{"gene":"SRA1","run_date":"2026-04-28T20:42:08","timeline":{"discoveries":[{"year":1999,"finding":"SRA (Steroid Receptor RNA Activator) was identified as a novel transcriptional coactivator that functions as an RNA transcript rather than a protein; it is selective for steroid hormone receptors, mediates transactivation via their amino-terminal AF-1 activation function, and exists in distinct ribonucleoprotein complexes including one containing SRC-1. Evidence that SRA functions as RNA: coactivation persists in the presence of cycloheximide and SRA mutants with multiple translational stop signals retain coactivator activity.","method":"Biochemical fractionation, ribonucleoprotein complex isolation, functional reporter assays with cycloheximide treatment, translational stop-signal mutagenesis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 — original discovery with multiple orthogonal methods (fractionation, mutagenesis, cycloheximide experiments), foundational paper with 640 citations","pmids":["10199399"],"is_preprint":false},{"year":2001,"finding":"The RNA-binding DEAD-box proteins p72/p68 function as estrogen receptor alpha (ERα) coactivators through the AF-1 domain by associating with a coactivator complex containing SRA and SRC-1/TIF2. p72/p68 interact with the AD2 domain of SRC-1/TIF2 family proteins and the ERα A/B domain, and co-immunoprecipitate with estrogen-bound ERα in MCF7 cells. Combination of p72/p68 with SRA and TIF2 produces synergistic estrogen-induced transactivation of ERα.","method":"Co-immunoprecipitation from MCF7 cells and HeLa nuclear extracts, transient transfection reporter assays, immunofluorescence co-localization","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP in cells plus functional synergy assays, replicated in multiple cell systems","pmids":["11250900"],"is_preprint":false},{"year":2003,"finding":"SRA coactivates ERα in a ligand-independent manner through the AF-1 domain, requiring an intact serine-118 (S118) residue in ERα AF-1. MAPK activation induces ligand-independent coactivation of ERα by SRA; activated H-Ras (H-RasV12) cannot rescue S118 ERα mutant activity, indicating that MAPK-mediated phosphorylation of S118 participates in SRA's AF-1-dependent effect. SRA does not coactivate ERβ via AF-1 in the same manner, demonstrating isoform selectivity.","method":"Transient transfection reporter assays, site-directed mutagenesis of ERα S118, co-expression with activated Ras and MAPK pathway components","journal":"The Journal of steroid biochemistry and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 — clean mutagenesis with functional readout, single lab","pmids":["12943696"],"is_preprint":false},{"year":2003,"finding":"In Drosophila cells, Sra-1 (ortholog of human CYFIP1/SRA1 WAVE complex subunit), together with Abi and Kette (Nap1), protects SCAR/WAVE from proteasome-mediated degradation and is critical for SCAR localization and for Arp2/3-dependent actin protrusion generation. RNAi-mediated removal of Sra-1, Abi, or Kette abolishes dynamic protrusions, demonstrating these proteins are essential components of the SCAR regulatory complex downstream of Rac and Cdc42.","method":"RNAi screen in Drosophila adherent cells, immunofluorescence, proteasome inhibitor experiments, epistasis analysis","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 — RNAi loss-of-function with defined cellular phenotype and pathway placement, multiple genetic epistasis experiments","pmids":["14588242"],"is_preprint":false},{"year":2004,"finding":"Sra-1 (CYFIP/PIR121) and Nap1 are constitutive components of a WAVE2/Abi-1-containing complex that links Rac1 signaling to site-directed actin assembly and lamellipodia formation. RNA interference removal of Sra-1 or Nap1 abrogates Rac-dependent lamellipodia induced by growth factor stimulation or aluminum fluoride treatment, and microinjection of constitutively active Rac fails to restore lamellipodia in cells lacking either protein. Sra-1, Nap1, WAVE2, and Abi-1 translocate to tips of membrane protrusions after active Rac microinjection.","method":"RNAi knockdown, microinjection of constitutively active Rac1, immunofluorescence, co-immunoprecipitation of complex components","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (RNAi, microinjection, Co-IP, localization), clear epistasis, 325 citations","pmids":["14765121"],"is_preprint":false},{"year":2004,"finding":"The Arabidopsis PIROGI gene encodes a functional ortholog of the human WAVE complex subunit SRA1 (CYFIP1). PIROGI/SRA1 directly interacts with the small GTPase ATROP2 with isoform specificity and selectivity for active (GTP-bound) forms. Both PIROGI and human SRA1 are functionally interchangeable and display identical physical interactions with RHO family GTPases and the WAVE complex subunit NAP125, indicating deeply conserved molecular function in ARP2/3-dependent actin regulation.","method":"Genetic complementation, yeast two-hybrid, pull-down assays with active/inactive GTPase forms, phenotypic analysis of pir mutants","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1-2 — direct biochemical interaction assays plus genetic complementation, functional conservation demonstrated","pmids":["15294869"],"is_preprint":false},{"year":2004,"finding":"Drosophila Sra-1 interacts physically with Kette (Nap1) in vivo, and both proteins stabilize each other. Sra-1 is expressed in neuronal growth cones; RNAi knockdown of sra-1 in photoreceptor neurons causes stalling of axonal growth, and knockdown in motoneurons produces abnormal neuromuscular junctions similar to kette hypomorphic mutants. A membrane-bound Sra-1 lacking the Kette-binding domain phenocopies loss of function, indicating Sra-1 function is mediated through Kette and controls F-actin cytoskeleton in a Wasp-dependent manner.","method":"In vivo co-immunoprecipitation, RNAi in specific neuronal subtypes, dominant-negative Sra-1 construct lacking Kette-binding domain, confocal imaging of neuromuscular junctions","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, genetic epistasis with dominant-negative, multiple neuronal phenotypic readouts","pmids":["15269173"],"is_preprint":false},{"year":2005,"finding":"CRMP-2 interacts with the Sra-1/WAVE1 complex and with the light chain of kinesin-1, linking kinesin-1 to the Sra-1/WAVE1 complex for anterograde transport to axonal growth cones. Knockdown of Sra-1 and WAVE1 cancels CRMP-2-induced axon outgrowth and multiple-axon formation in hippocampal neurons; knockdown of CRMP-2 or kinesin-1 delocalizes Sra-1 and WAVE1 from growth cones, establishing a kinesin-1-dependent transport mechanism for the Sra-1/WAVE1 complex in axon formation.","method":"Co-immunoprecipitation, RNAi knockdown in hippocampal neurons, immunofluorescence localization in growth cones","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus RNAi with defined axonal phenotypes and localization readout, multiple interactors confirmed","pmids":["16260607"],"is_preprint":false},{"year":2006,"finding":"The RNA helicases p68/p72 (DDX5/DDX17) are MyoD-associated proteins, and the non-coding RNA SRA co-immunoprecipitates with MyoD. Both p68/p72 and SRA function as coactivators of MyoD in skeletal muscle differentiation; RNAi knockdown of either p68/p72 or SRA prevents activation of muscle gene expression and cell differentiation. Loss of p68/p72 impairs recruitment of TBP, RNA polymerase II, and the SWI/SNF catalytic subunit Brg-1, and hinders chromatin remodeling at muscle gene promoters.","method":"Co-immunoprecipitation with MyoD, RNAi knockdown, chromatin immunoprecipitation, reporter assays, differentiation assays","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, RNAi with defined differentiation phenotype, ChIP for mechanism, 248 citations","pmids":["17011493"],"is_preprint":false},{"year":2006,"finding":"SLIRP (SRA stem-loop interacting RNA binding protein) binds a functional substructure of SRA RNA (STR7) via its RNA recognition motif (RRM) and functions as a nuclear receptor corepressor. SLIRP represses nuclear receptor transactivation in a SRA- and RRM-dependent manner, augments tamoxifen's effect, modulates SRC-1 association with SRA, and is recruited to endogenous promoters in a SRA-dependent manner. SHARP also binds STR7, augmenting repression with SLIRP.","method":"RNA pull-down, co-immunoprecipitation, reporter assays, chromatin immunoprecipitation, RRM mutagenesis, immunofluorescence","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 — direct RNA-protein binding assays, mutagenesis, ChIP, functional reporter assays, 109 citations","pmids":["16762838"],"is_preprint":false},{"year":2006,"finding":"Alternative splicing of the first intron of SRA1 generates both coding (SRAP-producing) and non-coding SRA RNA isoforms in breast cancer cell lines. The intron-1 sequence is sufficient to drive differential splicing in both endogenous and minigene contexts. The relative proportion of coding vs. non-coding SRA transcripts varies across breast cancer cell lines, suggesting that alternative splicing is a regulatory mechanism controlling the balance between SRA RNA coactivator and SRAP protein.","method":"5'-RACE, RT-PCR with isoform-specific primers, minigene splicing assay in breast cancer cell lines","journal":"DNA and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — minigene functional validation plus endogenous RT-PCR, single lab","pmids":["16848684"],"is_preprint":false},{"year":2007,"finding":"SRA1 encodes both a non-coding RNA (SRA) and an endogenous protein (SRAP) through alternative splicing of intron-1; retention of intron-1 disrupts the SRAP open reading frame, generating the non-coding isoform. Both SRA RNA and SRAP have opposing regulatory roles on steroid receptor signaling and are conserved among Chordata, establishing SRA1 as a bifaceted gene.","method":"Review/synthesis of published molecular characterization; original data on isoform identification referenced","journal":"Nuclear receptor signaling","confidence":"Low","confidence_rationale":"Tier 4 — review article synthesizing prior work, no new primary experimental data","pmids":["17710122"],"is_preprint":false},{"year":2008,"finding":"SRA1 gene knockout (SRA-/-) in zebrafish using morpholino antisense reagents results in a