{"gene":"SUGP1","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2019,"finding":"SF3B1 hotspot mutations (e.g., K700E) reduce the level of SUGP1 in spliceosomes, and SUGP1 knockdown alone completely recapitulates the aberrant 3' splice site usage caused by mutant SF3B1; conversely, SUGP1 overexpression partially rescues splicing in mutant SF3B1 cells, establishing that loss of SF3B1-SUGP1 interaction is the molecular defect underlying mutant SF3B1 splicing errors.","method":"Affinity purification of WT vs. K700E SF3B1 complexes followed by mass spectrometry; siRNA knockdown of SUGP1 with RNA-seq; SUGP1 overexpression rescue experiments in MDS patient-derived cells","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal complex purification, KD phenocopy, and OE rescue across multiple SF3B1 hotspot mutants, replicated by independent labs","pmids":["31474574"],"is_preprint":false},{"year":2022,"finding":"SUGP1 uses its G-patch motif to directly bind and activate the DEAH-box RNA helicase DHX15; DHX15 depletion or expression of AML-associated DHX15 mutants partially recapitulates mutant SF3B1 splicing defects; a DHX15-SUGP1 G-patch fusion rescues those splicing defects; crystal structure of the human DHX15-SUGP1 G-patch complex reveals the molecular basis of direct interaction.","method":"Protein-protein interaction assays (co-IP, pulldown), siRNA/shRNA knockdown with RNA-seq, DHX15 mutant expression, fusion protein rescue, crystal structure of DHX15-SUGP1 G-patch complex","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus multiple orthogonal biochemical and genetic methods in one study, identifying DHX15 as the cognate helicase for SUGP1","pmids":["36459648"],"is_preprint":false},{"year":2020,"finding":"Pan-cancer computational analysis followed by experimental validation showed that five different SUGP1 somatic mutations (identified in cancers) completely or partially recapitulate the cryptic 3' splice site usage seen in mutant SF3B1 cancers, genetically placing SUGP1 downstream in the same splicing pathway as SF3B1.","method":"Pan-cancer RNA-seq analysis (TCGA); experimental validation of SUGP1 mutants by plasmid expression in cell lines with splicing readout","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — computational screen plus experimental validation of five mutations, single lab but two orthogonal approaches","pmids":["32332164"],"is_preprint":false},{"year":2020,"finding":"Somatic SUGP1 mutations combined with loss-of-heterozygosity in lung adenocarcinoma and other cancers induce mutant SF3B1-like aberrant splicing, and modelling of SUGP1 loss or mutation in cell lines confirmed that both alterations generate this missplicing pattern.","method":"Pan-TCGA genomic screening; SUGP1 loss-of-function and mutation modelling in cell lines with RNA-seq splicing analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — independent pan-cancer screen plus cell-line functional validation, single lab","pmids":["33057152"],"is_preprint":false},{"year":2023,"finding":"Structural modeling and mutagenesis revealed that two regions flanking the SUGP1 G-patch make numerous contacts with the SF3B1 region harboring hotspot mutations; all cancer-associated mutations at the SF3B1-SUGP1 interface weaken or disrupt the interaction and alter splicing; the trimeric SF3B1-SUGP1-DHX15 model shows that the SF3B1-SUGP1 interaction 'loops out' the G-patch for DHX15 engagement.","method":"Structural modeling; mutagenesis of interface residues; co-IP interaction assays; splicing reporter assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — structural modeling with extensive mutagenesis and functional validation by co-IP and splicing assays in a single focused study","pmids":["37977822"],"is_preprint":false},{"year":2023,"finding":"DHX15's splicing quality control function in human cells—repressing suboptimal introns with weak splice sites, multiple branch points, and cryptic introns—requires SUGP1 as a G-patch activator; this interaction depends on both DHX15's ATPase activity and SUGP1's ULM (U2AF ligand motif) domain.","method":"Rapid protein depletion (auxin-inducible degron); nascent