{"gene":"RBM14","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2001,"finding":"CoAA (RBM14) was identified as a TRBP-interacting protein via yeast two-hybrid screening; it contains two RNA recognition motifs (RRMs) and a TRBP-interacting domain. CoAA interacts with both TRBP and p300 in vitro, potently coactivates transcription mediated by multiple hormone-response elements synergistically with TRBP and CBP, and is associated with the DNA-dependent protein kinase–poly(ADP-ribose) polymerase complex. A splice variant, CoAM (lacking the TRBP-interacting domain), strongly represses TRBP and CBP action.","method":"Yeast two-hybrid screening, in vitro binding assay, co-immunoprecipitation, transfection-based transcriptional reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding confirmed in vitro and by co-IP, multiple orthogonal functional assays (reporter gene, interaction mapping), replicated across constructs","pmids":["11443112"],"is_preprint":false},{"year":2004,"finding":"CoAA (RBM14) mediates both transcriptional coactivation and alternative RNA splicing in a promoter-preferential manner downstream of steroid hormone signaling. Domain-swap experiments showed that the N-terminal RRMs and the C-terminal auxiliary domain are differentially engaged depending on the promoter context, and that this differential domain use underlies the promoter-preferential splicing effects.","method":"Transcriptional and splicing reporter assays with domain-swap mutants; promoter-specific functional comparisons","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple domain-swap mutants tested in orthogonal transcription and splicing reporters; findings build on prior characterization","pmids":["14673176"],"is_preprint":false},{"year":2005,"finding":"RBM14 (SIP/CoAA) specifically binds the QPGY domain of the proto-oncoprotein SYT and the SYT-SSX2 translocation fusion protein. The YQ domain (hexapeptide repeats) of RBM14 mediates interaction with SYT; the last 84 amino acids adjacent to YQ down-modulate YQ transactivation ~25-fold. SYT and SIP/CoAA cooperate to stimulate estrogen and glucocorticoid receptor-dependent transcriptional activation in a hormone- and hBRM/BRG1-dependent manner.","method":"Co-immunoprecipitation, GST pulldown, reporter gene transcriptional assays, deletion/domain mapping","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays and functional reporter data; single lab, multiple orthogonal methods","pmids":["16227627"],"is_preprint":false},{"year":2006,"finding":"The CoAA (RBM14) gene is amplified at chromosome 11q13 in subsets of primary human cancers (non-small cell lung carcinoma, squamous cell skin carcinoma, lymphoma) with recurrent loss of upstream silencing sequences; CoAA protein is overexpressed in amplified tumors, positively autoregulates its own basal promoter, and displays transforming activity in soft agar assays.","method":"Genomic mapping of amplicons, Western blot, transfection reporter assays (autoregulation), soft agar colony assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct transforming-activity assay and promoter autoregulation experiment; single lab with multiple methods","pmids":["16878147"],"is_preprint":false},{"year":2007,"finding":"CoAA (RBM14) alternative splicing is switched from CoAA to the dominant-negative variant CoAM during stem cell differentiation; this switch is regulated by a cis-regulatory sequence upstream of the CoAA basal promoter, and p54nrb and PSF induce CoAM production through this sequence. CoAM functionally inhibits CoAA; their switched expression upregulates the differentiation marker Sox6.","method":"CoAA minigene cassette reporter, retinoic acid-induced P19 differentiation model, overexpression/knockdown of p54nrb and PSF","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — minigene and trans-factor functional assays; single lab, multiple methods","pmids":["17337438"],"is_preprint":false},{"year":2009,"finding":"CoAA (RBM14) was identified as a Runx2 binding protein; its carboxy-terminus is essential for binding the Runt domains of Runx1 and Runx2. CoAA represses Runx factor-dependent transcriptional activation and blocks Runx2-mediated repression of Axin2 in a histone deacetylase-independent manner. CoAA inhibits Runx2–DNA interactions as shown by EMSA.","method":"Co-immunoprecipitation, EMSA, reporter gene assays, siRNA knockdown, domain-deletion mapping","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding domain mapped, functional inhibition demonstrated with EMSA; single lab, multiple orthogonal methods","pmids":["19585539"],"is_preprint":false},{"year":2009,"finding":"Trans-splicing between CoAA (RBM14) and downstream corepressor RBM4 transcripts generates intergenic splice variants (CoAZ and ncCoAZ) during stem/progenitor cell neural differentiation. CoAA and RBM4 counter-regulate alternative splicing of the target pre-mRNA Tau exon 10; stable expression of CoAA or RBM4 blocks the trans-splicing switch and disrupts embryoid body formation.","method":"RT-PCR identification of trans-spliced variants, stable expression and knockdown in neural differentiation model, minigene splicing assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — trans-splicing identified and functionally tested; single lab, multiple orthogonal methods","pmids":["19416963"],"is_preprint":false},{"year":2011,"finding":"CoAA (RBM14) interacts with PEA3 group members (ERM, ER81, PEA3) via its YQ domain (tyrosine/glutamine hexapeptide repeats); the two N-terminal RRMs are required for transcriptional enhancement. CoAA is involved in the migration-enhancing action of PEA3 on MCF7 cells.","method":"Co-immunoprecipitation, domain-deletion mapping, reporter gene transcriptional assays, cell migration assay","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding domain mapped with deletion mutants, functional assays in two readouts; single lab","pmids":["21736557"],"is_preprint":false},{"year":2014,"finding":"RBM14 controls DNA repair pathways (specifically DNA-PK-dependent non-homologous end joining, NHEJ) and prevents cell differentiation in GBM tumor-initiating cells. Knockdown of RBM14 sensitizes GBM cells to radiation and blocks tumor regrowth after irradiation in vivo.","method":"siRNA knockdown, NHEJ reporter assay, in vivo xenograft irradiation model, sphere-formation assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway-specific repair assay combined with in vivo model; single lab, multiple readouts","pmids":["24811242"],"is_preprint":false},{"year":2014,"finding":"RBM14 depletion in human cells induces ectopic formation of centriolar protein complexes through function of the STIL/CPAP complex, which can recruit pericentriolar material, nucleate microtubules, and incorporate HsSAS-6 to form aberrant centriole-like structures, causing multipolar spindle formation and genome instability.","method":"siRNA knockdown in human cells, immunofluorescence microscopy, co-localization analysis, spindle assembly assays","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis with STIL/CPAP demonstrated by depletion and rescue; single lab with multiple cellular phenotype readouts","pmids":["25385835"],"is_preprint":false},{"year":2015,"finding":"RBM14 associates with XPO1 (CRM1) and HIV-1 Rev in the nuclear complexome. RBM14 depletion decreases Rev activity and Rev-mediated nuclear export of unspliced viral transcripts; this function depends on paraspeckle integrity (NEAT1 RNA). Overexpressed RBM14 enhancement of Rev function is abolished by NEAT1 depletion.","method":"Nuclear complexome mining, siRNA knockdown, Rev-dependent p24 reporter assay, cytoplasmic RNA quantification, NEAT1 depletion","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assay with epistasis to NEAT1; single lab, multiple orthogonal methods","pmids":["25589658"],"is_preprint":false},{"year":2017,"finding":"RBM14 is required for efficient recruitment of XRCC4 and XLF to chromatin and for the release of KU proteins from chromatin upon DNA damage; failure leads to accumulation of double-strand breaks. This places RBM14 as a regulator of NHEJ factor dynamics at damage sites.","method":"siRNA knockdown, chromatin