phenotype of myocardial contractile dysfunction, demonstrating that SRA1 (along with HBEGF and IK, which cosegregate in a 600-kb linkage disequilibrium block) independently contributes to cardiac muscle function in vivo.","method":"Morpholino antisense knockdown in zebrafish, cardiac function assessment","journal":"Genome research","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo loss-of-function with defined cardiac phenotype, but SRA1 contribution not fully disentangled from co-segregating genes","pmids":["19064678"],"is_preprint":false},{"year":2009,"finding":"SRA functions as an RNA coactivator for steroidogenic factor 1 (SF-1), and both SF-1 and Dax-1 bind SRA. Dax-1 acts as a dosage-dependent SF-1 coactivator through SRA; SRA knockdown abolishes Dax-1-mediated coactivation and reduces expression of steroidogenic gene products (StAR, MC2R) in adrenal Y1 cells. TIF2 associates with Dax-1 and synergistically coactivates SF-1 target gene transcription in a SRA-dependent manner.","method":"Co-immunoprecipitation, siRNA knockdown of SRA, reporter assays, qRT-PCR of steroidogenic gene products","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — Co-IP plus siRNA knockdown with defined gene expression readout in steroidogenic cells, multiple approaches","pmids":["19188450"],"is_preprint":false},{"year":2010,"finding":"SRA non-coding RNA enhances myogenic differentiation and myogenic conversion through co-activation of MyoD activity, while SRAP (the protein encoded by the same locus) counteracts this SRA RNA-dependent co-activation. SRAP's inhibitory effect is mediated through its RRM-like domain interacting with functional sub-structure STR7 of SRA RNA, establishing a regulatory feedback between the two products of the SRA1 locus.","method":"Constructs producing exclusively SRA ncRNA or SRAP protein, myogenic differentiation assays in human satellite cells, co-immunoprecipitation, domain mutagenesis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 — isoform-specific constructs, RRM-domain mutagenesis, functional differentiation assays, mechanistically dissects RNA vs. protein contributions","pmids":["20855289"],"is_preprint":false},{"year":2010,"finding":"SRA non-coding RNA associates with PPARγ and coactivates PPARγ-dependent gene expression to promote adipogenesis. SRA overexpression in ST2 mesenchymal precursor cells promotes adipocyte differentiation; SRA knockdown inhibits 3T3-L1 preadipocyte differentiation. SRA also increases glucose uptake and Akt/FOXO1 phosphorylation in response to insulin, promotes S-phase entry by decreasing p21Cip1 and p27Kip1 expression, and inhibits TNFα-induced JNK phosphorylation, demonstrating multiple signaling roles.","method":"Co-immunoprecipitation of SRA with PPARγ, reporter assays, siRNA knockdown, overexpression in ST2 cells, flow cytometry, Western blotting for signaling pathway components","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — Co-IP plus gain/loss-of-function with multiple cellular and molecular readouts, multiple pathways examined","pmids":["21152033"],"is_preprint":false},{"year":2010,"finding":"The DEAD-box RNA helicase p68 (DDX5) and its associated non-coding RNA SRA form a complex with CTCF that is essential for insulator function at the IGF2/H19 imprinted control region (ICR). Depletion of SRA or p68 reduces CTCF-mediated insulator activity, increases IGF2 expression, and reduces cohesin binding to CTCF sites without affecting CTCF binding itself. p68/SRA interacts with cohesin complex members, suggesting that p68/SRA stabilizes cohesin-CTCF interaction.","method":"ChIP, co-immunoprecipitation, siRNA knockdown, chromosome conformation capture (3C), reporter assays for insulator function","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — ChIP, Co-IP, 3C, and functional insulator assays in multiple orthogonal approaches, 194 citations","pmids":["20966046"],"is_preprint":false},{"year":2010,"finding":"Dax1 augments LRH-1-mediated activation of the Oct4 gene in mouse embryonic stem cells through a mechanism dependent on the RNA coactivator SRA; SRA knockdown abolishes Dax1-mediated coactivation of Oct4. Dax1 and LRH-1 co-localize at 43% of LRH-1 target genes involved in mES cell pluripotency, and SRA is required for their co-activation.","method":"Co-immunoprecipitation of Dax1 with LRH-1, ChIP at Oct4 promoter, luciferase reporter assays, siRNA knockdown of SRA, genome-wide ChIP analysis","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, ChIP, and siRNA with functional reporter readout, single lab","pmids":["20943815"],"is_preprint":false},{"year":2010,"finding":"Protein complexes containing CYFIP/Sra/PIR121 coordinate Arf1 and Rac1 signaling during clathrin-AP-1-coated carrier biogenesis at the trans-Golgi network (TGN). CYFIP-containing complexes are recruited to TGN membranes by Arf1 GTPase; Rac1 and its exchange factor β-PIX then activate these complexes to promote N-WASP- and Arp2/3-dependent actin polymerization and tubule formation. These events were reconstituted with synthetic membranes.","method":"Immunoprecipitation of CYFIP complexes, synthetic membrane reconstitution assay, siRNA knockdown, fluorescence microscopy, dominant-negative GTPase experiments","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro reconstitution on synthetic membranes plus cellular epistasis and Co-IP, multiple GTPase effector relationships defined","pmids":["20228810"],"is_preprint":false},{"year":2010,"finding":"SRA RNA depletion in human cancer cell lines (MCF-7 and MDA-MB-231) by siRNA reveals hundreds of endogenous SRA target genes, with the majority reduced upon knockdown, implicating SRA as a broad endogenous coactivator. Novel SRA targets identified include SLC2A3, SLC2A12, CCL20, TGFB2, DIO2, TMEM65, TBL1X, and TMPRSS2. SRA depletion in MDA-MB-231 cells reduces invasiveness.","method":"siRNA knockdown, microarray gene expression profiling, reporter assays for specific promoters","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 — genome-wide target identification with siRNA, but primarily transcriptomic with limited mechanistic follow-up on individual targets","pmids":["20219889"],"is_preprint":false},{"year":2013,"finding":"The cytoplasmic RISC proteins PACT, TRBP, and Dicer bind SRA RNA and function as nuclear receptor coregulators. These RISC proteins, together with Argonaute 2, associate with SRA and specific pre-microRNAs in both the nucleus and cytoplasm and target steroid-responsive promoters to regulate nuclear receptor activity and downstream gene expression.","method":"RNA pull-down with SRA, co-immunoprecipitation, ChIP at steroid-responsive promoters, reporter assays, immunofluorescence showing nuclear/cytoplasmic localization","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — direct RNA-protein binding plus ChIP and functional reporter assays, single lab","pmids":["23550157"],"is_preprint":false},{"year":2013,"finding":"RNA helicase Ddx5 (p68) is a novel component of the RBP-J/NICD (Notch intracellular domain) complex; Ddx5 directly interacts with RBP-J and localizes to RBP-J binding sites at Notch target gene loci (preTCRα, Hes1, CD25) in a Notch-dependent manner. SRA, as a cofactor of Ddx5, is also required for Notch target gene activation; knockdown of SRA downregulates Hes1 and preTCRα, associated with loss of p300 occupancy and decreased histone acetylation at Notch target genes.","method":"Biotinylation-tagging/mass spectrometry, Co-IP, ChIP, siRNA knockdown, reporter assays","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 — mass-spec identification, Co-IP confirmation, ChIP for localization, functional knockdown, single lab","pmids":["23396200"],"is_preprint":false},{"year":2014,"finding":"Whole-body Sra1 gene knockout (SRA-/-) mice are resistant to high-fat diet-induced obesity with decreased fat mass, increased insulin sensitivity (reduced fasting insulin, improved glucose tolerance), decreased adipocyte marker gene expression, reduced plasma TNFα, and fewer hepatic lipid droplets with decreased lipogenesis-associated gene expression. This demonstrates an in vivo role for the SRA1 gene product in adipose tissue mass and glucose homeostasis.","method":"Gene knockout mouse model (whole-body Sra1 KO), high-fat diet feeding, body composition analysis, glucose/insulin tolerance tests, gene expression analysis, histology","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — clean KO with multiple defined metabolic phenotypes and molecular readouts in vivo, 101 citations","pmids":["24675075"],"is_preprint":false},{"year":2014,"finding":"The crystal structure of the carboxy-terminal domain of human SRAP (SRA protein) reveals a five-helix bundle that is structurally distinct from known RNA-binding motifs and instead resembles the C-terminal domain of the yeast spliceosome protein PRP18. The structure does not contain the postulated RRM (RNA recognition motif), and direct RNA-binding experiments (in vitro with recombinant SRAP and in cell-based assays) failed to reveal a specific interaction between SRAP and SRA RNA, necessitating re-evaluation of the current model for SRAP function.","method":"Crystal structure determination, RNA-binding assays in vitro and in cells, siRNA knockdown with RNA-seq, immunofluorescence for subcellular localization","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus direct biochemical binding assays with rigorous negative controls, challenges previous model","pmids":["24486609"],"is_preprint":false},{"year":2015,"finding":"SRA lncRNA participates in transcriptional regulation through complex formation with both trithorax group (TrxG) and polycomb repressive complex 2 (PRC2) complexes. The SRA-associated RNA helicase p68 preferentially stabilizes SRA-TrxG complex formation over SRA-PRC2. SRA binding sites co-occupied by p68 are enriched for H3K4me3 in NTERA2 pluripotent stem cells. NANOG directly interacts with SRA and co-localizes with it genome-wide. SRA is required for maintaining the stem cell state and for reprogramming human fibroblasts to pluripotency.","method":"Co-immunoprecipitation of SRA with TrxG and PRC2 components, ChIP-seq for histone marks, RNA immunoprecipitation, genome-wide SRA binding analysis, reprogramming assays","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus ChIP-seq and functional reprogramming assay, single lab","pmids":["26496121"],"is_preprint":false},{"year":2016,"finding":"LncRNA SRA promotes hepatic steatosis by repressing expression of adipose triglyceride lipase (ATGL). SRA inhibits ATGL promoter activity primarily by inhibiting the inductive effects of the transcription factor FoxO1. Loss of SRA in primary hepatocytes or hepatocyte cell lines upregulates ATGL expression and free fatty acid β-oxidation, while forced SRA expression inhibits ATGL and β-oxidation. Hepatic SRA and ATGL levels are inversely regulated by fasting in mice.","method":"Sra KO mice, primary hepatocyte isolation, siRNA and overexpression in hepatocyte cell line, ATGL promoter-luciferase reporter assays, FoxO1 co-transfection experiments","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — KO mice plus reporter assays with defined transcription factor mechanism, single lab","pmids":["27759039"],"is_preprint":false},{"year":2016,"finding":"In ovarian endometriotic stromal cells (ESCs), SRA1 silencing via siRNA increases ERα expression but reduces ERβ expression, and attenuates proliferation while promoting early apoptosis. LncRNA SRA and ERα are expressed at lower levels, while SRAP and ERβ are higher, in ovarian endometriotic tissues versus normal endometrial tissues, establishing SRA1 products as regulators of estrogen receptor isoform balance in endometriosis.","method":"siRNA knockdown in primary ESCs, RT-PCR and Western blotting for ER isoforms, CCK-8 proliferation assay, flow cytometry for apoptosis, IHC on tissue specimens","journal":"Reproductive sciences (Thousand Oaks, Calif.)","confidence":"Low","confidence_rationale":"Tier 3 — siRNA knockdown with cellular phenotype but limited mechanistic detail on ER regulation pathway","pmids":["27694140"],"is_preprint":false},{"year":2021,"finding":"SRSF1 promotes inclusion of exon 3 of SRA1 pre-mRNA to generate the long isoform SRA1-L (which promotes HCC cell invasion) by directly binding to exon 3 of SRA1 pre-mRNA. RNA immunoprecipitation, cross-link immunoprecipitation, RNA pull-down, and minigene-MS2 mutation experiments all confirm SRSF1 binding to the SRA1 exon 3 sequence. SRA1-L overexpression increases CD44 expression and promotes HCC cell migration/invasion in vitro and lung metastasis in vivo; SRA1-S (lacking exon 3) reverses these effects.","method":"RNA immunoprecipitation (RIP), cross-link immunoprecipitation (CLIP), RNA pull-down, minigene-MS2 mutation, siRNA/overexpression, in vivo lung metastasis model","journal":"Cell death discovery","confidence":"High","confidence_rationale":"Tier 1-2 — multiple direct RNA-protein binding methods (RIP, CLIP, pull-down, mutagenesis) plus in vivo functional validation","pmids":["34011971"],"is_preprint":false}],"current_model":"SRA1 is a bifaceted gene encoding both a non-coding RNA coactivator (SRA) that functions as a scaffold RNA within ribonucleoprotein complexes to enhance steroid receptor (ERα, PR, AR), PPARγ, MyoD, SF-1, LRH-1, and Notch/RBP-J transcriptional activity through AF-1-dependent and other mechanisms, and a protein (SRAP) whose C-terminal domain adopts a five-helix bundle resembling the spliceosome protein PRP18 and antagonizes SRA RNA coactivation; the balance between coding and non-coding isoforms is controlled by alternative splicing of intron-1 regulated by SRSF1 among other factors, while the CYFIP1/SRA1 protein product (in the context of the WAVE regulatory complex) links Rac1 GTPase signaling to Arp2/3-dependent actin polymerization and lamellipodia formation by stabilizing SCAR/WAVE and mediating kinesin-1-dependent axonal transport of the WAVE complex."},"narrative":{"teleology":[],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":[],"other_free_text":[]},"mechanistic_narrative":"Insufficient on-target evidence to synthesize a narrative — discovery timeline does not match the canonical SRA1 protein."},"prefetch_data":{"uniprot":{"accession":"Q9HD15","full_name":"Steroid receptor RNA activator 1","aliases":["Steroid receptor RNA activator protein","SRAP"],"length_aa":224,"mass_kda":24.4,"function":"Functional RNA which acts as a transcriptional coactivator that selectively enhances steroid receptor-mediated transactivation ligand-independently through a mechanism involving the modulating N-terminal domain (AF-1) of steroid receptors. Also mediates transcriptional coactivation of steroid receptors ligand-dependently through the steroid-binding domain (AF-2). Enhances cellular proliferation and differentiation and promotes apoptosis in vivo. May play a role in tumorigenesis","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9HD15/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SRA1","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SRA1","total_profiled":1310},"omim":[{"mim_id":"617264","title":"SR-RELATED C-TERMINAL DOMAIN-ASSOCIATED FACTOR 1; SCAF1","url":"https://www.omim.org/entry/617264"},{"mim_id":"610211","title":"SRA STEM LOOP-INTERACTING RNA-BINDING PROTEIN; SLIRP","url":"https://www.omim.org/entry/610211"},{"mim_id":"608469","title":"DEAD-BOX HELICASE 17; DDX17","url":"https://www.omim.org/entry/608469"},{"mim_id":"608160","title":"SRY-BOX 9; SOX9","url":"https://www.omim.org/entry/608160"},{"mim_id":"606322","title":"CYTOPLASMIC FMRP-INTERACTING PROTEIN 1; CYFIP1","url":"https://www.omim.org/entry/606322"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Microtubules","reliability":"Additional"},{"location":"Cytokinetic bridge","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SRA1"},"hgnc":{"alias_symbol":["SRA","STRAA1"],"prev_symbol":[]},"alphafold":{"accession":"Q9H7N4","domains":[{"cath_id":"1.10.1900","chopping":"1206-1285","consensus_level":"medium","plddt":87.0701,"start":1206,"end":1285}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H7N4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H7N4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H7N4-F1-predicted_aligned_error_v6.png","plddt_mean":46.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SRA1","jax_strain_url":"https://www.jax.org/strain/search?query=SRA1"},"sequence":{"accession":"Q9H7N4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H7N4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H7N4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H7N4"}},"corpus_meta":[{"pmid":"17994007","id":"PMC_17994007","title":"The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA.","date":"2007","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/17994007","citation_count":985,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10199399","id":"PMC_10199399","title":"A steroid receptor coactivator, SRA, functions as an RNA and is present in an SRC-1 complex.","date":"1999","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/10199399","citation_count":640,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18772891","id":"PMC_18772891","title":"Recognition of hemi-methylated DNA by the SRA protein UHRF1 by a base-flipping mechanism.","date":"2008","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/18772891","citation_count":395,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18772889","id":"PMC_18772889","title":"Structural basis for recognition of hemi-methylated DNA by the SRA domain of human 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foundational paper\",\n      \"pmids\": [\"10199399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SRA RNA associates with a coactivator complex containing p72/p68 DEAD-box proteins and TIF2 (SRC-1 family) bound to estrogen receptor alpha (ERα); the complex is co-immunoprecipitated with estrogen-bound ERα from MCF7 cells and interacts specifically through the ERα A/B domain (AF-1).\",\n      \"method\": \"Co-immunoprecipitation from MCF7 cells, transient transfection coactivation assays, partial purification from HeLa nuclear extracts\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP confirmed in cell extracts, replicated with biochemical fractionation, reported by independent lab\",\n      \"pmids\": [\"11250900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SRA RNA coactivates ERα in a ligand-independent manner through the AF-1 domain, requiring an intact Ser118 residue in ERα AF-1; MAPK activation induces this ligand-independent coactivation, and H-Ras-induced phosphorylation of Ser118 participates in SRA's effect on ERα.\",\n      \"method\": \"Transient transfection reporter assays, site-directed mutagenesis of ERα Ser118, dominant-active H-Ras cotransfection\",\n      \"journal\": \"The Journal of steroid biochemistry and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis + functional assays in single lab\",\n      \"pmids\": [\"12943696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SRA RNA co-immunoprecipitates with MyoD and acts as a coactivator of MyoD-dependent skeletal muscle gene expression and differentiation; RNA interference against SRA prevents proper activation of muscle gene expression and cell differentiation.\",\n      \"method\": \"Co-immunoprecipitation with MyoD, RNA interference knockdown with gene expression and differentiation readouts, in vitro and in vivo experiments\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus RNAi with specific phenotypic readouts, multiple orthogonal methods\",\n      \"pmids\": [\"17011493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SLIRP (SRA stem-loop interacting RNA binding protein) binds specifically to functional substructure STR7 of SRA RNA via its RRM domain and represses nuclear receptor transactivation in a SRA- and RRM-dependent manner; SLIRP modulates SRC-1 association with SRA and is recruited to endogenous promoters in a SRA-dependent manner.\",\n      \"method\": \"RNA pulldown, co-immunoprecipitation, reporter assays, chromatin immunoprecipitation, RNA interference\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including ChIP, Co-IP, and functional reporter assays\",\n      \"pmids\": [\"16762838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SRA RNA functions as a coactivator for steroidogenic factor 1 (SF-1) through interaction with both SF-1 and Dax-1; SRA knockdown reduces expression of steroidogenic gene products StAR and melanocortin 2 receptor in adrenal Y1 cells, and SRA is required for Dax-1-mediated coactivation of SF-1.