and mature RNA-seq; domain mutagenesis; protein interaction assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — rapid depletion system enriching for direct effects, domain mutagenesis, RNA-seq, replicated independently from PNAS 2022 study","pmids":["37805921"],"is_preprint":false},{"year":2016,"finding":"SUGP1 regulates cholesterol metabolism: rs10401969 causes SUGP1 exon 8 skipping and nonsense-mediated decay; hepatic Sugp1 overexpression in mice increased plasma cholesterol 20–50%; SUGP1 knockdown in human hepatoma cells stimulated HMGCR alternative splicing and decreased HMGCR transcript stability, reducing cholesterol synthesis and increasing LDL uptake.","method":"Mouse hepatic overexpression model (plasma cholesterol measurement); siRNA knockdown in hepatoma cell lines; RT-PCR for HMGCR alternative splicing; mRNA stability assay; LDL uptake assay","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse model plus cell-line KD with multiple functional readouts, single lab","pmids":["27206982"],"is_preprint":false},{"year":2003,"finding":"SUGP1 (SF4) was identified as a protein containing two SURP motifs (found in spliceosomal proteins including SWAP and yeast prp21p) and a C-terminal G-patch domain (present in RNA-binding proteins), establishing its domain architecture consistent with a splicing factor.","method":"Bioinformatic domain analysis and cDNA cloning; identification of mouse ortholog by sequence similarity and conserved domain organization","journal":"Gene","confidence":"Low","confidence_rationale":"Tier 4 / Weak — domain identification by computational analysis only, no functional experiment performed on SUGP1 itself","pmids":["12594045"],"is_preprint":false},{"year":2025,"finding":"A computational screen of 600 splicing-related proteins showed that only SUGP1 loss recapitulates nearly all splicing defects induced by SF3B1 hotspot mutations; AQR knockdown reproduced ~40% of those defects but was found to act indirectly by causing SUGP1 missplicing and reduced SUGP1 protein levels.","method":"Computational screen with knockdown/knockout of 600 splicing factors; RNA-seq splicing analysis; Western blot for SUGP1 protein levels after AQR knockdown","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — large-scale functional screen plus mechanistic follow-up showing indirect effect of AQR via SUGP1, single lab","pmids":["40714635"],"is_preprint":false},{"year":2025,"finding":"AQR (Aquarius) knockdown causes significant SUGP1 missplicing and reduced SUGP1 protein levels, establishing that AQR acts upstream of SUGP1 and that the splicing defects attributed to AQR loss are indirect consequences of SUGP1 reduction.","method":"siRNA knockdown of AQR; RNA-seq for SUGP1 splicing; Western blot for SUGP1 protein","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, limited methodological detail in abstract","pmids":["40027711"],"is_preprint":true},{"year":2024,"finding":"U2 IP-seq profiling in SF3B1 K700E cells showed that cryptic 3' splice sites activated by K700E are associated with shifted branch site (BS) binding, supporting SUGP1's positive role in early BS choice; thousands of additional BS binding changes were detected that do not alter 3' splice site selection, expanding the known physiological consequences of disrupting the SF3B1-SUGP1 axis.","method":"U2 IP-seq (transcriptome-wide branch site profiling) in SF3B1 K700E K562 cells","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, novel method, single lab, no independent replication yet","pmids":[],"is_preprint":true}],"current_model":"SUGP1 is a spliceosomal G-patch protein that directly binds SF3B1 and recruits/activates the DEAH-box RNA helicase DHX15 via its G-patch motif; this trimeric SF3B1–SUGP1–DHX15 complex is essential for accurate branchsite recognition and 3' splice site selection, and its disruption—either by SF3B1 or SUGP1 cancer-associated mutations—causes widespread aberrant cryptic 3' splice site usage that drives missplicing in cancer; additionally, SUGP1 regulates HMGCR alternative splicing to control cholesterol metabolism in the liver."