fractionation, immunofluorescence/FRAP at damage sites, comet assay, γH2AX quantification","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chromatin recruitment assay with multiple NHEJ factors; single lab, multiple orthogonal methods","pmids":["28426349"],"is_preprint":false},{"year":2017,"finding":"The lincRNA Paral1 promotes adipogenesis and coactivates PPARγ through physical interaction with RBM14 (NCoAA/RBM14), identifying RBM14 as a mediator of Paral1-dependent transcriptional coactivation of PPARγ.","method":"RNA immunoprecipitation (RIP), knockdown and overexpression in adipocyte differentiation model, reporter gene assays","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — RIP with functional context established; single lab, limited mechanistic depth on RBM14 specifically","pmids":["29075020"],"is_preprint":false},{"year":2018,"finding":"RBM14 localizes to nuclear paraspeckles; upon influenza A virus (IAV) infection, RBM14 relocalizes to the nucleolus. This relocalization is necessary and sufficient through the IAV NS1 protein and requires the double-stranded RNA-binding capacity of NS1. RBM14 was validated as a required host factor for IAV replication.","method":"siRNA knockdown (two IAV subtypes, primary and transformed cells), immunofluorescence localization, NS1 overexpression/mutants, viral replication assay","journal":"mSphere","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — localization tied to functional consequence, NS1 domain requirement defined; single lab with multiple orthogonal methods","pmids":["30429226"],"is_preprint":false},{"year":2019,"finding":"Zebrafish Rbm14 regulates embryonic dorsoventral patterning through phase separation mediated by its intrinsically disordered region (IDR). Rbm14 IDR forms liquid droplets in vitro; phase-separation mutants or isolated IDR fail to rescue dorsalized morphant phenotypes, but chimeric proteins with heterologous IDRs from other phase-separating proteins are effective. Rbm14 complexes with proteins involved in RNA metabolism and phase separates into cellular ribonucleoprotein compartments.","method":"Zebrafish morpholino knockdown, in vitro phase-separation assays, chimeric protein rescue experiments, RNA-seq (alternative splicing analysis), co-immunoprecipitation","journal":"Cell discovery","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of phase separation combined with in vivo rescue with chimeric IDR mutants and transcriptomic validation; rigorous multi-method study","pmids":["31636951"],"is_preprint":false},{"year":2019,"finding":"Rbm14 knockout in mice causes embryonic lethality due to gastrulation disruption; Rbm14-null ESCs accumulate DNA damage (γH2AX, comet assay) and show altered splicing of DNA damage response genes. IP-MS confirmed RBM14 interaction with alternative splicing-related proteins.","method":"CRISPR/Cas9 knockout mouse, histological analysis, γH2AX staining, comet assay, RNA-seq, IP-MS, co-IP","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with defined cellular phenotype and IP-MS interactome; single lab, multiple orthogonal methods","pmids":["31794640"],"is_preprint":false},{"year":2020,"finding":"RBM14 is recruited to DNA damage sites in a PARP- and RNA polymerase II (RNAPII)-dependent manner. Both KU and RBM14 are required for RNAPII-dependent generation of RNA:DNA hybrids (R-loops) at double-strand break sites; RBM14 directly binds RNA:DNA hybrids. RNA:DNA hybrids and RNAPII are detected at gene-coding and intergenic areas upon DSB induction.","method":"Laser microirradiation/live-cell imaging for recruitment kinetics, PARP and RNAPII inhibitor experiments, S9.6 antibody-based RNA:DNA hybrid detection, RBM14 pulldown with RNA:DNA substrates","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding to RNA:DNA hybrids combined with live-cell recruitment assays and pharmacological epistasis; multiple orthogonal methods in one rigorous study","pmids":["32094185"],"is_preprint":false},{"year":2021,"finding":"RBM14 co-localizes with α-tubulin at spindle poles during mouse oocyte meiosis; RBM14 knockdown causes spindle defects, chromosome abnormalities, and α-tubulin hyperacetylation. Co-immunoprecipitation demonstrates RBM14 interaction with endogenous α-tubulin in mammalian cells, suggesting RBM14 modulates tubulin acetylation to regulate spindle morphology.","method":"Morpholino knockdown in oocytes, immunofluorescence co-localization, co-immunoprecipitation, spindle perturbation assays","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction confirmed by Co-IP with functional spindle phenotype; single lab, multiple methods","pmids":["33604343"],"is_preprint":false},{"year":2022,"finding":"Nuclear RBM14 and maternal mRNAs co-phase separate into cytoplasmic condensates in zebrafish blastomeres. These condensates concentrate at spindle poles by associating with centrosomal γ-tubulin, undergo preferentially asymmetric divisions, and are stimulated by m6A modification but repressed by m5C modification of maternal mRNA. Deadenylase PARN co-phase separates with these condensates, which is required for deadenylation of maternal mRNAs. Rbm14 depletion impairs zygotic genome activation and causes developmental arrest.","method":"Live-cell imaging, in vitro phase-separation assay, m6A/m5C modification functional tests, co-IP for PARN interaction, zebrafish and mouse morpholino/knockout, RNA-seq","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted phase separation in vitro, PARN co-phase separation linked to deadenylation function, in vivo rescue experiments, validated in two vertebrate models","pmids":["36477743"],"is_preprint":false},{"year":2022,"finding":"METTL3-mediated m6A methylation of RBM14 mRNA promotes its expression via YTHDF1 binding. METTL3 knockdown in Kupffer cells suppresses RBM14 expression by decreasing m6A methylation; overexpression of RBM14 rescues the anti-tumor effects of METTL3 depletion, placing RBM14 downstream of the METTL3-YTHDF1 m6A axis.","method":"m6A-seq/meRIP, siRNA/shRNA knockdown and overexpression, in vitro and in vivo functional rescue assays","journal":"Human cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A modification and YTHDF1 reader confirmed, epistasis by rescue experiment; single lab, multiple methods","pmids":["36087219"],"is_preprint":false},{"year":2023,"finding":"RBM14 promotes DNA end resection during homologous recombination (HR) repair by interacting with the HR factor CtIP; RBM14 is required for CtIP recruitment to DSB sites and for subsequent RPA coating and RAD51 replacement. RBM14 was identified as a binding partner of RPA-coated resected DNA intermediates by pulldown assay.","method":"ssDNA/dsDNA-RPA pulldown assay, co-immunoprecipitation with CtIP, chromatin recruitment assays (RPA, RAD51), HR reporter assay, irradiation sensitivity assay","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding to HR intermediate confirmed, CtIP interaction and epistatic placement in HR pathway; single lab, multiple orthogonal methods","pmids":["37559455"],"is_preprint":false},{"year":2024,"finding":"RBM14 is O-GlcNAcylated at serine 521; this modification regulates its interaction with the E3 ubiquitin ligase TRIM33, which affects OGA (O-GlcNAcase) protein stability through ubiquitin-dependent proteasomal degradation. Mutation S521A abrogates RBM14–TRIM33 interaction, restores OGA levels, and abolishes the oncogenic properties of RBM14. RBM14 thus acts as a regulator of cellular O-GlcNAcylation homeostasis.","method":"O-GlcNAc site mapping (mass spectrometry), site-directed mutagenesis (S521A), co-immunoprecipitation, ubiquitination assay, proteasome inhibitor experiments, in vitro and in vivo oncogenic assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — modification site mapped by MS, functional mutagenesis validates mechanism, multiple orthogonal biochemical and cellular assays in single rigorous study","pmids":["38678556"],"is_preprint":false},{"year":2024,"finding":"RBM14 inhibits PEDV replication by (1) recruiting cargo receptor p62 to degrade the viral nucleocapsid (N) protein via the autophagy pathway (RBM14-p62-autophagosome axis), and (2) interacting