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown with qRT-PCR readout, transient transfection reporter assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP plus functional knockdown in single lab\",\n      \"pmids\": [\"19188450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SRA RNA forms a complex with p68 (DDX5) RNA helicase and CTCF at the IGF2/H19 imprinted control region; depletion of SRA or p68 reduces CTCF-mediated insulator activity and cohesin binding at these sites, while p68/SRA stabilizes cohesin interaction with CTCF by binding both.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, RNA interference knockdown with reporter and ChIP readouts\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods: Co-IP, ChIP, functional insulator assays, RNAi with defined molecular phenotype\",\n      \"pmids\": [\"20966046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SRA RNA acts as a coactivator of PPARγ and promotes adipocyte differentiation; SRA knockdown inhibits 3T3-L1 preadipocyte differentiation, promotes S-phase entry during mitotic clonal expansion by decreasing p21Cip1 and p27Kip1, and increases glucose uptake and insulin-stimulated Akt/FOXO1 phosphorylation.\",\n      \"method\": \"Overexpression, siRNA knockdown, reporter assays, flow cytometry, glucose uptake assays, Western blotting for signaling\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple functional readouts from single lab\",\n      \"pmids\": [\"21152033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SRAP (SRA protein) antagonizes SRA ncRNA-mediated coactivation of MyoD and inhibits myogenic differentiation; this inhibitory effect is mediated through SRAP's RRM-like domain interacting with the STR7 functional substructure of SRA RNA.\",\n      \"method\": \"Constructs exclusively producing ncRNA or protein, myogenic differentiation assays, domain-interaction analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mutagenesis and functional rescue experiments in single lab\",\n      \"pmids\": [\"20855289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RNA helicase Ddx5 (p68) and SRA RNA function as coactivators in Notch signaling; Ddx5 directly interacts with RBP-J and is recruited to Notch target gene promoters in a Notch-dependent manner; SRA knockdown/overexpression affects Hes1 and preTCRα expression and is accompanied by loss of p300 occupancy and decreased histone acetylation.\",\n      \"method\": \"Biotinylation-tagging mass spectrometry, Co-IP, chromatin immunoprecipitation, siRNA knockdown\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mass spectrometry identification confirmed by Co-IP and ChIP, functional knockdown\",\n      \"pmids\": [\"23396200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RISC proteins PACT, TRBP, and Dicer bind SRA RNA and function as nuclear receptor coregulators; they associate with SRA and Argonaute 2 together with specific pre-microRNAs in both the nucleus and cytoplasm, and target steroid-responsive promoters to regulate NR activity.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, reporter assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and ChIP from single lab\",\n      \"pmids\": [\"23550157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Sra1 gene knockout in mice (SRA−/−) causes resistance to high-fat diet-induced obesity with decreased fat mass, increased lean content, reduced adipocyte marker gene expression, improved insulin sensitivity, and decreased hepatic lipogenesis, establishing SRA as a functional regulator of adipose tissue biology and glucose homeostasis in vivo.\",\n      \"method\": \"Whole-mouse gene knockout, high-fat diet challenge, body composition analysis, glucose/insulin tolerance tests, gene expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean in vivo KO with multiple orthogonal metabolic phenotyping readouts\",\n      \"pmids\": [\"24675075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SRA RNA associates with both TrxG (trithorax group) and PRC2 (polycomb repressive complex 2) complexes; p68 helicase preferentially stabilizes SRA-TrxG but not SRA-PRC2 complex formation; SRA is required for maintaining the stem cell state and human fibroblast reprogramming to pluripotency; NANOG directly interacts with SRA and co-localizes with it genome-wide.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, genome-wide binding analysis, pluripotency/reprogramming functional assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus genome-wide ChIP-seq plus functional pluripotency assays\",\n      \"pmids\": [\"26496121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SRA ncRNA promotes hepatic steatosis by inhibiting ATGL (adipose triglyceride lipase) promoter activity, primarily by inhibiting the inductive effects of transcription factor FoxO1 on the ATGL promoter; SRA loss in hepatocytes upregulates ATGL and increases fatty acid β-oxidation.\",\n      \"method\": \"SRA knockout mice, primary hepatocyte experiments, siRNA knockdown, promoter-reporter assays, qRT-PCR\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — in vivo KO plus promoter assays and cellular knockdown\",\n      \"pmids\": [\"27759039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SRAP (SRA protein) is present in both the nucleus and cytoplasm of MCF-7 cells; the C-terminal domain of SRAP does not contain a canonical RRM but instead adopts a five-helix bundle structurally similar to yeast spliceosome protein PRP18; specific SRAP-SRA RNA interaction was not detected in vitro or in cultured cells, challenging the prevailing model of SRAP function.\",\n      \"method\": \"Crystal structure of SRAP C-terminal domain, in vitro RNA binding assays, subcellular fractionation/immunofluorescence, siRNA knockdown with RNA-seq\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional binding assays and in-cell validation\",\n      \"pmids\": [\"24486609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SRSF1 promotes inclusion of exon 3 of SRA1 pre-mRNA by directly binding to exon 3 sequences, generating the long isoform SRA1-L which promotes HCC cell invasion and migration by increasing CD44 expression; the short isoform SRA1-S (exon 3-skipped) reverses this effect.\",\n      \"method\": \"RNA immunoprecipitation, cross-link immunoprecipitation, RNA pulldown, minigene MS2-mutation assays, in vitro/in vivo invasion assays\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — CLIP, RNA pulldown, minigene mutagenesis, and in vivo mouse metastasis model\",\n      \"pmids\": [\"34011971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Sra-1 (CYFIP1/PIR121) and Nap1 are constitutive components of a WAVE2/Abi-1-containing complex that links Rac1 to site-directed actin assembly; Sra-1 and Nap1 translocate to membrane protrusion tips after Rac activation, and their removal by RNAi abrogates Rac-dependent lamellipodia formation induced by growth factor stimulation.\",\n      \"method\": \"RNA interference, microinjection of constitutively active Rac, co-immunoprecipitation, immunofluorescence localization\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RNAi with specific lamellipodia phenotype, Co-IP, and localization, replicated with multiple stimuli\",\n      \"pmids\": [\"14765121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In Drosophila cells, Sra-1 (ortholog of human CYFIP1/SRA1) protects SCAR/WAVE from proteasome-mediated degradation and is critical for SCAR localization and Arp2/3-dependent actin protrusion formation downstream of Rac and Cdc42.\",\n      \"method\": \"RNAi screen, genetic epistasis, immunofluorescence localization, proteasome inhibitor experiments\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RNAi with mechanistic follow-up (proteasome, epistasis) in Drosophila ortholog\",\n      \"pmids\": [\"14588242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CRMP-2 interacts with the Sra-1/WAVE1 complex and with kinesin-1 light chain, linking kinesin-1 to the Sra-1/WAVE1 complex for anterograde axonal transport; CRMP-2 and kinesin-1 knockdown delocalizes Sra-1 and WAVE1 from axonal growth cones, and Sra-1/WAVE1 knockdown cancels CRMP-2-induced axon outgrowth.\",\n      \"method\": \"Co-immunoprecipitation, RNA interference, immunofluorescence localization in hippocampal neurons\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP confirmed interaction, RNAi with specific neuronal phenotype, localization experiments\",\n      \"pmids\": [\"16260607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Drosophila Sra-1 interacts directly with Kette (Nap1) in vivo; both proteins stabilize each other and directly regulate F-actin cytoskeleton in a Wasp-dependent manner; membrane-bound Sra-1 lacking the Kette-binding domain produces abnormal neuromuscular junctions similar to kette mutations, indicating Sra-1 function is mediated through Kette.\",\n      \"method\": \"Genetic analysis, RNAi in photoreceptor neurons, domain-deletion construct expression, immunoprecipitation\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain-deletion epistasis plus in vivo Co-IP in Drosophila ortholog\",\n      \"pmids\": [\"15269173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CYFIP/Sra/PIR121-containing protein complexes coordinate Arf1 and Rac1 signaling during clathrin-AP-1-coated transport carrier biogenesis at the TGN; Arf1 GTPase synchronizes TGN association of clathrin-AP-1 and CYFIP complexes, while Rac1 and β-PIX activate N-WASP/Arp2/3-dependent actin polymerization promoting tubule formation.\",\n      \"method\": \"Reconstitution with synthetic membranes, Co-immunoprecipitation, siRNA knockdown, live imaging\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstitution with synthetic membranes, Co-IP, and functional knockdown with multiple orthogonal readouts\",\n      \"pmids\": [\"20228810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SLNCR1 lncRNA mediates melanoma invasion through a conserved SRA1-like sequence region by recruiting the androgen receptor (AR) and brain-specific homeobox protein Brn3a to activate transcription of MMP9; SLNCR1, AR, and Brn3a are specifically required for MMP9 transcriptional activation and increased melanoma invasion.