},"narrative":{"mechanistic_narrative":"SUGP1 is a spliceosomal G-patch protein that ensures accurate branchsite recognition and 3' splice site selection by physically linking the U2 snRNP component SF3B1 to the catalytic RNA helicase machinery [PMID:31474574, PMID:36459648]. It directly binds SF3B1 through regions flanking its G-patch motif, and cancer-associated SF3B1 hotspot mutations (e.g., K700E) act by reducing SUGP1 association with the spliceosome; SUGP1 knockdown alone fully phenocopies the aberrant cryptic 3' splice site usage of mutant SF3B1, and SUGP1 overexpression partially rescues it, identifying loss of the SF3B1–SUGP1 interaction as the molecular defect underlying mutant SF3B1 missplicing [PMID:31474574, PMID:37977822]. SUGP1 uses its G-patch motif to directly bind and activate the DEAH-box helicase DHX15, an interaction defined at atomic resolution; within the trimeric SF3B1–SUGP1–DHX15 assembly the SF3B1 contact 'loops out' the G-patch for DHX15 engagement, and this helicase recruitment underlies a splicing quality-control function that represses suboptimal introns with weak splice sites and cryptic branch points, dependent on DHX15 ATPase activity and the SUGP1 ULM domain [PMID:36459648, PMID:37977822, PMID:37805921]. Independently of its core spliceosomal role, SUGP1 controls cholesterol homeostasis by regulating HMGCR alternative splicing and transcript stability in hepatocytes, with hepatic overexpression raising plasma cholesterol and knockdown reducing cholesterol synthesis [PMID:27206982]. Recurrent somatic SUGP1 mutations and loss-of-heterozygosity across cancers genetically place SUGP1 in the same splicing pathway as SF3B1, reproducing the mutant-SF3B1 missplicing signature [PMID:32332164, PMID:33057152].","teleology":[{"year":2003,"claim":"Established SUGP1's domain architecture, framing it as a candidate splicing factor before any functional test.","evidence":"Bioinformatic domain analysis and cDNA cloning identifying two SURP motifs and a C-terminal G-patch domain","pmids":["12594045"],"confidence":"Low","gaps":["No functional experiment performed on SUGP1 itself","Domain assignments inferred from homology only","No interaction partners identified"]},{"year":2016,"claim":"Connected SUGP1 to a physiological output—cholesterol metabolism—by showing it regulates HMGCR alternative splicing and transcript stability.","evidence":"Mouse hepatic overexpression with plasma cholesterol measurement, hepatoma cell knockdown, RT-PCR for HMGCR splicing, mRNA stability and LDL uptake assays","pmids":["27206982"],"confidence":"Medium","gaps":["Mechanism linking SUGP1 to HMGCR splice site choice not defined","Single lab","Relationship to SUGP1's core spliceosomal role unclear"]},{"year":2019,"claim":"Identified loss of SF3B1–SUGP1 interaction as the causal molecular defect of mutant SF3B1, resolving how a single SF3B1 hotspot mutation produces widespread missplicing.","evidence":"Affinity purification/MS of WT vs K700E SF3B1 complexes, siRNA knockdown with RNA-seq phenocopy, and overexpression rescue in patient-derived cells","pmids":["31474574"],"confidence":"High","gaps":["Structural basis of SF3B1–SUGP1 contact not yet defined","Downstream effector of SUGP1 not identified","Why specific 3' splice sites are sensitive unresolved"]},{"year":2020,"claim":"Placed SUGP1 genetically within the SF3B1 splicing pathway in cancer by showing SUGP1 somatic mutations and LOH reproduce the mutant-SF3B1 missplicing signature.","evidence":"Pan-cancer RNA-seq screens (TCGA) with experimental validation of multiple SUGP1 mutants and loss-of-function models in cell lines","pmids":["32332164","33057152"],"confidence":"Medium","gaps":["Mechanism by which each mutation impairs function not dissected at residue level","Oncogenic consequence of the missplicing not established","Single-lab validation per study"]},{"year":2022,"claim":"Identified DHX15 as the cognate helicase activated by SUGP1's G-patch, providing the catalytic effector downstream of SF3B1–SUGP1.","evidence":"Co-IP/pulldown, knockdown with RNA-seq, DHX15 mutant and SUGP1-G-patch fusion rescue, and crystal structure of the DHX15–SUGP1 G-patch complex","pmids":["36459648"],"confidence":"High","gaps":["Structure