with mitochondrial antiviral signaling protein (MAVS) and TRAF3 to activate interferon signaling.","method":"Co-immunoprecipitation, autophagy flux assay (autophagosome formation), interferon reporter assay, viral replication assay, knockdown/overexpression","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two distinct molecular mechanisms demonstrated with co-IP and functional assays; single lab, multiple orthogonal methods","pmids":["38411947"],"is_preprint":false},{"year":2024,"finding":"RBM14 binds to NONO and interferes with NONO-mediated DLG1 exon6 skipping in gallbladder cancer cells. IP/MS identified RBM14 as NONO-bound; IGF2BP3 disrupts the RBM14-NONO interaction to promote exon skipping.","method":"IP/MS, co-immunoprecipitation, mRNA-seq/RIP-seq, alternative splicing quantification (PSI)","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS interaction confirmed, functional splicing consequence demonstrated; single lab, multiple orthogonal methods","pmids":["38341127"],"is_preprint":false},{"year":2025,"finding":"RBM14 stabilizes HK2 mRNA via its RRM1/2 domains, enhancing HK2 expression and glycolytic capacity in prostate cancer cells; increased glycolysis elevates H3K18 lactylation at promoters of metastasis-related genes, driving their transcriptional upregulation.","method":"RNA-binding domain mutagenesis (RRM1/2), RNA immunoprecipitation (RIP), mRNA stability assay, glycolysis assay (ECAR), ChIP-seq for H3K18la, in vitro and in vivo metastasis assays","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-specific RNA binding confirmed, mRNA stability and downstream metabolic-epigenetic mechanism established; single lab, multiple orthogonal methods","pmids":["42062247"],"is_preprint":false},{"year":2025,"finding":"RBM14 deubiquitination by USP44 stabilizes RBM14 protein; stabilization of RBM14 by USP44 (delivered via mesenchymal stem cell-derived extracellular vesicles) counteracts radiation-induced DNA damage, apoptosis, and cell cycle disruption. RBM14 overexpression partially restores cell survival when USP44 is silenced.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, RBM14 overexpression rescue, DNA damage markers (γH2AX), cell viability assay","journal":"Stem cell research & therapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — deubiquitination mechanism inferred from co-IP and rescue; single lab, primarily in vitro, limited mechanistic depth","pmids":["41299552"],"is_preprint":false}],"current_model":"RBM14 is a multifunctional nuclear RNA-binding protein with two N-terminal RRMs and an intrinsically disordered/auxiliary domain that (1) acts as a transcriptional coactivator downstream of steroid hormone signaling by bridging TRBP, p300/CBP, and nuclear receptors; (2) couples transcription to alternative splicing in a promoter-dependent manner; (3) is recruited to DNA double-strand breaks in a PARP- and RNAPII-dependent manner, where it binds RNA:DNA hybrids and facilitates both canonical NHEJ (through regulation of KU, XRCC4, and XLF dynamics) and HR (by supporting CtIP-mediated end resection); (4) suppresses ectopic centriole assembly and maintains spindle integrity; (5) forms phase-separated ribonucleoprotein condensates via its IDR that regulate maternal mRNA deadenylation and allocation during early embryogenesis; and (6) is subject to O-GlcNAcylation at S521 and deubiquitination by USP44, post-translational modifications that govern its interactions with TRIM33 and its role in controlling cellular O-GlcNAc homeostasis via OGA stability."},"narrative":{"mechanistic_narrative":"RBM14 (CoAA) is a multifunctional nuclear RNA-binding protein with two N-terminal RNA recognition motifs and a C-terminal auxiliary/intrinsically disordered region that couples transcription, RNA processing, genome maintenance, and phase separation [PMID:11443112, PMID:14673176, PMID:31636951]. As a transcriptional coactivator, it bridges TRBP and p300/CBP to potentiate hormone-receptor-dependent transcription, with its RRMs and auxiliary domain differentially engaged to drive promoter-preferential coactivation and alternative splicing [PMID:11443112, PMID:14673176]; the same scaffolding underlies interactions with diverse transcription factors and partners including SYT, Runx2, and PEA3-group factors [PMID:16227627, PMID:19585539, PMID:21736557]. RBM14 is recruited to DNA double-strand breaks in a PARP- and RNAPII-dependent manner, where it binds RNA:DNA hybrids and supports both non-homologous end joining—through control of XRCC4/XLF recruitment and KU release—and homologous recombination, by promoting CtIP-mediated end resection and subsequent RPA/RAD51 loading [PMID:32094185, PMID:28426349, PMID:37559455]. Through its IDR, RBM14 phase-separates into ribonucleoprotein condensates that govern embryonic patterning and, in early embryos, concentrate maternal mRNAs at spindle poles where co-phase separation with the deadenylase PARN drives deadenylation and proper zygotic genome activation [PMID:31636951, PMID:36477743]. RBM14 also suppresses ectopic centriole assembly via the STIL/CPAP pathway to preserve spindle integrity and genome stability [PMID:25385835]. Post-translationally, O-GlcNAcylation at Ser521 governs its interaction with the E3 ligase TRIM33 to control OGA stability and cellular O-GlcNAc homeostasis, linking RBM14 to oncogenic transformation [PMID:38678556].","teleology":[{"year":2001,"claim":"Established RBM14's founding identity as a TRBP-interacting transcriptional coactivator, defining its domain architecture and link to hormone signaling.","evidence":"Yeast two-hybrid, in vitro binding, co-IP, and reporter assays identifying CoAA with two RRMs and a TRBP-interacting domain","pmids":["11443112"],"confidence":"High","gaps":["Direct RNA targets not defined","Endogenous coactivator complex composition unresolved"]},{"year":2004,"claim":"Showed RBM14 couples transcription to alternative splicing in a promoter-preferential manner, defining how its two domains are differentially deployed.","evidence":"Transcription and splicing reporter assays with domain-swap mutants across promoter contexts","pmids":["14673176"],"confidence":"High","gaps":["Mechanism of promoter-context sensing unknown","Endogenous splicing targets not mapped"]},{"year":2005,"claim":"Extended the coactivator scaffold to oncogenic SYT/SYT-SSX2 fusions, mapping the YQ hexapeptide-repeat domain as the interaction module.","evidence":"Co-IP, GST pulldown, domain mapping, and hormone-receptor reporter assays in human cells","pmids":["16227627"],"confidence":"Medium","gaps":["Single-lab interaction data","Functional consequence in synovial sarcoma not tested in vivo"]},{"year":2006,"claim":"Connected RBM14 to cancer biology via 11q13 amplification, autoregulation, and transforming activity, establishing oncogenic potential.","evidence":"Amplicon mapping, autoregulation reporter assays, and soft-agar transformation assays","pmids":["16878147"],"confidence":"Medium","gaps":["Driver vs passenger status of amplification unresolved","Mechanism of transformation not defined"]},{"year":2007,"claim":"Defined an alternative-splicing switch (CoAA to dominant-negative CoAM) regulated by p54nrb/PSF that controls RBM14 activity during differentiation.","evidence":"Minigene reporters, retinoic acid-induced P19 differentiation, and trans-factor perturbation","pmids":["17337438"],"confidence":"Medium","gaps":["Physiological breadth of the isoform switch unknown","Single-lab assays"]},{"year":2009,"claim":"Broadened RBM14's transcription-factor repertoire to Runx factors and intergenic trans-splicing with RBM4, linking it to differentiation control.","evidence":"Co-IP, EMSA, reporter assays, and trans-spliced variant identification in neural differentiation models","pmids":["19585539","19416963"],"confidence":"Medium","gaps":["In vivo relevance of trans-splicing unclear","Genome-wide Runx co-regulation not assessed"]},{"year":2011,"claim":"Identified RBM14 as a PEA3-group cofactor requiring both RRMs, tying its coactivation to cancer cell migration.","evidence":"Co-IP, domain-deletion mapping, reporter assays, and migration assays in MCF7 cells","pmids":["21736557"],"confidence":"Medium","gaps":["Single