\",\n      \"method\": \"RNA-associated transcription factor array (RATA), RNA binding assays, siRNA knockdown, invasion assays, reporter assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — novel RATA technique with functional validation, single lab\",\n      \"pmids\": [\"27210747\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SRA1 encodes both a noncoding RNA (SRA) and a protein (SRAP): the ncRNA functions as a molecular scaffold/coactivator in ribonucleoprotein complexes—including those with SRC-1/TIF2, p68/p72 helicases, SLIRP, CTCF/cohesin, TrxG, and PRC2—to modulate steroid receptor (ER, AR, PR), MyoD, PPARγ, SF-1, and Notch transcriptional activity via AF-1-dependent mechanisms, while the CYFIP1/SRA1 protein (a distinct gene product sharing the symbol) is an essential component of the WAVE regulatory complex that links Rac1 GTPase signaling to Arp2/3-dependent actin polymerization and lamellipodia formation through stabilization and localization of WAVE/SCAR.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification of key papers:**\n\nThe gene SRA1 in the human/mammalian context refers to the **Steroid Receptor RNA Activator 1** gene, which encodes both a non-coding RNA (SRA) and a protein (SRAP). This is the canonical human SRA1 gene.\n\n**KEEP papers** (about canonical SRA1/SRAP or its direct orthologs in model organisms relevant to actin/WAVE complex function as CYFIP1/SRA1):\n- [2] SRA coactivator - original discovery (PMID:10199399) ✓\n- [6] Sra-1/Nap1/WAVE/actin (PMID:14765121) ✓ - CYFIP/SRA1 protein in WAVE complex\n- [8] Abi/Sra1/Kette/SCAR (PMID:14588242) ✓ - Drosophila ortholog\n- [11] p68/p72/SRA/MyoD (PMID:17011493) ✓\n- [12] DEAD-box/SRA/ERα (PMID:11250900) ✓\n- [14] CRMP-2/Sra-1/WAVE1/kinesin (PMID:16260607) ✓\n- [15] p68/SRA/CTCF insulator (PMID:20966046) ✓\n- [16] SRA/PPARγ/adipogenesis (PMID:21152033) ✓\n- [24] SRAP counteracts SRA RNA/MyoD (PMID:20855289) ✓\n- [28] SLIRP/SRA/NR corepressor (PMID:16762838) ✓\n- [31] SRA KO/obesity/glucose (PMID:24675075) ✓\n- [32] SLNCR1/SRA1-like/melanoma (PMID:27210747) - about SLNCR1's conserved region similar to SRA1, not SRA1 itself → EXCLUDE\n- [33] SRA1 bifaceted products review (PMID:17710122) ✓\n- [34] lncRNA SRA/ATGL/hepatic steatosis (PMID:27759039) ✓\n- [35] PIROGI/SRA1 WAVE complex/Arabidopsis (PMID:15294869) ✓ - functional ortholog\n- [37] Dax-1/SRA/SF-1/steroidogenesis (PMID:19188450) ✓\n- [40] RISC proteins/SRA/NR coregulators (PMID:23550157) ✓\n- [41] Alternative splicing SRA1/SRAP (PMID:16848684) ✓\n- [42] CYFIP/Sra/PIR121/Arf1/Rac1/TGN (PMID:20228810) ✓\n- [44] HBEGF/SRA1/IK/cardiomyopathy (PMID:19064678) ✓\n- [47] Oligonucleotide modulation of SRA splicing (PMID:19483093) ✓\n- [57] Drosophila sra/calcineurin/meiosis (PMID:16860743) - \"sarah\" gene, MCIP/RCAN family, NOT SRA1 WAVE complex → EXCLUDE (symbol collision)\n- [58] SRA expression profiling/target genes (PMID:20219889) ✓\n- [59] SRA/ERα AF-1/MAPK (PMID:12943696) ✓\n- [63] Ddx5/SRA/Notch signaling (PMID:23396200) ✓\n- [67] Drosophila Sra-1/Kette/Wasp (PMID:15269173) ✓ - clear WAVE complex ortholog\n- [70] lncRNA SRA review (PMID:30238005) ✓ (review - extract if mechanistic)\n- [71] Dax1/SRA/LRH-1/Oct4 (PMID:20943815) ✓\n- [72] Drosophila sra/calcineurin/sleep - \"sarah\" RCAN → EXCLUDE\n- [73] Drosophila sra/calcineurin/meiosis - \"sarah\" RCAN → EXCLUDE\n- [77] p68/p72/SRA review (PMID:17495528) ✓\n- [78] SRA/TrxG/PRC2 complexes (PMID:26496121) ✓\n- [81] SRA binding partners review (PMID:19280430) - review only\n- [84] SRA1 silencing/ER/endometriosis (PMID:27694140) ✓\n- [89] LncRNA-SRA1/osteosarcoma (PMID:31106680) - expression/phenotype only → EXCLUDE\n- [92] SRSF1/SRA1 splicing/HCC (PMID:34011971) ✓\n- [100] SRAP structure/function (PMID:24486609) ✓\n\n**EXCLUDE** (alias collisions or off-target):\n- Papers about SR-A (scavenger receptor A/MSR1): [13,23,26,27,29,30,43,48,49,51,52,53,54,61,62,66,68,69,74,76,80,82,83,85,86,87,88,95,96,97,99] - these are about MSR1/CD204 scavenger receptor, NOT SRA1\n- Papers about UHRF1 SRA domain: [1,3,4,5,7,9,10,19,20,21,25,36,38,45,75,91,98] - SRA domain of UHRF1, not the SRA1 gene\n- Papers about Trypanosoma SRA: [17,39,64,94] - parasite gene\n- Papers about SRA1 sex reversal locus = SOX9: [18] and all gene2pubmed SOX9 papers\n- Papers about C. elegans SRA-13 chemosensory receptor: [79] - symbol collision\n- Papers about E. coli SRA ribosomal protein: [51] - symbol collision\n- Papers about Drosophila sarah/RCAN: [57,72,73] - different gene\n- Papers about severe refractory asthma (SRA): [46] - abbreviation collision\n- Papers about darifenacin M3 SRA: [55] - abbreviation\n- Papers about Structure Relaxation Approximation (SRA): [60] - abbreviation\n- Papers about Xenbase/SRA database: [56,83] - abbreviation\n- Papers about SLNCR1: [32] - different lncRNA\n- gene2pubmed SOX9 papers: all EXCLUDE (SRA1 locus = SOX9 locus historically, but these papers are about SOX9 protein function)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"SRA (Steroid Receptor RNA Activator) was identified as a novel transcriptional coactivator that functions as an RNA transcript rather than a protein; it is selective for steroid hormone receptors, mediates transactivation via their amino-terminal AF-1 activation function, and exists in distinct ribonucleoprotein complexes including one containing SRC-1. Evidence that SRA functions as RNA: coactivation persists in the presence of cycloheximide and SRA mutants with multiple translational stop signals retain coactivator activity.\",\n      \"method\": \"Biochemical fractionation, ribonucleoprotein complex isolation, functional reporter assays with cycloheximide treatment, translational stop-signal mutagenesis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — original discovery with multiple orthogonal methods (fractionation, mutagenesis, cycloheximide experiments), foundational paper with 640 citations\",\n      \"pmids\": [\"10199399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The RNA-binding DEAD-box proteins p72/p68 function as estrogen receptor alpha (ERα) coactivators through the AF-1 domain by associating with a coactivator complex containing SRA and SRC-1/TIF2. p72/p68 interact with the AD2 domain of SRC-1/TIF2 family proteins and the ERα A/B domain, and co-immunoprecipitate with estrogen-bound ERα in MCF7 cells. Combination of p72/p68 with SRA and TIF2 produces synergistic estrogen-induced transactivation of ERα.\",\n      \"method\": \"Co-immunoprecipitation from MCF7 cells and HeLa nuclear extracts, transient transfection reporter assays, immunofluorescence co-localization\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP in cells plus functional synergy assays, replicated in multiple cell systems\",\n      \"pmids\": [\"11250900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SRA coactivates ERα in a ligand-independent manner through the AF-1 domain, requiring an intact serine-118 (S118) residue in ERα AF-1. MAPK activation induces ligand-independent coactivation of ERα by SRA; activated H-Ras (H-RasV12) cannot rescue S118 ERα mutant activity, indicating that MAPK-mediated phosphorylation of S118 participates in SRA's AF-1-dependent effect. SRA does not coactivate ERβ via AF-1 in the same manner, demonstrating isoform selectivity.\",\n      \"method\": \"Transient transfection reporter assays, site-directed mutagenesis of ERα S118, co-expression with activated Ras and MAPK pathway components\",\n      \"journal\": \"The Journal of steroid biochemistry and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean mutagenesis with functional readout, single lab\",\n      \"pmids\": [\"12943696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In Drosophila cells, Sra-1 (ortholog of human CYFIP1/SRA1 WAVE complex subunit), together with Abi and Kette (Nap1), protects SCAR/WAVE from proteasome-mediated degradation and is critical for SCAR localization and for Arp2/3-dependent actin protrusion generation. RNAi-mediated removal of Sra-1, Abi, or Kette abolishes dynamic protrusions, demonstrating these proteins are essential components of the SCAR regulatory complex downstream of Rac and Cdc42.\",\n      \"method\": \"RNAi screen in Drosophila adherent cells, immunofluorescence, proteasome inhibitor experiments, epistasis analysis\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RNAi loss-of-function with defined cellular phenotype and pathway placement, multiple genetic epistasis experiments\",\n      \"pmids\": [\"14588242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Sra-1 (CYFIP/PIR121) and Nap1 are constitutive components of a WAVE2/Abi-1-containing complex that links Rac1 signaling to site-directed actin assembly and lamellipodia formation. RNA interference removal of Sra-1 or Nap1 abrogates Rac-dependent lamellipodia induced by growth factor stimulation or aluminum fluoride treatment, and microinjection of constitutively active Rac fails to restore lamellipodia in cells lacking either protein. Sra-1, Nap1, WAVE2, and Abi-1 translocate to tips of membrane protrusions after active Rac microinjection.\",\n      \"method\": \"RNAi knockdown, microinjection of constitutively active Rac1, immunofluorescence, co-immunoprecipitation of complex components\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (RNAi, microinjection, Co-IP, localization), clear epistasis, 325 citations\",\n      \"pmids\": [\"14765121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The Arabidopsis PIROGI gene encodes a functional ortholog of the human WAVE complex subunit SRA1 (CYFIP1). PIROGI/SRA1 directly interacts with the small GTPase ATROP2 with isoform specificity and selectivity for active (GTP-bound) forms. Both PIROGI and human SRA1 are functionally interchangeable and display identical physical interactions with RHO family GTPases and the WAVE complex subunit NAP125, indicating deeply conserved molecular function in ARP2/3-dependent actin regulation.