limited to the G-patch–DHX15 interface, not the full trimer","RNA substrate engaged by the helicase not defined","How helicase action enforces correct splice site choice unresolved"]},{"year":2023,"claim":"Defined the trimeric SF3B1–SUGP1–DHX15 architecture and showed all interface cancer mutations weaken SF3B1–SUGP1 binding, and that DHX15 quality control requires SUGP1's G-patch and ULM domains.","evidence":"Structural modeling with interface mutagenesis, co-IP and splicing reporter assays; auxin-inducible degron depletion with nascent/mature RNA-seq and domain mutagenesis","pmids":["37977822","37805921"],"confidence":"High","gaps":["No experimental structure of the full trimeric complex","ULM-binding partner in this context not directly mapped","How the 'looped-out' G-patch is regulated dynamically unknown"]},{"year":2025,"claim":"Demonstrated SUGP1's uniqueness among splicing factors—only SUGP1 loss recapitulates nearly all mutant-SF3B1 defects—and resolved that AQR acts only indirectly via SUGP1.","evidence":"Computational screen of 600 splicing factors with knockdown/knockout RNA-seq; Western blot for SUGP1 protein after AQR knockdown; preprint follow-up on AQR-SUGP1 dependency","pmids":["40714635","40027711"],"confidence":"Medium","gaps":["AQR-SUGP1 link partly from a preprint","How AQR loss causes SUGP1 missplicing not mechanistically detailed","Full set of SUGP1-dependent vs SUGP1-independent SF3B1 effects not partitioned"]},{"year":null,"claim":"How disruption of the SF3B1–SUGP1–DHX15 axis is converted into oncogenic phenotypes, and how branch-site selection is mechanistically governed by SUGP1, remain open.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length trimeric complex structure","Causal link between specific missplicing events and tumorigenesis unestablished","Branch-site profiling consequences (U2 IP-seq) reported only in preprint"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,5]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[6]}],"complexes":["spliceosome (U2 snRNP-associated)","SF3B1–SUGP1–DHX15 complex"],"partners":["SF3B1","DHX15","AQR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IWZ8","full_name":"SURP and G-patch domain-containing protein 1","aliases":["RNA-binding protein RBP","Splicing factor 4"],"length_aa":645,"mass_kda":72.5,"function":"Plays a role in pre-mRNA splicing","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q8IWZ8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SUGP1","classification":"Common Essential","n_dependent_lines":1099,"n_total_lines":1208,"dependency_fraction":0.9097682119205298},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"RANBP2","stoichiometry":10.0},{"gene":"U2SURP","stoichiometry":4.0},{"gene":"COMMD4","stoichiometry":0.2},{"gene":"CTPS1","stoichiometry":0.2},{"gene":"RBM17","stoichiometry":0.2},{"gene":"RBM39","stoichiometry":0.2},{"gene":"SF3A1","stoichiometry":0.2},{"gene":"SF3B1","stoichiometry":0.2},{"gene":"SF3B2","stoichiometry":0.2},{"gene":"SF3B3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SUGP1","total_profiled":1310},"omim":[{"mim_id":"621458","title":"WD REPEAT-CONTAINING PROTEIN 89; WDR89","url":"https://www.omim.org/entry/621458"},{"mim_id":"607993","title":"SURP AND G-PATCH DOMAINS-CONTAINING PROTEIN 2; SUGP2","url":"https://www.omim.org/entry/607993"},{"mim_id":"607992","title":"SURP AND G-PATCH DOMAINS-CONTAINING PROTEIN 1; SUGP1","url":"https://www.omim.org/entry/607992"},{"mim_id":"604979","title":"CLEAVAGE AND POLYADENYLATION SPECIFICITY FACTOR 6; CPSF6","url":"https://www.omim.org/entry/604979"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SUGP1"},"hgnc":{"alias_symbol":["F23858","DKFZp434E2216","RBP"],"prev_symbol":["SF4"]},"alphafold":{"accession":"Q8IWZ8","domains":[{"cath_id":"1.10.10.790","chopping":"169-254","consensus_level":"high","plddt":81.7274,"start":169,"end":254},{"cath_id":"1.10.10.790","chopping":"262-323","consensus_level":"high","plddt":86.6135,"start":262,"end":323},{"cath_id":"-","chopping":"526-578_609-645","consensus_level":"medium","plddt":73.1998,"start":526,"end":645}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IWZ8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IWZ8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IWZ8-F1-predicted_aligned_error_v6.png","plddt_mean":64.