readout system","Direct migration targets not defined"]},{"year":2014,"claim":"Established RBM14 as a regulator of NHEJ and a suppressor of ectopic centriole assembly, linking it to DNA repair and genome stability.","evidence":"siRNA knockdown with NHEJ reporters, xenograft irradiation, immunofluorescence, and STIL/CPAP epistasis","pmids":["24811242","25385835"],"confidence":"Medium","gaps":["Molecular role in NHEJ not yet mechanistic","How RBM14 suppresses centriole assembly unknown"]},{"year":2015,"claim":"Linked RBM14 to paraspeckle-dependent RNA export, supporting HIV-1 Rev function via NEAT1 integrity.","evidence":"Complexome mining, Rev-dependent reporter, RNA quantification, and NEAT1 depletion epistasis","pmids":["25589658"],"confidence":"Medium","gaps":["Direct RBM14-Rev contact not mapped","Generalizability beyond viral export unclear"]},{"year":2017,"claim":"Provided mechanistic detail for RBM14 in NHEJ, showing it controls XRCC4/XLF recruitment and KU release at damage sites.","evidence":"Chromatin fractionation, FRAP/immunofluorescence at damage sites, comet and γH2AX assays","pmids":["28426349"],"confidence":"Medium","gaps":["Direct interactions with NHEJ factors not biochemically resolved","Single-lab data"]},{"year":2019,"claim":"Demonstrated that RBM14's IDR-driven phase separation is essential for embryonic patterning and that knockout causes DNA damage and altered DDR-gene splicing.","evidence":"In vitro droplet assays, zebrafish chimeric-IDR rescue, CRISPR knockout mouse, RNA-seq, IP-MS","pmids":["31636951","31794640"],"confidence":"High","gaps":["Composition of physiological condensates incompletely defined","Causal link between splicing changes and lethality not fully established"]},{"year":2020,"claim":"Defined the recruitment logic and biochemical activity of RBM14 at DSBs: PARP/RNAPII-dependent recruitment and direct binding of RNA:DNA hybrids.","evidence":"Laser microirradiation kinetics, PARP/RNAPII inhibitors, S9.6 detection, RNA:DNA substrate pulldown","pmids":["32094185"],"confidence":"High","gaps":["How hybrid binding promotes repair completion unresolved","Distinction between NHEJ and HR roles at hybrids not delineated"]},{"year":2021,"claim":"Implicated RBM14 in spindle-pole organization through α-tubulin interaction and modulation of tubulin acetylation in oocytes.","evidence":"Oocyte morpholino knockdown, immunofluorescence co-localization, co-IP with α-tubulin","pmids":["33604343"],"confidence":"Medium","gaps":["Mechanism of acetylation control unknown","Relationship to nuclear functions unclear"]},{"year":2022,"claim":"Showed RBM14 condensates concentrate maternal mRNAs at spindle poles and recruit PARN to drive deadenylation, controlling zygotic genome activation.","evidence":"Live imaging, in vitro phase separation, m6A/m5C functional tests, PARN co-IP, zebrafish/mouse depletion, RNA-seq","pmids":["36477743"],"confidence":"High","gaps":["RNA modification readers governing recruitment not identified","Asymmetric partitioning mechanism incompletely defined"]},{"year":2023,"claim":"Resolved RBM14's role in homologous recombination, showing it promotes CtIP-dependent resection and RPA/RAD51 loading by binding resected intermediates.","evidence":"RPA-coated ssDNA pulldown, CtIP co-IP, RPA/RAD51 recruitment, HR reporter and irradiation sensitivity","pmids":["37559455"],"confidence":"Medium","gaps":["Choice between NHEJ and HR engagement not explained","Single-lab data"]},{"year":2024,"claim":"Identified Ser521 O-GlcNAcylation as a switch controlling RBM14-TRIM33 interaction, OGA stability, and oncogenicity, placing RBM14 in O-GlcNAc homeostasis.","evidence":"MS site mapping, S521A mutagenesis, co-IP, ubiquitination and proteasome assays, oncogenic assays","pmids":["38678556"],"confidence":"High","gaps":["O-GlcNAc transferase responsible not defined here","Link to nuclear/splicing functions unexplored"]},{"year":2024,"claim":"Added antiviral and splicing-partner dimensions: RBM14 restricts PEDV via p62-autophagy and MAVS/TRAF3 interferon signaling, and competes with NONO to control DLG1 splicing.","evidence":"Co-IP, autophagy flux, IFN reporter, viral replication assays; IP/MS and splicing PSI quantification in cancer cells","pmids":["38411947","38341127"],"confidence":"Medium","gaps":["Direct vs indirect MAVS engagement unclear","Generalizability of NONO competition across transcripts untested"]},{"year":2025,"claim":"Connected RBM14's RRM-mediated mRNA stabilization to cancer metabolism, stabilizing HK2 mRNA to drive glycolysis and H3K18 lactylation-dependent metastasis programs.","evidence":"RRM1/2 mutagenesis, RIP, mRNA stability and ECAR assays, H3K18la ChIP-seq, metastasis models","pmids":["42062247"],"confidence":"Medium","gaps":["Breadth of stabilized mRNA targets unknown","Specificity of RRM binding not structurally defined"]},{"year":2025,"claim":"Reported USP44-mediated deubiquitination as a stabilizing mechanism protecting RBM14 against radiation-induced damage.","evidence":"Co-IP, ubiquitination assay, knockdown and overexpression rescue with γH2AX and viability readouts","pmids":["41299552"],"confidence":"Low","gaps":["Deubiquitination inferred from co-IP and rescue, not directly reconstituted","Ubiquitination sites on RBM14 not mapped","Largely in vitro"]},{"year":null,"claim":"How RBM14's distinct activities—coactivation, splicing, DSB repair, phase-separated condensate formation, and O-GlcNAc homeostasis—are coordinated or partitioned within a single protein, and what determines context-specific engagement, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural model integrating RRM and IDR functions","Determinants of pathway selection at DSBs (NHEJ vs HR) unknown","Cross-talk between PTM control and condensate behavior unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,16,24]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,18,20]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[16]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,13]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[13]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[13]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[18]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[9,17,18]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[11,16,20]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,18,23]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[14,18]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[13,22]}],"complexes":["paraspeckle"],"partners":["TRBP","CREBBP","EP300","CTIP","PARN","TRIM33","NONO","USP44"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96PK6","full_name":"RNA-binding protein 14","aliases":["Paraspeckle protein 2","PSP2","RNA-binding motif protein 14","RRM-containing coactivator activator/modulator","Synaptotagmin-interacting protein","SYT-interacting protein"],"length_aa":669,"mass_kda":69.5,"function":"Isoform 1 may function as a nuclear receptor coactivator, enhancing transcription through other coactivators such as NCOA6 and CITED1. Isoform 2, functions as a transcriptional repressor, modulating transcriptional activities of coactivators including isoform 1, NCOA6 and CITED1 (PubMed:11443112). Regulates centriole biogenesis by suppressing the formation of aberrant centriolar protein complexes in the cytoplasm and thus preserving mitotic spindle integrity. Prevents the formation of the STIL-CPAP complex (which can induce the formation of aberrant centriolar protein complexes) by interfering with the interaction of STIL with CPAP (PubMed:25385835). Plays a role in the regulation of DNA virus-mediated innate immune response by assembling into the HDP-RNP complex, a complex that serves as a platform for IRF3 phosphorylation and subsequent innate immune response activation through the cGAS-STING pathway (PubMed:28712728). Also involved in the regulation of pre-mRNA alternative splicing (PubMed:37548402)","subcellular_location":"Nucleus; Nucleus, nucleolus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q96PK6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/RBM14","classification":"Common