamydial lung infection model\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — SND1 KO mouse with defined immunological phenotype, multiple functional DC assays, adoptive transfer epistasis, single lab\",\n      \"pmids\": [\"33635920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The SN domain of SND1 interacts with MHC-I heavy chain at K490-containing sites (as determined by structure-based virtual screening and docking analysis); EGC (-)-Epigallocatechin prevents SND1-MHC-I binding by altering the spatial conformation of SND1 at this site, restoring MHC-I surface presentation and CD8+ T cell responses.\",\n      \"method\": \"Structure-based virtual screening, molecular docking, EGC treatment with MHC-I surface expression readout, in vivo melanoma mouse model, CD8+ T cell functional assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — docking-guided inhibitor and cell/in vivo functional readout but direct binding confirmation by biochemical assay not detailed; single lab\",\n      \"pmids\": [\"38710299\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SND1 is a multifunctional nuclear/cytoplasmic/ER/mitochondrial protein that acts as: (1) a transcriptional co-activator recruiting histone acetyltransferases (GCN5, CBP/p300, KAT2B) to target promoters including Smad2/3/4, SLUG, SRF-target genes, and hTERT; (2) an RNA-binding protein and m6A reader that stabilizes or destabilizes specific mRNAs (e.g., AT1R, GPX4, Tap1/Tap2, SESN2) and modulates miRNA processing; (3) a structural component of RISC; (4) an ER membrane-associated protein (via SEC61A) that redirects nascent MHC-I heavy chain to ERAD to suppress antigen presentation; (5) a mitochondrially-imported protein (via N-terminal MTS/TOM70) that promotes PGAM5-mediated mitophagy; and (6) a scaffold that stabilizes its oncogenic partner MTDH (and the interaction surface is defined by crystal structure showing MTDH tryptophan residues in SND1's SN1/2 groove), with the MTDH-SND1 complex degrading tumor-suppressor mRNAs and driving breast and prostate cancer progression — all of which are regulated by post-translational modifications including PIM1/CDK1-mediated phosphorylation (S426), USP37-mediated deubiquitination, and N-glycosylation at Asn50.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SND1 is a multifunctional staphylococcal-nuclease-domain protein that couples RNA metabolism, chromatin-based transcriptional co-activation, and protein turnover to drive cancer progression and tissue remodeling [#7, #25]. As a transcriptional co-activator it binds defined promoter motifs and recruits histone acetyltransferases — GCN5 to Smad2/3/4 promoters via its Tudor domain to amplify TGF-\\u03b21 signaling [#7], GCN5 and CBP/p300 to the SLUG promoter to drive EMT [#19], and KAT2B to SRF target genes where it competes with myocardin to promote vascular smooth-muscle proliferation [#29]; it likewise co-activates HIF1\\u03b1/EZH2 in tumor-initiating cells [#35]. As an RNA-binding protein and m6A reader it determines the fate of specific transcripts, stabilizing GPX4 and AT1R mRNAs and m6A-modified viral and Nrf2 RNAs while destabilizing HSPA5, with these activities controlling ferroptosis sensitivity and TGF\\u03b2/ERK signaling [#3, #18, #26, #27, #34]. SND1 is most prominently a scaffold for the oncoprotein MTDH: an 11-residue MTDH motif inserts two tryptophan residues into pockets of the SND1 SN1/SN2 groove, and this interaction stabilizes SND1, is required to sustain breast cancer, and forms an MTDH-SND1 complex that destabilizes tumor-suppressor and antigen-presentation mRNAs (Tap1/Tap2, SESN2) [#0, #1, #10, #38]. SND1 additionally evades immune detection at the ER, where its N-terminus associates with SEC61A and its SN domain diverts nascent MHC-I heavy chain to ERAD [#12], and it localizes to mitochondria via an N-terminal targeting sequence to promote PGAM5-dependent mitophagy [#13]. SND1 activity and abundance are tuned by PIM1/CDK1-driven phosphorylation, USP37-mediated deubiquitination, and N-glycosylation at Asn50 [#32, #36, #37]. Genetically, an SND1-BRAF fusion produces a constitutively active MAPK-driving oncoprotein [#15], and SND1 is required for dendritic-cell-driven Th1 immunity in vivo [#39].