\",\n      \"method\": \"Genetic complementation, yeast two-hybrid, pull-down assays with active/inactive GTPase forms, phenotypic analysis of pir mutants\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct biochemical interaction assays plus genetic complementation, functional conservation demonstrated\",\n      \"pmids\": [\"15294869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Drosophila Sra-1 interacts physically with Kette (Nap1) in vivo, and both proteins stabilize each other. Sra-1 is expressed in neuronal growth cones; RNAi knockdown of sra-1 in photoreceptor neurons causes stalling of axonal growth, and knockdown in motoneurons produces abnormal neuromuscular junctions similar to kette hypomorphic mutants. A membrane-bound Sra-1 lacking the Kette-binding domain phenocopies loss of function, indicating Sra-1 function is mediated through Kette and controls F-actin cytoskeleton in a Wasp-dependent manner.\",\n      \"method\": \"In vivo co-immunoprecipitation, RNAi in specific neuronal subtypes, dominant-negative Sra-1 construct lacking Kette-binding domain, confocal imaging of neuromuscular junctions\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, genetic epistasis with dominant-negative, multiple neuronal phenotypic readouts\",\n      \"pmids\": [\"15269173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CRMP-2 interacts with the Sra-1/WAVE1 complex and with the light chain of kinesin-1, linking kinesin-1 to the Sra-1/WAVE1 complex for anterograde transport to axonal growth cones. Knockdown of Sra-1 and WAVE1 cancels CRMP-2-induced axon outgrowth and multiple-axon formation in hippocampal neurons; knockdown of CRMP-2 or kinesin-1 delocalizes Sra-1 and WAVE1 from growth cones, establishing a kinesin-1-dependent transport mechanism for the Sra-1/WAVE1 complex in axon formation.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown in hippocampal neurons, immunofluorescence localization in growth cones\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus RNAi with defined axonal phenotypes and localization readout, multiple interactors confirmed\",\n      \"pmids\": [\"16260607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The RNA helicases p68/p72 (DDX5/DDX17) are MyoD-associated proteins, and the non-coding RNA SRA co-immunoprecipitates with MyoD. Both p68/p72 and SRA function as coactivators of MyoD in skeletal muscle differentiation; RNAi knockdown of either p68/p72 or SRA prevents activation of muscle gene expression and cell differentiation. Loss of p68/p72 impairs recruitment of TBP, RNA polymerase II, and the SWI/SNF catalytic subunit Brg-1, and hinders chromatin remodeling at muscle gene promoters.\",\n      \"method\": \"Co-immunoprecipitation with MyoD, RNAi knockdown, chromatin immunoprecipitation, reporter assays, differentiation assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, RNAi with defined differentiation phenotype, ChIP for mechanism, 248 citations\",\n      \"pmids\": [\"17011493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SLIRP (SRA stem-loop interacting RNA binding protein) binds a functional substructure of SRA RNA (STR7) via its RNA recognition motif (RRM) and functions as a nuclear receptor corepressor. SLIRP represses nuclear receptor transactivation in a SRA- and RRM-dependent manner, augments tamoxifen's effect, modulates SRC-1 association with SRA, and is recruited to endogenous promoters in a SRA-dependent manner. SHARP also binds STR7, augmenting repression with SLIRP.\",\n      \"method\": \"RNA pull-down, co-immunoprecipitation, reporter assays, chromatin immunoprecipitation, RRM mutagenesis, immunofluorescence\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct RNA-protein binding assays, mutagenesis, ChIP, functional reporter assays, 109 citations\",\n      \"pmids\": [\"16762838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Alternative splicing of the first intron of SRA1 generates both coding (SRAP-producing) and non-coding SRA RNA isoforms in breast cancer cell lines. The intron-1 sequence is sufficient to drive differential splicing in both endogenous and minigene contexts. The relative proportion of coding vs. non-coding SRA transcripts varies across breast cancer cell lines, suggesting that alternative splicing is a regulatory mechanism controlling the balance between SRA RNA coactivator and SRAP protein.\",\n      \"method\": \"5'-RACE, RT-PCR with isoform-specific primers, minigene splicing assay in breast cancer cell lines\",\n      \"journal\": \"DNA and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — minigene functional validation plus endogenous RT-PCR, single lab\",\n      \"pmids\": [\"16848684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SRA1 encodes both a non-coding RNA (SRA) and an endogenous protein (SRAP) through alternative splicing of intron-1; retention of intron-1 disrupts the SRAP open reading frame, generating the non-coding isoform. Both SRA RNA and SRAP have opposing regulatory roles on steroid receptor signaling and are conserved among Chordata, establishing SRA1 as a bifaceted gene.\",\n      \"method\": \"Review/synthesis of published molecular characterization; original data on isoform identification referenced\",\n      \"journal\": \"Nuclear receptor signaling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — review article synthesizing prior work, no new primary experimental data\",\n      \"pmids\": [\"17710122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SRA1 gene knockout (SRA-/-) in zebrafish using morpholino antisense reagents results in a phenotype of myocardial contractile dysfunction, demonstrating that SRA1 (along with HBEGF and IK, which cosegregate in a 600-kb linkage disequilibrium block) independently contributes to cardiac muscle function in vivo.\",\n      \"method\": \"Morpholino antisense knockdown in zebrafish, cardiac function assessment\",\n      \"journal\": \"Genome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo loss-of-function with defined cardiac phenotype, but SRA1 contribution not fully disentangled from co-segregating genes\",\n      \"pmids\": [\"19064678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SRA functions as an RNA coactivator for steroidogenic factor 1 (SF-1), and both SF-1 and Dax-1 bind SRA. Dax-1 acts as a dosage-dependent SF-1 coactivator through SRA; SRA knockdown abolishes Dax-1-mediated coactivation and reduces expression of steroidogenic gene products (StAR, MC2R) in adrenal Y1 cells. TIF2 associates with Dax-1 and synergistically coactivates SF-1 target gene transcription in a SRA-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown of SRA, reporter assays, qRT-PCR of steroidogenic gene products\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus siRNA knockdown with defined gene expression readout in steroidogenic cells, multiple approaches\",\n      \"pmids\": [\"19188450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SRA non-coding RNA enhances myogenic differentiation and myogenic conversion through co-activation of MyoD activity, while SRAP (the protein encoded by the same locus) counteracts this SRA RNA-dependent co-activation. SRAP's inhibitory effect is mediated through its RRM-like domain interacting with functional sub-structure STR7 of SRA RNA, establishing a regulatory feedback between the two products of the SRA1 locus.\",\n      \"method\": \"Constructs producing exclusively SRA ncRNA or SRAP protein, myogenic differentiation assays in human satellite cells, co-immunoprecipitation, domain mutagenesis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — isoform-specific constructs, RRM-domain mutagenesis, functional differentiation assays, mechanistically dissects RNA vs. protein contributions\",\n      \"pmids\": [\"20855289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SRA non-coding RNA associates with PPARγ and coactivates PPARγ-dependent gene expression to promote adipogenesis. SRA overexpression in ST2 mesenchymal precursor cells promotes adipocyte differentiation; SRA knockdown inhibits 3T3-L1 preadipocyte differentiation. SRA also increases glucose uptake and Akt/FOXO1 phosphorylation in response to insulin, promotes S-phase entry by decreasing p21Cip1 and p27Kip1 expression, and inhibits TNFα-induced JNK phosphorylation, demonstrating multiple signaling roles.\",\n      \"method\": \"Co-immunoprecipitation of SRA with PPARγ, reporter assays, siRNA knockdown, overexpression in ST2 cells, flow cytometry, Western blotting for signaling pathway components\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus gain/loss-of-function with multiple cellular and molecular readouts, multiple pathways examined\",\n      \"pmids\": [\"21152033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The DEAD-box RNA helicase p68 (DDX5) and its associated non-coding RNA SRA form a complex with CTCF that is essential for insulator function at the IGF2/H19 imprinted control region (ICR). Depletion of SRA or p68 reduces CTCF-mediated insulator activity, increases IGF2 expression, and reduces cohesin binding to CTCF sites without affecting CTCF binding itself. p68/SRA interacts with cohesin complex members, suggesting that p68/SRA stabilizes cohesin-CTCF interaction.\",\n      \"method\": \"ChIP, co-immunoprecipitation, siRNA knockdown, chromosome conformation capture (3C), reporter assays for insulator function\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP, Co-IP, 3C, and functional insulator assays in multiple orthogonal approaches, 194 citations\",\n      \"pmids\": [\"20966046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Dax1 augments LRH-1-mediated activation of the Oct4 gene in mouse embryonic stem cells through a mechanism dependent on the RNA coactivator SRA; SRA knockdown abolishes Dax1-mediated coactivation of Oct4. Dax1 and LRH-1 co-localize at 43% of LRH-1 target genes involved in mES cell pluripotency, and SRA is required for their co-activation.\",\n      \"method\": \"Co-immunoprecipitation of Dax1 with LRH-1, ChIP at Oct4 promoter, luciferase reporter assays, siRNA knockdown of SRA, genome-wide ChIP analysis\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ChIP, and siRNA with functional reporter readout, single lab\",\n      \"pmids\": [\"20943815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Protein complexes containing CYFIP/Sra/PIR121 coordinate Arf1 and Rac1 signaling during clathrin-AP-1-coated carrier biogenesis at the trans-Golgi network (TGN). CYFIP-containing complexes are recruited to TGN membranes by Arf1 GTPase; Rac1 and its exchange factor β-PIX then activate these complexes to promote N-WASP- and Arp2/3-dependent actin polymerization and tubule formation. These events were reconstituted with synthetic membranes.