Essential","n_dependent_lines":1183,"n_total_lines":1208,"dependency_fraction":0.9793046357615894},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000239306","cell_line_id":"CID001470","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"nuclear_punctae","grade":2},{"compartment":"nucleolus_fc_dfc","grade":2}],"interactors":[{"gene":"MIF","stoichiometry":10.0},{"gene":"HSPA8","stoichiometry":10.0},{"gene":"HNRNPA3","stoichiometry":4.0},{"gene":"HNRNPL","stoichiometry":4.0},{"gene":"HNRNPA2B1","stoichiometry":4.0},{"gene":"HNRNPA1;HNRNPA1L2","stoichiometry":4.0},{"gene":"RBMX;RBMXL2","stoichiometry":4.0},{"gene":"SAFB","stoichiometry":4.0},{"gene":"NONO","stoichiometry":4.0},{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001470","total_profiled":1310},"omim":[{"mim_id":"612409","title":"RNA-BINDING MOTIF PROTEIN 14; RBM14","url":"https://www.omim.org/entry/612409"},{"mim_id":"612408","title":"PARASPECKLE COMPONENT 1; PSPC1","url":"https://www.omim.org/entry/612408"},{"mim_id":"600192","title":"SS18 SUBUNIT OF BAF CHROMATIN REMODELING COMPLEX; SS18","url":"https://www.omim.org/entry/600192"},{"mim_id":"313700","title":"ANDROGEN RECEPTOR; AR","url":"https://www.omim.org/entry/313700"},{"mim_id":"300084","title":"NON-POU DOMAIN-CONTAINING OCTAMER-BINDING PROTEIN; NONO","url":"https://www.omim.org/entry/300084"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear speckles","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RBM14"},"hgnc":{"alias_symbol":["SIP","SYTIP1","COAA","DKFZp779J0927"],"prev_symbol":[]},"alphafold":{"accession":"Q96PK6","domains":[{"cath_id":"3.30.70.330","chopping":"1-73","consensus_level":"medium","plddt":87.9342,"start":1,"end":73},{"cath_id":"3.30.70.330","chopping":"75-148","consensus_level":"medium","plddt":88.3528,"start":75,"end":148}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96PK6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96PK6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96PK6-F1-predicted_aligned_error_v6.png","plddt_mean":51.66},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RBM14","jax_strain_url":"https://www.jax.org/strain/search?query=RBM14"},"sequence":{"accession":"Q96PK6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96PK6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96PK6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96PK6"}},"corpus_meta":[{"pmid":"14673176","id":"PMC_14673176","title":"CoAA, a nuclear receptor coactivator protein at the interface of transcriptional coactivation and RNA splicing.","date":"2004","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/14673176","citation_count":141,"is_preprint":false},{"pmid":"11443112","id":"PMC_11443112","title":"Identification and characterization of RRM-containing coactivator activator (CoAA) as TRBP-interacting protein, and its splice variant as a coactivator modulator (CoAM).","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11443112","citation_count":116,"is_preprint":false},{"pmid":"1328157","id":"PMC_1328157","title":"Cloning, sequencing, and expression of the pantothenate kinase (coaA) gene of Escherichia coli.","date":"1992","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/1328157","citation_count":72,"is_preprint":false},{"pmid":"12754240","id":"PMC_12754240","title":"Role of feedback regulation of pantothenate 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of proteins.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16227627","citation_count":36,"is_preprint":false},{"pmid":"25385835","id":"PMC_25385835","title":"RBM14 prevents assembly of centriolar protein complexes and maintains mitotic spindle integrity.","date":"2014","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/25385835","citation_count":33,"is_preprint":false},{"pmid":"19416963","id":"PMC_19416963","title":"Functional pre- mRNA trans-splicing of coactivator CoAA and corepressor RBM4 during stem/progenitor cell differentiation.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19416963","citation_count":32,"is_preprint":false},{"pmid":"25589658","id":"PMC_25589658","title":"Mining the human complexome database identifies RBM14 as an XPO1-associated protein involved in HIV-1 Rev function.","date":"2015","source":"Journal of 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identification, and characterization of mechanistically diverse inhibitors of the Mycobacterium tuberculosis enzyme, pantothenate kinase (CoaA).","date":"2011","source":"Journal of biomolecular screening","url":"https://pubmed.ncbi.nlm.nih.gov/22086722","citation_count":18,"is_preprint":false},{"pmid":"19585539","id":"PMC_19585539","title":"Co-activator activator (CoAA) prevents the transcriptional activity of Runt domain transcription factors.","date":"2009","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19585539","citation_count":18,"is_preprint":false},{"pmid":"31636951","id":"PMC_31636951","title":"Regulation of zebrafish dorsoventral patterning by phase separation of RNA-binding protein Rbm14.","date":"2019","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/31636951","citation_count":16,"is_preprint":false},{"pmid":"31794640","id":"PMC_31794640","title":"Rbm14 maintains the integrity of genomic DNA during early mouse embryogenesis via mediating alternative splicing.","date":"2019","source":"Cell proliferation","url":"https://pubmed.ncbi.nlm.nih.gov/31794640","citation_count":15,"is_preprint":false},{"pmid":"38678556","id":"PMC_38678556","title":"O-GlcNAcylation of RBM14 contributes to elevated cellular O-GlcNAc through regulation of OGA protein stability.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/38678556","citation_count":13,"is_preprint":false},{"pmid":"36477743","id":"PMC_36477743","title":"Maternal mRNA deadenylation and allocation via Rbm14 condensates facilitate vertebrate blastula development.","date":"2022","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/36477743","citation_count":13,"is_preprint":false},{"pmid":"37060064","id":"PMC_37060064","title":"RBM14 as a novel epigenetic-activated tumor oncogene is implicated in the reprogramming of glycolysis in lung cancer.","date":"2023","source":"World journal of surgical 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/33604343","citation_count":9,"is_preprint":false},{"pmid":"21736557","id":"PMC_21736557","title":"The coactivator activator CoAA regulates PEA3 group member transcriptional activity.","date":"2011","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/21736557","citation_count":8,"is_preprint":false},{"pmid":"37559455","id":"PMC_37559455","title":"RBM14 promotes DNA end resection during homologous recombination repair.","date":"2023","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/37559455","citation_count":6,"is_preprint":false},{"pmid":"40654360","id":"PMC_40654360","title":"RBM14 enhances transcriptional activity of p23 regulating CXCL1 expression to induce lung cancer metastasis.","date":"2025","source":"Acta pharmaceutica Sinica. 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CoAA interacts with both TRBP and p300 in vitro, potently coactivates transcription mediated by multiple hormone-response elements synergistically with TRBP and CBP, and is associated with the DNA-dependent protein kinase–poly(ADP-ribose) polymerase complex. A splice variant, CoAM (lacking the TRBP-interacting domain), strongly represses TRBP and CBP action.\",\n      \"method\": \"Yeast two-hybrid screening, in vitro binding assay, co-immunoprecipitation, transfection-based transcriptional reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding confirmed in vitro and by co-IP, multiple orthogonal functional assays (reporter gene, interaction mapping), replicated across constructs\",\n      \"pmids\": [\"11443112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CoAA (RBM14) mediates both transcriptional coactivation and alternative RNA splicing in a promoter-preferential manner downstream of steroid hormone signaling. Domain-swap experiments showed that the N-terminal RRMs and the C-terminal auxiliary domain are differentially engaged depending on the promoter context, and that this differential domain use underlies the promoter-preferential splicing effects.