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that SND1 overexpression has oncogenic potential and acts post-transcriptionally, by downregulating APC protein without changing its mRNA and redistributing E-cadherin in intestinal epithelial cells.\",\n      \"evidence\": \"stable overexpression in IEC6/colon cancer cells with APC protein-vs-mRNA Western blots and proliferation assays\",\n      \"pmids\": [\"17909068\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mechanism of APC protein loss without mRNA change not resolved\", \"RISC component role asserted but not biochemically dissected\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified SND1 as a physical MTDH partner and a driver of metastasis and chemoresistance, opening the MTDH-SND1 oncogenic axis.\",\n      \"evidence\": \"mass spectrometry pulldown and Co-IP with knockdown metastasis assays in breast cancer cells\",\n      \"pmids\": [\"21478147\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"interaction interface unknown at this stage\", \"downstream mRNA targets of the complex not yet defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mapped SND1 into discrete signaling and oncogenic outputs — an NF-\\u03baB/miR-221/angiogenic-factor cascade in HCC and a constitutively active SND1-BRAF fusion driving MAPK and inhibitor resistance.\",\n      \"evidence\": \"gain/loss-of-function with angiogenesis assays and pathway inhibitors; SND1-BRAF fusion expression with ERK readout and inhibitor combinations\",\n      \"pmids\": [\"22396537\", \"22745804\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether SND1 directly activates NF-\\u03baB or acts indirectly unresolved\", \"SND1-BRAF fusion is a rearrangement-specific event, not general SND1 function\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined how SND1 expression itself is controlled, showing its promoter is bound and regulated by NF-\\u03baB, Sp1 and NF-Y and induced by TNF-\\u03b1.\",\n      \"evidence\": \"EMSA, ChIP, luciferase reporters with deletion and site-directed mutagenesis\",\n      \"pmids\": [\"23160072\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"physiological stimuli engaging each factor not fully mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed SND1 roles in RNA processing — promoting CD44 alternative splicing via SAM68 and binding/regulating miR-17-92a cluster processing under hypoxia.\",\n      \"evidence\": \"MS, Co-IP, SAM68 knockdown epistasis and pre-mRNA mutation; RNA pulldown/MS and knockdown miRNA processing assays\",\n      \"pmids\": [\"23995791\", \"23770094\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct RNA-binding determinants on SND1 not defined\", \"generality of miRNA processing role beyond hypoxia unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Solved the structural and functional basis of the MTDH-SND1 interaction, showing two MTDH tryptophans dock into SN1/SN2 pockets and that MTDH stabilizes SND1 to sustain tumor-initiating cell survival in vivo.\",\n      \"evidence\": \"X-ray crystallography with pocket mutagenesis; Co-IP and multiple mouse mammary tumor models\",\n      \"pmids\": [\"25242325\", \"24981741\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"structure does not define the complex's RNA-degrading active mechanism\", \"stabilization mechanism (which ubiquitin machinery is countered) not identified here\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established SND1 as a TGF\\u03b2-induced effector and an mRNA-stability regulator, being activated by Smad2/3 and in turn promoting Smurf1-mediated RhoA degradation and stabilizing AT1R mRNA to amplify TGF\\u03b2/ERK signaling.\",\n      \"evidence\": \"promoter ChIP/EMSA, RhoA ubiquitination, mRNA stability assays and metastasis models\",\n      \"pmids\": [\"25596283\", \"24918049\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct SND1 binding to AT1R mRNA not shown\", \"feedforward loop with TGF\\u03b2 not quantified in vivo\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined SND1 as a chromatin-associated factor on a genome scale, occupying hundreds of promoters and reprogramming glycerolipid gene expression in response to TNF\\u03b1.