\",\n      \"method\": \"Immunoprecipitation of CYFIP complexes, synthetic membrane reconstitution assay, siRNA knockdown, fluorescence microscopy, dominant-negative GTPase experiments\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution on synthetic membranes plus cellular epistasis and Co-IP, multiple GTPase effector relationships defined\",\n      \"pmids\": [\"20228810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SRA RNA depletion in human cancer cell lines (MCF-7 and MDA-MB-231) by siRNA reveals hundreds of endogenous SRA target genes, with the majority reduced upon knockdown, implicating SRA as a broad endogenous coactivator. Novel SRA targets identified include SLC2A3, SLC2A12, CCL20, TGFB2, DIO2, TMEM65, TBL1X, and TMPRSS2. SRA depletion in MDA-MB-231 cells reduces invasiveness.\",\n      \"method\": \"siRNA knockdown, microarray gene expression profiling, reporter assays for specific promoters\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide target identification with siRNA, but primarily transcriptomic with limited mechanistic follow-up on individual targets\",\n      \"pmids\": [\"20219889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The cytoplasmic RISC proteins PACT, TRBP, and Dicer bind SRA RNA and function as nuclear receptor coregulators. These RISC proteins, together with Argonaute 2, associate with SRA and specific pre-microRNAs in both the nucleus and cytoplasm and target steroid-responsive promoters to regulate nuclear receptor activity and downstream gene expression.\",\n      \"method\": \"RNA pull-down with SRA, co-immunoprecipitation, ChIP at steroid-responsive promoters, reporter assays, immunofluorescence showing nuclear/cytoplasmic localization\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct RNA-protein binding plus ChIP and functional reporter assays, single lab\",\n      \"pmids\": [\"23550157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RNA helicase Ddx5 (p68) is a novel component of the RBP-J/NICD (Notch intracellular domain) complex; Ddx5 directly interacts with RBP-J and localizes to RBP-J binding sites at Notch target gene loci (preTCRα, Hes1, CD25) in a Notch-dependent manner. SRA, as a cofactor of Ddx5, is also required for Notch target gene activation; knockdown of SRA downregulates Hes1 and preTCRα, associated with loss of p300 occupancy and decreased histone acetylation at Notch target genes.\",\n      \"method\": \"Biotinylation-tagging/mass spectrometry, Co-IP, ChIP, siRNA knockdown, reporter assays\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mass-spec identification, Co-IP confirmation, ChIP for localization, functional knockdown, single lab\",\n      \"pmids\": [\"23396200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Whole-body Sra1 gene knockout (SRA-/-) mice are resistant to high-fat diet-induced obesity with decreased fat mass, increased insulin sensitivity (reduced fasting insulin, improved glucose tolerance), decreased adipocyte marker gene expression, reduced plasma TNFα, and fewer hepatic lipid droplets with decreased lipogenesis-associated gene expression. This demonstrates an in vivo role for the SRA1 gene product in adipose tissue mass and glucose homeostasis.\",\n      \"method\": \"Gene knockout mouse model (whole-body Sra1 KO), high-fat diet feeding, body composition analysis, glucose/insulin tolerance tests, gene expression analysis, histology\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple defined metabolic phenotypes and molecular readouts in vivo, 101 citations\",\n      \"pmids\": [\"24675075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The crystal structure of the carboxy-terminal domain of human SRAP (SRA protein) reveals a five-helix bundle that is structurally distinct from known RNA-binding motifs and instead resembles the C-terminal domain of the yeast spliceosome protein PRP18. The structure does not contain the postulated RRM (RNA recognition motif), and direct RNA-binding experiments (in vitro with recombinant SRAP and in cell-based assays) failed to reveal a specific interaction between SRAP and SRA RNA, necessitating re-evaluation of the current model for SRAP function.\",\n      \"method\": \"Crystal structure determination, RNA-binding assays in vitro and in cells, siRNA knockdown with RNA-seq, immunofluorescence for subcellular localization\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus direct biochemical binding assays with rigorous negative controls, challenges previous model\",\n      \"pmids\": [\"24486609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SRA lncRNA participates in transcriptional regulation through complex formation with both trithorax group (TrxG) and polycomb repressive complex 2 (PRC2) complexes. The SRA-associated RNA helicase p68 preferentially stabilizes SRA-TrxG complex formation over SRA-PRC2. SRA binding sites co-occupied by p68 are enriched for H3K4me3 in NTERA2 pluripotent stem cells. NANOG directly interacts with SRA and co-localizes with it genome-wide. SRA is required for maintaining the stem cell state and for reprogramming human fibroblasts to pluripotency.\",\n      \"method\": \"Co-immunoprecipitation of SRA with TrxG and PRC2 components, ChIP-seq for histone marks, RNA immunoprecipitation, genome-wide SRA binding analysis, reprogramming assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus ChIP-seq and functional reprogramming assay, single lab\",\n      \"pmids\": [\"26496121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LncRNA SRA promotes hepatic steatosis by repressing expression of adipose triglyceride lipase (ATGL). SRA inhibits ATGL promoter activity primarily by inhibiting the inductive effects of the transcription factor FoxO1. Loss of SRA in primary hepatocytes or hepatocyte cell lines upregulates ATGL expression and free fatty acid β-oxidation, while forced SRA expression inhibits ATGL and β-oxidation. Hepatic SRA and ATGL levels are inversely regulated by fasting in mice.\",\n      \"method\": \"Sra KO mice, primary hepatocyte isolation, siRNA and overexpression in hepatocyte cell line, ATGL promoter-luciferase reporter assays, FoxO1 co-transfection experiments\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mice plus reporter assays with defined transcription factor mechanism, single lab\",\n      \"pmids\": [\"27759039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In ovarian endometriotic stromal cells (ESCs), SRA1 silencing via siRNA increases ERα expression but reduces ERβ expression, and attenuates proliferation while promoting early apoptosis. LncRNA SRA and ERα are expressed at lower levels, while SRAP and ERβ are higher, in ovarian endometriotic tissues versus normal endometrial tissues, establishing SRA1 products as regulators of estrogen receptor isoform balance in endometriosis.\",\n      \"method\": \"siRNA knockdown in primary ESCs, RT-PCR and Western blotting for ER isoforms, CCK-8 proliferation assay, flow cytometry for apoptosis, IHC on tissue specimens\",\n      \"journal\": \"Reproductive sciences (Thousand Oaks, Calif.)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — siRNA knockdown with cellular phenotype but limited mechanistic detail on ER regulation pathway\",\n      \"pmids\": [\"27694140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SRSF1 promotes inclusion of exon 3 of SRA1 pre-mRNA to generate the long isoform SRA1-L (which promotes HCC cell invasion) by directly binding to exon 3 of SRA1 pre-mRNA. RNA immunoprecipitation, cross-link immunoprecipitation, RNA pull-down, and minigene-MS2 mutation experiments all confirm SRSF1 binding to the SRA1 exon 3 sequence. SRA1-L overexpression increases CD44 expression and promotes HCC cell migration/invasion in vitro and lung metastasis in vivo; SRA1-S (lacking exon 3) reverses these effects.\",\n      \"method\": \"RNA immunoprecipitation (RIP), cross-link immunoprecipitation (CLIP), RNA pull-down, minigene-MS2 mutation, siRNA/overexpression, in vivo lung metastasis model\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple direct RNA-protein binding methods (RIP, CLIP, pull-down, mutagenesis) plus in vivo functional validation\",\n      \"pmids\": [\"34011971\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SRA1 is a bifaceted gene encoding both a non-coding RNA coactivator (SRA) that functions as a scaffold RNA within ribonucleoprotein complexes to enhance steroid receptor (ERα, PR, AR), PPARγ, MyoD, SF-1, LRH-1, and Notch/RBP-J transcriptional activity through AF-1-dependent and other mechanisms, and a protein (SRAP) whose C-terminal domain adopts a five-helix bundle resembling the spliceosome protein PRP18 and antagonizes SRA RNA coactivation; the balance between coding and non-coding isoforms is controlled by alternative splicing of intron-1 regulated by SRSF1 among other factors, while the CYFIP1/SRA1 protein product (in the context of the WAVE regulatory complex) links Rac1 GTPase signaling to Arp2/3-dependent actin polymerization and lamellipodia formation by stabilizing SCAR/WAVE and mediating kinesin-1-dependent axonal transport of the WAVE complex.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SRA1 encodes both a long noncoding RNA (SRA) and a protein (SRAP) from the same locus, functioning primarily as an RNA-based transcriptional coactivator scaffold that assembles ribonucleoprotein complexes to regulate diverse gene expression programs. The SRA ncRNA coactivates steroid receptors (ERα, AR, PR), MyoD, PPARγ, SF-1, and Notch target genes through AF-1-dependent mechanisms, forming complexes with SRC-1/TIF2, p68/p72 DEAD-box helicases, SLIRP, CTCF/cohesin, TrxG, and PRC2 at target gene promoters and insulator elements [PMID:10199399, PMID:11250900, PMID:16762838, PMID:20966046, PMID:26496121, PMID:23396200]. SRA RNA promotes adipogenesis via PPARγ coactivation, maintains pluripotency through TrxG/PRC2 interactions with NANOG, and regulates hepatic lipid metabolism by modulating ATGL transcription; Sra1-knockout mice are resistant to diet-induced obesity with improved insulin sensitivity [PMID:21152033, PMID:24675075, PMID:27759039, PMID:26496121]. SRAP, translated from coding isoforms, antagonizes SRA ncRNA-mediated MyoD coactivation through its RRM-like domain, though structural analysis reveals this domain adopts a PRP18-like five-helix bundle rather than a canonical RRM, and direct SRAP–SRA RNA interaction was not confirmed in vitro [PMID:20855289, PMID:24486609].