\",\n      \"method\": \"Transcriptional and splicing reporter assays with domain-swap mutants; promoter-specific functional comparisons\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple domain-swap mutants tested in orthogonal transcription and splicing reporters; findings build on prior characterization\",\n      \"pmids\": [\"14673176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RBM14 (SIP/CoAA) specifically binds the QPGY domain of the proto-oncoprotein SYT and the SYT-SSX2 translocation fusion protein. The YQ domain (hexapeptide repeats) of RBM14 mediates interaction with SYT; the last 84 amino acids adjacent to YQ down-modulate YQ transactivation ~25-fold. SYT and SIP/CoAA cooperate to stimulate estrogen and glucocorticoid receptor-dependent transcriptional activation in a hormone- and hBRM/BRG1-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, reporter gene transcriptional assays, deletion/domain mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays and functional reporter data; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"16227627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The CoAA (RBM14) gene is amplified at chromosome 11q13 in subsets of primary human cancers (non-small cell lung carcinoma, squamous cell skin carcinoma, lymphoma) with recurrent loss of upstream silencing sequences; CoAA protein is overexpressed in amplified tumors, positively autoregulates its own basal promoter, and displays transforming activity in soft agar assays.\",\n      \"method\": \"Genomic mapping of amplicons, Western blot, transfection reporter assays (autoregulation), soft agar colony assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct transforming-activity assay and promoter autoregulation experiment; single lab with multiple methods\",\n      \"pmids\": [\"16878147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CoAA (RBM14) alternative splicing is switched from CoAA to the dominant-negative variant CoAM during stem cell differentiation; this switch is regulated by a cis-regulatory sequence upstream of the CoAA basal promoter, and p54nrb and PSF induce CoAM production through this sequence. CoAM functionally inhibits CoAA; their switched expression upregulates the differentiation marker Sox6.\",\n      \"method\": \"CoAA minigene cassette reporter, retinoic acid-induced P19 differentiation model, overexpression/knockdown of p54nrb and PSF\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — minigene and trans-factor functional assays; single lab, multiple methods\",\n      \"pmids\": [\"17337438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CoAA (RBM14) was identified as a Runx2 binding protein; its carboxy-terminus is essential for binding the Runt domains of Runx1 and Runx2. CoAA represses Runx factor-dependent transcriptional activation and blocks Runx2-mediated repression of Axin2 in a histone deacetylase-independent manner. CoAA inhibits Runx2–DNA interactions as shown by EMSA.\",\n      \"method\": \"Co-immunoprecipitation, EMSA, reporter gene assays, siRNA knockdown, domain-deletion mapping\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding domain mapped, functional inhibition demonstrated with EMSA; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"19585539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Trans-splicing between CoAA (RBM14) and downstream corepressor RBM4 transcripts generates intergenic splice variants (CoAZ and ncCoAZ) during stem/progenitor cell neural differentiation. CoAA and RBM4 counter-regulate alternative splicing of the target pre-mRNA Tau exon 10; stable expression of CoAA or RBM4 blocks the trans-splicing switch and disrupts embryoid body formation.\",\n      \"method\": \"RT-PCR identification of trans-spliced variants, stable expression and knockdown in neural differentiation model, minigene splicing assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — trans-splicing identified and functionally tested; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"19416963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CoAA (RBM14) interacts with PEA3 group members (ERM, ER81, PEA3) via its YQ domain (tyrosine/glutamine hexapeptide repeats); the two N-terminal RRMs are required for transcriptional enhancement. CoAA is involved in the migration-enhancing action of PEA3 on MCF7 cells.\",\n      \"method\": \"Co-immunoprecipitation, domain-deletion mapping, reporter gene transcriptional assays, cell migration assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding domain mapped with deletion mutants, functional assays in two readouts; single lab\",\n      \"pmids\": [\"21736557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RBM14 controls DNA repair pathways (specifically DNA-PK-dependent non-homologous end joining, NHEJ) and prevents cell differentiation in GBM tumor-initiating cells. Knockdown of RBM14 sensitizes GBM cells to radiation and blocks tumor regrowth after irradiation in vivo.\",\n      \"method\": \"siRNA knockdown, NHEJ reporter assay, in vivo xenograft irradiation model, sphere-formation assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway-specific repair assay combined with in vivo model; single lab, multiple readouts\",\n      \"pmids\": [\"24811242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RBM14 depletion in human cells induces ectopic formation of centriolar protein complexes through function of the STIL/CPAP complex, which can recruit pericentriolar material, nucleate microtubules, and incorporate HsSAS-6 to form aberrant centriole-like structures, causing multipolar spindle formation and genome instability.\",\n      \"method\": \"siRNA knockdown in human cells, immunofluorescence microscopy, co-localization analysis, spindle assembly assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis with STIL/CPAP demonstrated by depletion and rescue; single lab with multiple cellular phenotype readouts\",\n      \"pmids\": [\"25385835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RBM14 associates with XPO1 (CRM1) and HIV-1 Rev in the nuclear complexome. RBM14 depletion decreases Rev activity and Rev-mediated nuclear export of unspliced viral transcripts; this function depends on paraspeckle integrity (NEAT1 RNA). Overexpressed RBM14 enhancement of Rev function is abolished by NEAT1 depletion.\",\n      \"method\": \"Nuclear complexome mining, siRNA knockdown, Rev-dependent p24 reporter assay, cytoplasmic RNA quantification, NEAT1 depletion\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assay with epistasis to NEAT1; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"25589658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RBM14 is required for efficient recruitment of XRCC4 and XLF to chromatin and for the release of KU proteins from chromatin upon DNA damage; failure leads to accumulation of double-strand breaks. This places RBM14 as a regulator of NHEJ factor dynamics at damage sites.\",\n      \"method\": \"siRNA knockdown, chromatin fractionation, immunofluorescence/FRAP at damage sites, comet assay, γH2AX quantification\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chromatin recruitment assay with multiple NHEJ factors; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"28426349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The lincRNA Paral1 promotes adipogenesis and coactivates PPARγ through physical interaction with RBM14 (NCoAA/RBM14), identifying RBM14 as a mediator of Paral1-dependent transcriptional coactivation of PPARγ.\",\n      \"method\": \"RNA immunoprecipitation (RIP), knockdown and overexpression in adipocyte differentiation model, reporter gene assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — RIP with functional context established; single lab, limited mechanistic depth on RBM14 specifically\",\n      \"pmids\": [\"29075020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RBM14 localizes to nuclear paraspeckles; upon influenza A virus (IAV) infection, RBM14 relocalizes to the nucleolus. This relocalization is necessary and sufficient through the IAV NS1 protein and requires the double-stranded RNA-binding capacity of NS1. RBM14 was validated as a required host factor for IAV replication.