\",\n      \"evidence\": \"ChIP-chip with TNF\\u03b1 stimulation and lipid metabolism knockdown readouts\",\n      \"pmids\": [\"26323317\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct vs indirect promoter occupancy not distinguished for all loci\", \"co-activator partners at most promoters unidentified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Mechanistically defined SND1 as a Tudor-domain co-activator that recruits GCN5 to Smad2/3/4 promoters and increases H3K9 acetylation, linking its DNA binding to chromatin modification.\",\n      \"evidence\": \"EMSA, GST pulldown for Tudor requirement, ChIP and phospho-Smad readouts\",\n      \"pmids\": [\"28263968\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether Tudor domain reads a histone or protein mark to recruit GCN5 not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected SND1 to lipid/metabolic transcriptional control and stress-granule biology, showing SREBP-2 activates and SREBP-1 represses its promoter, and SND1 assembles into microtubule-dependent stress granules under heat shock.\",\n      \"evidence\": \"ChIP/reporter mutagenesis with SREBP modulation; live-cell imaging with nocodazole disruption\",\n      \"pmids\": [\"29296233\", \"28758359\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"functional consequence of stress-granule recruitment unknown\", \"metabolic feedback between SREBP and SND1 not closed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Broadened the co-activator model to EMT by showing SND1 recruits GCN5 and CBP/p300 to the SLUG promoter, and linked SND1 to PIM1-mediated phosphorylation and senescence.\",\n      \"evidence\": \"ChIP, co-activator recruitment and invasion assays; LC-MS/MS, Co-IP and senescence (SASP) readouts\",\n      \"pmids\": [\"30509125\", \"31860636\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PIM1 phosphorylation site not defined in this study (Low confidence)\", \"SLUG co-activation generality across tumor types untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed an ER-membrane function for SND1: anchored via SEC61A, its SN domain diverts nascent MHC-I heavy chain to ERAD, providing a direct mechanism for tumor immune evasion.\",\n      \"evidence\": \"fractionation, Co-IP (SEC61A, MHC-I), ERAD assays and syngeneic mouse tumor models with CD8+ T-cell readout\",\n      \"pmids\": [\"32917674\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"selectivity determinants for MHC-I substrate engagement not defined\", \"balance between ER and nuclear pools not quantified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Validated the MTDH-SND1 interaction as a therapeutic target across breast cancer and immune evasion, showing complex disruption destabilizes Tap1/Tap2 mRNA, enhances antigen presentation, and that small molecules suppress tumor growth.\",\n      \"evidence\": \"Mtdh genetic ablation mice, PPI small-molecule inhibitors (C26-A2/A6), mRNA stability and T-cell infiltration readouts\",\n      \"pmids\": [\"35121987\", \"35121988\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"nuclease/destabilization catalytic step within the complex not biochemically isolated\", \"full mRNA target spectrum of the complex unmapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established prostate-cancer-specific control of SND1 localization, showing ERG binds the SND1 Tudor domain to drive nuclear localization of the SND1/MTDH complex and growth, and that SND1 supports dendritic-cell Th1 immunity in vivo.\",\n      \"evidence\": \"domain Co-IP, forced-nuclear-localization experiments, conditional Snd1 knockout prostate model; SND1-KO DC functional and adoptive-transfer assays\",\n      \"pmids\": [\"37973913\", \"33635920\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how nuclear vs cytoplasmic partitioning is normally regulated unresolved\", \"molecular basis of SND1's DC function not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined SND1 as a regulator of ferroptosis through opposing mRNA-fate decisions — stabilizing GPX4 to confer cisplatin resistance and destabilizing HSPA5 to promote ferroptosis — and uncovered mitochondrial and glycosylation-dependent functions.