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"The foundational question of whether SRA functions as an RNA or a protein was resolved: SRA operates as a noncoding RNA coactivator of steroid receptors through AF-1, establishing a new paradigm for RNA-mediated transcriptional coactivation.\",\n      \"evidence\": \"Cycloheximide resistance, translational stop-codon mutants, and biochemical fractionation in mammalian cells\",\n      \"pmids\": [\"10199399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of SRA RNA functional subdomains not yet mapped\", \"Whether SRA also encodes a functional protein remained unresolved\", \"Range of transcription factors beyond steroid receptors unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"The composition of the SRA ribonucleoprotein complex was expanded to include p68/p72 DEAD-box helicases and TIF2, showing that SRA functions within a multi-component coactivator assembly recruited to ERα AF-1.\",\n      \"evidence\": \"Co-immunoprecipitation from MCF7 cells and partial purification from HeLa nuclear extracts\",\n      \"pmids\": [\"11250900\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether p68/p72 helicase activity is required for SRA function unknown\", \"Stoichiometry and assembly order of the complex not determined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"SRA's coactivation of ERα was shown to be ligand-independent and dependent on MAPK-mediated phosphorylation of ERα Ser118, linking SRA function to growth factor signaling crosstalk.\",\n      \"evidence\": \"Site-directed mutagenesis of ERα Ser118, dominant-active H-Ras cotransfection, reporter assays\",\n      \"pmids\": [\"12943696\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SRA directly senses phosphorylation state or is recruited differentially is unknown\", \"Single-lab observation without independent replication\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Studies in Drosophila and mammalian cells established that Sra-1/CYFIP1 (a distinct gene product sharing the symbol) is a constitutive WAVE regulatory complex subunit that protects WAVE/SCAR from proteasomal degradation and is essential for Rac-dependent lamellipodia formation and actin polymerization.\",\n      \"evidence\": \"RNAi screens in Drosophila S2 cells and mammalian fibroblasts, Co-IP, proteasome inhibitor rescue, microinjection of active Rac\",\n      \"pmids\": [\"14588242\", \"14765121\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"This is a distinct gene (CYFIP1) from SRA1 ncRNA/SRAP — nomenclature confusion persists\", \"Structural basis of Sra-1/WAVE interaction not resolved at this stage\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"SRA RNA's functional repertoire was extended beyond steroid receptors: it coactivates MyoD-dependent muscle differentiation and is regulated by SLIRP, which binds the STR7 stem-loop to repress nuclear receptor transactivation.\",\n      \"evidence\": \"Co-IP with MyoD, RNAi-mediated SRA depletion blocking differentiation, RNA pulldown identifying SLIRP–STR7 interaction, ChIP showing SLIRP recruitment\",\n      \"pmids\": [\"17011493\", \"16762838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SLIRP and SRC-1 compete for SRA STR7 binding mechanistically unresolved\", \"Whether SRA acts catalytically or stoichiometrically unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"SRA's coactivation role was further extended to steroidogenic factor SF-1 in adrenal cells, with Dax-1 acting as a mediator of SRA-dependent SF-1 activation.\",\n      \"evidence\": \"Co-IP, siRNA knockdown with qRT-PCR in adrenal Y1 cells, reporter assays\",\n      \"pmids\": [\"19188450\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding without independent validation\", \"Direct vs. indirect SRA–SF-1 interaction not distinguished\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Three parallel advances revealed SRA functions in chromatin insulation (via CTCF/cohesin/p68 at the IGF2/H19 locus), adipogenesis (via PPARγ coactivation), and vesicle trafficking (CYFIP1/Sra-1 coordinates Arf1/Rac1 at the TGN for clathrin-AP-1 carrier biogenesis).\",\n      \"evidence\": \"ChIP plus RNAi showing SRA/p68 required for CTCF insulator activity; PPARγ reporter and 3T3-L1 differentiation assays; synthetic membrane reconstitution for CYFIP complex\",\n      \"pmids\": [\"20966046\", \"21152033\", \"20228810\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SRA's chromatin insulator role is genome-wide or locus-specific unknown\", \"CYFIP1/Sra-1 findings concern a distinct protein from SRA ncRNA\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"SRA RNA was shown to participate in Notch signaling through p68/RBP-J complexes and to interact with RISC components (PACT, TRBP, Dicer, Ago2), suggesting intersection with the miRNA pathway at steroid-responsive promoters.\",\n      \"evidence\": \"Mass spectrometry, Co-IP, ChIP at Notch targets (Hes1, preTCRα); Co-IP and ChIP for RISC components at NR-responsive genes\",\n      \"pmids\": [\"23396200\", \"23550157\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of SRA–RISC interaction for miRNA biogenesis not demonstrated\", \"Whether Notch coactivation is direct or secondary to p68 recruitment is unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"In vivo knockout of Sra1 in mice established SRA as a physiological regulator of energy homeostasis, while structural analysis of SRAP's C-terminal domain revealed a PRP18-like five-helix bundle rather than a canonical RRM, and failed to detect direct SRAP–SRA RNA binding.\",\n      \"evidence\": \"Sra1−/− mice on high-fat diet with metabolic phenotyping; X-ray crystallography of SRAP C-terminal domain with in vitro RNA binding assays\",\n      \"pmids\": [\"24675075\", \"24486609\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether metabolic phenotype is attributable to loss of ncRNA, SRAP, or both is unresolved\", \"SRAP's molecular function remains unclear if it does not bind SRA RNA directly\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"SRA RNA was linked to pluripotency maintenance: it associates with both TrxG and PRC2 complexes, with p68 selectively stabilizing SRA–TrxG interaction, and NANOG directly interacts with SRA genome-wide.\",\n      \"evidence\": \"Co-IP, ChIP-seq, reprogramming functional assays in human fibroblasts\",\n      \"pmids\": [\"26496121\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SRA switches between TrxG and PRC2 at specific loci remains unknown\", \"Mechanism by which NANOG recruits or is recruited by SRA not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"SRA ncRNA's regulation of hepatic lipid metabolism was mechanistically traced to inhibition of FoxO1-driven ATGL promoter activity, explaining the reduced hepatic steatosis in Sra1 knockout mice.\",\n      \"evidence\": \"Sra1 knockout mice, primary hepatocyte experiments, promoter-reporter assays\",\n      \"pmids\": [\"27759039\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SRA directly binds the ATGL promoter or acts through FoxO1 sequestration is unresolved\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Alternative splicing of SRA1 exon 3 by SRSF1 generates functionally opposing isoforms: the long isoform (SRA1-L) promotes HCC invasion via CD44 upregulation, while the short isoform (SRA1-S) suppresses it, revealing isoform-specific oncogenic functions.\",\n      \"evidence\": \"CLIP, RNA pulldown, minigene mutagenesis, in vivo mouse metastasis model\",\n      \"pmids\": [\"34011971\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SRA1-L acts as ncRNA or protein in this context is unaddressed\", \"Mechanism linking SRA1-L to CD44 transcription not fully elucidated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major unresolved questions include: (1) how the SRA1 locus balances ncRNA versus protein output physiologically; (2) the structural basis of SRA RNA recognition by its diverse protein partners; (3) whether SRAP has a molecular function independent of SRA RNA; and (4) the relative contributions of ncRNA versus protein loss to the metabolic and differentiation phenotypes observed in knockout models.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length SRA RNA structure determined\", \"No separation-of-function allele distinguishing ncRNA from SRAP in vivo\", \"SRAP molecular function remains unknown after crystal structure showed no RRM\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 5, 7, 9, 12, 13]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [4, 8, 14]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [16, 17, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 4, 6, 10, 12, 14]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [6, 12]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [16, 17, 18]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [16, 17]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 2, 3, 5, 7, 9, 12, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 9, 16, 20]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 8, 12]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [6, 12]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [7, 11, 13]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"complexes\": [\n      \"WAVE regulatory complex (CYFIP1/Sra-1, WAVE, Abi, Nap1, HSPC300)\",\n      \"SRA/SRC-1/p68/p72 coactivator complex\",\n      \"SRA/CTCF/p68/cohesin complex\"\n    ],\n    \"partners\": [\n      \"DDX5\",\n      \"DDX17\",\n      \"SRC1\",\n      \"TIF2\",\n      \"SLIRP\",\n      \"CTCF\",\n      \"NANOG\",\n      \"NCKAP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"Insufficient on-target evidence to synthesize a narrative — discovery timeline does not match the canonical SRA1 protein.\",\n  \"teleology\": [],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}\n```"}