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SUGP1","jax_strain_url":"https://www.jax.org/strain/search?query=SUGP1"},"sequence":{"accession":"Q8IWZ8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IWZ8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IWZ8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IWZ8"}},"corpus_meta":[{"pmid":"31474574","id":"PMC_31474574","title":"Disease-Causing Mutations in SF3B1 Alter Splicing by Disrupting Interaction with SUGP1.","date":"2019","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/31474574","citation_count":104,"is_preprint":false},{"pmid":"36459648","id":"PMC_36459648","title":"DHX15 is involved in SUGP1-mediated RNA missplicing by mutant SF3B1 in cancer.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/36459648","citation_count":44,"is_preprint":false},{"pmid":"32332164","id":"PMC_32332164","title":"Pan-cancer analysis identifies mutations in SUGP1 that recapitulate mutant SF3B1 splicing dysregulation.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/32332164","citation_count":39,"is_preprint":false},{"pmid":"27206982","id":"PMC_27206982","title":"SUGP1 is a novel regulator of cholesterol 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\"SF3B1 hotspot mutations (e.g., K700E) reduce the level of SUGP1 in spliceosomes, and SUGP1 knockdown alone completely recapitulates the aberrant 3' splice site usage caused by mutant SF3B1; conversely, SUGP1 overexpression partially rescues splicing in mutant SF3B1 cells, establishing that loss of SF3B1-SUGP1 interaction is the molecular defect underlying mutant SF3B1 splicing errors.\",\n      \"method\": \"Affinity purification of WT vs. K700E SF3B1 complexes followed by mass spectrometry; siRNA knockdown of SUGP1 with RNA-seq; SUGP1 overexpression rescue experiments in MDS patient-derived cells\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal complex purification, KD phenocopy, and OE rescue across multiple SF3B1 hotspot mutants, replicated by independent labs\",\n      \"pmids\": [\"31474574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SUGP1 uses its G-patch motif to directly bind and activate the DEAH-box RNA helicase DHX15; DHX15 depletion or expression of AML-associated DHX15 mutants partially recapitulates mutant SF3B1 splicing defects; a DHX15-SUGP1 G-patch fusion rescues those splicing defects; crystal structure of the human DHX15-SUGP1 G-patch complex reveals the molecular basis of direct interaction.\",\n      \"method\": \"Protein-protein interaction assays (co-IP, pulldown), siRNA/shRNA knockdown with RNA-seq, DHX15 mutant expression, fusion protein rescue, crystal structure of DHX15-SUGP1 G-patch complex\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus multiple orthogonal biochemical and genetic methods in one study, identifying DHX15 as the cognate helicase for SUGP1\",\n      \"pmids\": [\"36459648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Pan-cancer computational analysis followed by experimental validation showed that five different SUGP1 somatic mutations (identified in cancers) completely or partially recapitulate the cryptic 3' splice site usage seen in mutant SF3B1 cancers, genetically placing SUGP1 downstream in the same splicing pathway as SF3B1.\",\n      \"method\": \"Pan-cancer RNA-seq analysis (TCGA); experimental validation of SUGP1 mutants by plasmid expression in cell lines with splicing readout\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — computational screen plus experimental validation of five mutations, single lab but two orthogonal approaches\",\n      \"pmids\": [\"32332164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Somatic SUGP1 mutations combined with loss-of-heterozygosity in lung adenocarcinoma and other cancers induce mutant SF3B1-like aberrant splicing, and modelling of SUGP1 loss or mutation in cell lines confirmed that both alterations generate this missplicing pattern.