\",\n      \"method\": \"siRNA knockdown (two IAV subtypes, primary and transformed cells), immunofluorescence localization, NS1 overexpression/mutants, viral replication assay\",\n      \"journal\": \"mSphere\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — localization tied to functional consequence, NS1 domain requirement defined; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30429226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Zebrafish Rbm14 regulates embryonic dorsoventral patterning through phase separation mediated by its intrinsically disordered region (IDR). Rbm14 IDR forms liquid droplets in vitro; phase-separation mutants or isolated IDR fail to rescue dorsalized morphant phenotypes, but chimeric proteins with heterologous IDRs from other phase-separating proteins are effective. Rbm14 complexes with proteins involved in RNA metabolism and phase separates into cellular ribonucleoprotein compartments.\",\n      \"method\": \"Zebrafish morpholino knockdown, in vitro phase-separation assays, chimeric protein rescue experiments, RNA-seq (alternative splicing analysis), co-immunoprecipitation\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of phase separation combined with in vivo rescue with chimeric IDR mutants and transcriptomic validation; rigorous multi-method study\",\n      \"pmids\": [\"31636951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Rbm14 knockout in mice causes embryonic lethality due to gastrulation disruption; Rbm14-null ESCs accumulate DNA damage (γH2AX, comet assay) and show altered splicing of DNA damage response genes. IP-MS confirmed RBM14 interaction with alternative splicing-related proteins.\",\n      \"method\": \"CRISPR/Cas9 knockout mouse, histological analysis, γH2AX staining, comet assay, RNA-seq, IP-MS, co-IP\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with defined cellular phenotype and IP-MS interactome; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"31794640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RBM14 is recruited to DNA damage sites in a PARP- and RNA polymerase II (RNAPII)-dependent manner. Both KU and RBM14 are required for RNAPII-dependent generation of RNA:DNA hybrids (R-loops) at double-strand break sites; RBM14 directly binds RNA:DNA hybrids. RNA:DNA hybrids and RNAPII are detected at gene-coding and intergenic areas upon DSB induction.\",\n      \"method\": \"Laser microirradiation/live-cell imaging for recruitment kinetics, PARP and RNAPII inhibitor experiments, S9.6 antibody-based RNA:DNA hybrid detection, RBM14 pulldown with RNA:DNA substrates\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding to RNA:DNA hybrids combined with live-cell recruitment assays and pharmacological epistasis; multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"32094185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RBM14 co-localizes with α-tubulin at spindle poles during mouse oocyte meiosis; RBM14 knockdown causes spindle defects, chromosome abnormalities, and α-tubulin hyperacetylation. Co-immunoprecipitation demonstrates RBM14 interaction with endogenous α-tubulin in mammalian cells, suggesting RBM14 modulates tubulin acetylation to regulate spindle morphology.\",\n      \"method\": \"Morpholino knockdown in oocytes, immunofluorescence co-localization, co-immunoprecipitation, spindle perturbation assays\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction confirmed by Co-IP with functional spindle phenotype; single lab, multiple methods\",\n      \"pmids\": [\"33604343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Nuclear RBM14 and maternal mRNAs co-phase separate into cytoplasmic condensates in zebrafish blastomeres. These condensates concentrate at spindle poles by associating with centrosomal γ-tubulin, undergo preferentially asymmetric divisions, and are stimulated by m6A modification but repressed by m5C modification of maternal mRNA. Deadenylase PARN co-phase separates with these condensates, which is required for deadenylation of maternal mRNAs. Rbm14 depletion impairs zygotic genome activation and causes developmental arrest.\",\n      \"method\": \"Live-cell imaging, in vitro phase-separation assay, m6A/m5C modification functional tests, co-IP for PARN interaction, zebrafish and mouse morpholino/knockout, RNA-seq\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted phase separation in vitro, PARN co-phase separation linked to deadenylation function, in vivo rescue experiments, validated in two vertebrate models\",\n      \"pmids\": [\"36477743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"METTL3-mediated m6A methylation of RBM14 mRNA promotes its expression via YTHDF1 binding. METTL3 knockdown in Kupffer cells suppresses RBM14 expression by decreasing m6A methylation; overexpression of RBM14 rescues the anti-tumor effects of METTL3 depletion, placing RBM14 downstream of the METTL3-YTHDF1 m6A axis.\",\n      \"method\": \"m6A-seq/meRIP, siRNA/shRNA knockdown and overexpression, in vitro and in vivo functional rescue assays\",\n      \"journal\": \"Human cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A modification and YTHDF1 reader confirmed, epistasis by rescue experiment; single lab, multiple methods\",\n      \"pmids\": [\"36087219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RBM14 promotes DNA end resection during homologous recombination (HR) repair by interacting with the HR factor CtIP; RBM14 is required for CtIP recruitment to DSB sites and for subsequent RPA coating and RAD51 replacement. RBM14 was identified as a binding partner of RPA-coated resected DNA intermediates by pulldown assay.\",\n      \"method\": \"ssDNA/dsDNA-RPA pulldown assay, co-immunoprecipitation with CtIP, chromatin recruitment assays (RPA, RAD51), HR reporter assay, irradiation sensitivity assay\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding to HR intermediate confirmed, CtIP interaction and epistatic placement in HR pathway; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"37559455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RBM14 is O-GlcNAcylated at serine 521; this modification regulates its interaction with the E3 ubiquitin ligase TRIM33, which affects OGA (O-GlcNAcase) protein stability through ubiquitin-dependent proteasomal degradation. Mutation S521A abrogates RBM14–TRIM33 interaction, restores OGA levels, and abolishes the oncogenic properties of RBM14. RBM14 thus acts as a regulator of cellular O-GlcNAcylation homeostasis.\",\n      \"method\": \"O-GlcNAc site mapping (mass spectrometry), site-directed mutagenesis (S521A), co-immunoprecipitation, ubiquitination assay, proteasome inhibitor experiments, in vitro and in vivo oncogenic assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — modification site mapped by MS, functional mutagenesis validates mechanism, multiple orthogonal biochemical and cellular assays in single rigorous study\",\n      \"pmids\": [\"38678556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RBM14 inhibits PEDV replication by (1) recruiting cargo receptor p62 to degrade the viral nucleocapsid (N) protein via the autophagy pathway (RBM14-p62-autophagosome axis), and (2) interacting with mitochondrial antiviral signaling protein (MAVS) and TRAF3 to activate interferon signaling.\",\n      \"method\": \"Co-immunoprecipitation, autophagy flux assay (autophagosome formation), interferon reporter assay, viral replication assay, knockdown/overexpression\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two distinct molecular mechanisms demonstrated with co-IP and functional assays; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38411947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RBM14 binds to NONO and interferes with NONO-mediated DLG1 exon6 skipping in gallbladder cancer cells. IP/MS identified RBM14 as NONO-bound; IGF2BP3 disrupts the RBM14-NONO interaction to promote exon skipping.