\",\n      \"evidence\": \"3'UTR binding/luciferase and ferroptosis rescue assays; mitochondrial fractionation/IP-MS with PGAM5; Asn50 glycosylation mutagenesis with ERAD readout\",\n      \"pmids\": [\"36453257\", \"35320827\", \"35433434\", \"36213325\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"context determining stabilization vs destabilization of bound transcripts unknown\", \"mitochondrial import and ER/nuclear roles not reconciled into one regulatory logic\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended SND1's RNA-reader role to viral and stress RNAs and to lncRNA-guided chromatin remodeling, including m6A-dependent Nrf2 regulation, NSP9-dependent SARS-CoV-2 replication, lncTCF7-directed SWI/SNF recruitment, and HIF1\\u03b1 co-activation.\",\n      \"evidence\": \"RIP/MeRIP/RNA pulldown and rescue; viral RNA binding, Co-IP and covalent-linkage mapping; RNA pulldown/MS and ChIP; PyMT Snd1-KO tumor model\",\n      \"pmids\": [\"37202791\", \"37794589\", \"39169000\", \"37622244\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether m6A reading and protein-scaffolding use the same SND1 surface unknown\", \"physiological RNA target hierarchy not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined SND1 functions in genome protection and vascular remodeling and refined its post-translational control, including KDM6A-dependent fork protection, ELK1-driven SND1/SRF/KAT2B vascular signaling, and PIM1-S426 phosphorylation strengthening SND1-SMARCA5 chromatin activity.\",\n      \"evidence\": \"Co-IP and nascent-DNA chromatin analysis; SMC-specific Snd1 KO with wire-injury model, ChIP/Co-IP; PIM1 S426 mutagenesis with Co-IP, ChIP and tumor models\",\n      \"pmids\": [\"38850159\", \"38279051\", \"39725102\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"how SND1 partitions between fork protection and transcriptional roles unknown\", \"ordering of phosphorylation events relative to partner choice undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Integrated SND1 into translational and degradative control loops, showing mTORC1/4E-BP1 represses SND1 translation while SND1 transcriptionally drives a UBE2N DNA-repair program, and that USP37 (CDK1-activated) deubiquitinates and stabilizes SND1, and SREBF1-induced SND1 forms an MTDH complex degrading SESN2 mRNA to activate mTOR.\",\n      \"evidence\": \"ribosome profiling and mTORC1 modulation with DNA-repair readouts; proteomics, CDK1 T631 site mapping and DUB activity assays; ChIP/RIP-seq with C26-A6 disruption\",\n      \"pmids\": [\"39895626\", \"40486858\", \"40775338\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"feedback between SND1-mTOR signaling and its own translational repression not closed\", \"in vivo relevance of USP37-SND1 axis beyond CRC untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SND1 selects between stabilizing versus destabilizing bound mRNAs, and how its activities are partitioned across nuclear chromatin, cytoplasmic RNA, ER membrane, and mitochondria within a single cell, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no unifying biochemical model linking the SN-domain nuclease/scaffold and Tudor reader functions\", \"regulatory logic governing subcellular partitioning undefined\", \"catalytic step of MTDH-SND1 mRNA degradation not reconstituted\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [3, 26, 27, 34]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [7, 19, 20]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [7, 19, 29, 35]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 8, 31]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [12, 17, 36]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7, 25, 28]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [14, 23]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [3, 26, 27, 34]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7, 19, 29]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 1, 10, 11, 15]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 12, 39]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 7, 18, 38]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [28, 30]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [21, 22]}\n    ],\n    \"complexes\": [\n      \"MTDH-SND1 complex\",\n      \"RISC\"\n    ],\n    \"partners\": [\n      \"MTDH\",\n      \"SEC61A\",\n      \"GCN5\",\n      \"PGAM5\",\n      \"SAM68\",\n      \"ERG\",\n      \"SMARCA5\",\n      \"KDM6A\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}