\",\n      \"method\": \"Pan-TCGA genomic screening; SUGP1 loss-of-function and mutation modelling in cell lines with RNA-seq splicing analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — independent pan-cancer screen plus cell-line functional validation, single lab\",\n      \"pmids\": [\"33057152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Structural modeling and mutagenesis revealed that two regions flanking the SUGP1 G-patch make numerous contacts with the SF3B1 region harboring hotspot mutations; all cancer-associated mutations at the SF3B1-SUGP1 interface weaken or disrupt the interaction and alter splicing; the trimeric SF3B1-SUGP1-DHX15 model shows that the SF3B1-SUGP1 interaction 'loops out' the G-patch for DHX15 engagement.\",\n      \"method\": \"Structural modeling; mutagenesis of interface residues; co-IP interaction assays; splicing reporter assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — structural modeling with extensive mutagenesis and functional validation by co-IP and splicing assays in a single focused study\",\n      \"pmids\": [\"37977822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DHX15's splicing quality control function in human cells—repressing suboptimal introns with weak splice sites, multiple branch points, and cryptic introns—requires SUGP1 as a G-patch activator; this interaction depends on both DHX15's ATPase activity and SUGP1's ULM (U2AF ligand motif) domain.\",\n      \"method\": \"Rapid protein depletion (auxin-inducible degron); nascent and mature RNA-seq; domain mutagenesis; protein interaction assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rapid depletion system enriching for direct effects, domain mutagenesis, RNA-seq, replicated independently from PNAS 2022 study\",\n      \"pmids\": [\"37805921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SUGP1 regulates cholesterol metabolism: rs10401969 causes SUGP1 exon 8 skipping and nonsense-mediated decay; hepatic Sugp1 overexpression in mice increased plasma cholesterol 20–50%; SUGP1 knockdown in human hepatoma cells stimulated HMGCR alternative splicing and decreased HMGCR transcript stability, reducing cholesterol synthesis and increasing LDL uptake.\",\n      \"method\": \"Mouse hepatic overexpression model (plasma cholesterol measurement); siRNA knockdown in hepatoma cell lines; RT-PCR for HMGCR alternative splicing; mRNA stability assay; LDL uptake assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse model plus cell-line KD with multiple functional readouts, single lab\",\n      \"pmids\": [\"27206982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SUGP1 (SF4) was identified as a protein containing two SURP motifs (found in spliceosomal proteins including SWAP and yeast prp21p) and a C-terminal G-patch domain (present in RNA-binding proteins), establishing its domain architecture consistent with a splicing factor.\",\n      \"method\": \"Bioinformatic domain analysis and cDNA cloning; identification of mouse ortholog by sequence similarity and conserved domain organization\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — domain identification by computational analysis only, no functional experiment performed on SUGP1 itself\",\n      \"pmids\": [\"12594045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A computational screen of 600 splicing-related proteins showed that only SUGP1 loss recapitulates nearly all splicing defects induced by SF3B1 hotspot mutations; AQR knockdown reproduced ~40% of those defects but was found to act indirectly by causing SUGP1 missplicing and reduced SUGP1 protein levels.\",\n      \"method\": \"Computational screen with knockdown/knockout of 600 splicing factors; RNA-seq splicing analysis; Western blot for SUGP1 protein levels after AQR knockdown\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — large-scale functional screen plus mechanistic follow-up showing indirect effect of AQR via SUGP1, single lab\",\n      \"pmids\": [\"40714635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AQR (Aquarius) knockdown causes significant SUGP1 missplicing and reduced SUGP1 protein levels, establishing that AQR acts upstream of SUGP1 and that the splicing defects attributed to AQR loss are indirect consequences of SUGP1 reduction.\",\n      \"method\": \"siRNA knockdown of AQR; RNA-seq for SUGP1 splicing; Western blot for SUGP1 protein\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, limited methodological detail in abstract\",\n      \"pmids\": [\"40027711\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"U2 IP-seq profiling in SF3B1 K700E cells showed that cryptic 3' splice sites activated by K700E are associated with shifted branch site (BS) binding, supporting SUGP1's positive role in early BS choice; thousands of additional BS binding changes were detected that do not alter 3' splice site selection, expanding the known physiological consequences of disrupting the SF3B1-SUGP1 axis.\",\n      \"method\": \"U2 IP-seq (transcriptome-wide branch site profiling) in SF3B1 K700E K562 cells\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, novel method, single lab, no independent replication yet\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SUGP1 is a spliceosomal G-patch protein that directly binds SF3B1 and recruits/activates the DEAH-box RNA helicase DHX15 via its G-patch motif; this trimeric SF3B1–SUGP1–DHX15 complex is essential for accurate branchsite recognition and 3' splice site selection, and its disruption—either by SF3B1 or SUGP1 cancer-associated mutations—causes widespread aberrant cryptic 3' splice site usage that drives missplicing in cancer; additionally, SUGP1 regulates HMGCR alternative splicing to control cholesterol metabolism in the liver.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SUGP1 is a spliceosomal G-patch protein that ensures accurate branchsite recognition and 3' splice site selection by physically linking the U2 snRNP component SF3B1 to the catalytic RNA helicase machinery [#0, #1]. It directly binds SF3B1 through regions flanking its G-patch motif, and cancer-associated SF3B1 hotspot mutations (e.g., K700E) act by reducing SUGP1 association with the spliceosome; SUGP1 knockdown alone fully phenocopies the aberrant cryptic 3' splice site usage of mutant SF3B1, and SUGP1 overexpression partially rescues it, identifying loss of the SF3B1–SUGP1 interaction as the molecular defect underlying mutant SF3B1 missplicing [#0, #4]. SUGP1 uses its G-patch motif to directly bind and activate the DEAH-box helicase DHX15, an interaction defined at atomic resolution; within the trimeric SF3B1–SUGP1–DHX15 assembly the SF3B1 contact 'loops out' the G-patch for DHX15 engagement, and this helicase recruitment underlies a splicing quality-control function that represses suboptimal introns with weak splice sites and cryptic branch points, dependent on DHX15 ATPase activity and the SUGP1 ULM domain [#1, #4, #5]. Independently of its core spliceosomal role, SUGP1 controls cholesterol homeostasis by regulating HMGCR alternative splicing and transcript stability in hepatocytes, with hepatic overexpression raising plasma cholesterol and knockdown reducing cholesterol synthesis [#6]. Recurrent somatic SUGP1 mutations and loss-of-heterozygosity across cancers genetically place SUGP1 in the same splicing pathway as SF3B1, reproducing the mutant-SF3B1 missplicing signature [#2, #3].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established SUGP1's domain architecture, framing it as a candidate splicing factor before any functional test.\",\n      \"evidence\": \"Bioinformatic domain analysis and cDNA cloning identifying two SURP motifs and a C-terminal G-patch domain\",\n      \"pmids\": [\"12594045\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional experiment performed on SUGP1 itself\", \"Domain assignments inferred from homology only\", \"No interaction partners identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected SUGP1 to a physiological output—cholesterol metabolism—by showing it regulates HMGCR alternative splicing and transcript stability.\",\n      \"evidence\": \"Mouse hepatic overexpression with plasma cholesterol measurement, hepatoma cell knockdown, RT-PCR for HMGCR splicing, mRNA stability and LDL uptake assays\",\n      \"pmids\": [\"27206982\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking SUGP1 to HMGCR splice site choice not defined\", \"Single lab\", \"Relationship to SUGP1's core spliceosomal role unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified loss of SF3B1–SUGP1 interaction as the causal molecular defect of mutant SF3B1, resolving how a single SF3B1 hotspot mutation produces widespread missplicing.\",\n      \"evidence\": \"Affinity purification/MS of WT vs K700E SF3B1 complexes, siRNA knockdown with RNA-seq phenocopy, and overexpression rescue in patient-derived cells\",\n      \"pmids\": [\"31474574\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of SF3B1–SUGP1 contact not yet defined\", \"Downstream effector of SUGP1 not identified\", \"Why specific 3' splice sites are sensitive unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed SUGP1 genetically within the SF3B1 splicing pathway in cancer by showing SUGP1 somatic mutations and LOH reproduce the mutant-SF3B1 missplicing signature.\",\n      \"evidence\": \"Pan-cancer RNA-seq screens (TCGA) with experimental validation of multiple SUGP1 mutants and loss-of-function models in cell lines\",\n      \"pmids\": [\"32332164\", \"33057152\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which each mutation impairs function not dissected at residue level\", \"Oncogenic consequence of the missplicing not established\", \"Single-lab validation per study\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified DHX15 as the cognate helicase activated by SUGP1's G-patch, providing the catalytic effector downstream of SF3B1–SUGP1.\",\n      \"evidence\": \"Co-IP/pulldown, knockdown with RNA-seq, DHX15 mutant and SUGP1-G-patch fusion rescue, and crystal structure of the DHX15–SUGP1 G-patch complex\",\n      \"pmids\": [\"36459648\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure limited to the G-patch–DHX15 interface, not the full trimer\", \"RNA substrate engaged by the helicase not defined\", \"How helicase action enforces correct splice site choice unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined the trimeric SF3B1–SUGP1–DHX15 architecture and showed all interface cancer mutations weaken SF3B1–SUGP1 binding, and that DHX15 quality control requires SUGP1's G-patch and ULM domains.\",\n      \"evidence\": \"Structural modeling with interface mutagenesis, co-IP and splicing reporter assays; auxin-inducible degron depletion with nascent/mature RNA-seq and domain mutagenesis\",\n      \"pmids\": [\"37977822\", \"37805921\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No experimental structure of the full trimeric complex\", \"ULM-binding partner in this context not directly mapped\", \"How the 'looped-out' G-patch is regulated dynamically unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated SUGP1's uniqueness among splicing factors—only SUGP1 loss recapitulates nearly all mutant-SF3B1 defects—and resolved that AQR acts only indirectly via SUGP1.\",\n      \"evidence\": \"Computational screen of 600 splicing factors with knockdown/knockout RNA-seq; Western blot for SUGP1 protein after AQR knockdown; preprint follow-up on AQR-SUGP1 dependency\",\n      \"pmids\": [\"40714635\", \"40027711\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"AQR-SUGP1 link partly from a preprint\", \"How AQR loss causes SUGP1 missplicing not mechanistically detailed\", \"Full set of SUGP1-dependent vs SUGP1-independent SF3B1 effects not partitioned\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How disruption of the SF3B1–SUGP1–DHX15 axis is converted into oncogenic phenotypes, and how branch-site selection is mechanistically governed by SUGP1, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length trimeric complex structure\", \"Causal link between specific missplicing events and tumorigenesis unestablished\", \"Branch-site profiling consequences (U2 IP-seq) reported only in preprint\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [\"spliceosome (U2 snRNP-associated)\", \"SF3B1–SUGP1–DHX15 complex\"],\n    \"partners\": [\"SF3B1\", \"DHX15\", \"AQR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":5,"faith_pct":100.0}}