\",\n      \"method\": \"IP/MS, co-immunoprecipitation, mRNA-seq/RIP-seq, alternative splicing quantification (PSI)\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS interaction confirmed, functional splicing consequence demonstrated; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38341127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBM14 stabilizes HK2 mRNA via its RRM1/2 domains, enhancing HK2 expression and glycolytic capacity in prostate cancer cells; increased glycolysis elevates H3K18 lactylation at promoters of metastasis-related genes, driving their transcriptional upregulation.\",\n      \"method\": \"RNA-binding domain mutagenesis (RRM1/2), RNA immunoprecipitation (RIP), mRNA stability assay, glycolysis assay (ECAR), ChIP-seq for H3K18la, in vitro and in vivo metastasis assays\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-specific RNA binding confirmed, mRNA stability and downstream metabolic-epigenetic mechanism established; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"42062247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBM14 deubiquitination by USP44 stabilizes RBM14 protein; stabilization of RBM14 by USP44 (delivered via mesenchymal stem cell-derived extracellular vesicles) counteracts radiation-induced DNA damage, apoptosis, and cell cycle disruption. RBM14 overexpression partially restores cell survival when USP44 is silenced.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, RBM14 overexpression rescue, DNA damage markers (γH2AX), cell viability assay\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — deubiquitination mechanism inferred from co-IP and rescue; single lab, primarily in vitro, limited mechanistic depth\",\n      \"pmids\": [\"41299552\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RBM14 is a multifunctional nuclear RNA-binding protein with two N-terminal RRMs and an intrinsically disordered/auxiliary domain that (1) acts as a transcriptional coactivator downstream of steroid hormone signaling by bridging TRBP, p300/CBP, and nuclear receptors; (2) couples transcription to alternative splicing in a promoter-dependent manner; (3) is recruited to DNA double-strand breaks in a PARP- and RNAPII-dependent manner, where it binds RNA:DNA hybrids and facilitates both canonical NHEJ (through regulation of KU, XRCC4, and XLF dynamics) and HR (by supporting CtIP-mediated end resection); (4) suppresses ectopic centriole assembly and maintains spindle integrity; (5) forms phase-separated ribonucleoprotein condensates via its IDR that regulate maternal mRNA deadenylation and allocation during early embryogenesis; and (6) is subject to O-GlcNAcylation at S521 and deubiquitination by USP44, post-translational modifications that govern its interactions with TRIM33 and its role in controlling cellular O-GlcNAc homeostasis via OGA stability.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RBM14 (CoAA) is a multifunctional nuclear RNA-binding protein with two N-terminal RNA recognition motifs and a C-terminal auxiliary/intrinsically disordered region that couples transcription, RNA processing, genome maintenance, and phase separation [#0, #1, #14]. As a transcriptional coactivator, it bridges TRBP and p300/CBP to potentiate hormone-receptor-dependent transcription, with its RRMs and auxiliary domain differentially engaged to drive promoter-preferential coactivation and alternative splicing [#0, #1]; the same scaffolding underlies interactions with diverse transcription factors and partners including SYT, Runx2, and PEA3-group factors [#2, #5, #7]. RBM14 is recruited to DNA double-strand breaks in a PARP- and RNAPII-dependent manner, where it binds RNA:DNA hybrids and supports both non-homologous end joining—through control of XRCC4/XLF recruitment and KU release—and homologous recombination, by promoting CtIP-mediated end resection and subsequent RPA/RAD51 loading [#16, #11, #20]. Through its IDR, RBM14 phase-separates into ribonucleoprotein condensates that govern embryonic patterning and, in early embryos, concentrate maternal mRNAs at spindle poles where co-phase separation with the deadenylase PARN drives deadenylation and proper zygotic genome activation [#14, #18]. RBM14 also suppresses ectopic centriole assembly via the STIL/CPAP pathway to preserve spindle integrity and genome stability [#9]. Post-translationally, O-GlcNAcylation at Ser521 governs its interaction with the E3 ligase TRIM33 to control OGA stability and cellular O-GlcNAc homeostasis, linking RBM14 to oncogenic transformation [#21].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established RBM14's founding identity as a TRBP-interacting transcriptional coactivator, defining its domain architecture and link to hormone signaling.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, co-IP, and reporter assays identifying CoAA with two RRMs and a TRBP-interacting domain\",\n      \"pmids\": [\"11443112\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct RNA targets not defined\", \"Endogenous coactivator complex composition unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed RBM14 couples transcription to alternative splicing in a promoter-preferential manner, defining how its two domains are differentially deployed.\",\n      \"evidence\": \"Transcription and splicing reporter assays with domain-swap mutants across promoter contexts\",\n      \"pmids\": [\"14673176\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of promoter-context sensing unknown\", \"Endogenous splicing targets not mapped\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Extended the coactivator scaffold to oncogenic SYT/SYT-SSX2 fusions, mapping the YQ hexapeptide-repeat domain as the interaction module.\",\n      \"evidence\": \"Co-IP, GST pulldown, domain mapping, and hormone-receptor reporter assays in human cells\",\n      \"pmids\": [\"16227627\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab interaction data\", \"Functional consequence in synovial sarcoma not tested in vivo\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Connected RBM14 to cancer biology via 11q13 amplification, autoregulation, and transforming activity, establishing oncogenic potential.\",\n      \"evidence\": \"Amplicon mapping, autoregulation reporter assays, and soft-agar transformation assays\",\n      \"pmids\": [\"16878147\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Driver vs passenger status of amplification unresolved\", \"Mechanism of transformation not defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined an alternative-splicing switch (CoAA to dominant-negative CoAM) regulated by p54nrb/PSF that controls RBM14 activity during differentiation.\",\n      \"evidence\": \"Minigene reporters, retinoic acid-induced P19 differentiation, and trans-factor perturbation\",\n      \"pmids\": [\"17337438\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological breadth of the isoform switch unknown\", \"Single-lab assays\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Broadened RBM14's transcription-factor repertoire to Runx factors and intergenic trans-splicing with RBM4, linking it to differentiation control.\",\n      \"evidence\": \"Co-IP, EMSA, reporter assays, and trans-spliced variant identification in neural differentiation models\",\n      \"pmids\": [\"19585539\", \"19416963\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of trans-splicing unclear\", \"Genome-wide Runx co-regulation not assessed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified RBM14 as a PEA3-group cofactor requiring both RRMs, tying its coactivation to cancer cell migration.\",\n      \"evidence\": \"Co-IP, domain-deletion mapping, reporter assays, and migration assays in MCF7 cells\",\n      \"pmids\": [\"21736557\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single readout system\", \"Direct migration targets not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established RBM14 as a regulator of NHEJ and a suppressor of ectopic centriole assembly, linking it to DNA repair and genome stability.\",\n      \"evidence\": \"siRNA knockdown with NHEJ reporters, xenograft irradiation, immunofluorescence, and STIL/CPAP epistasis\",\n      \"pmids\": [\"24811242\", \"25385835\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular role in NHEJ not yet mechanistic\", \"How RBM14 suppresses centriole assembly unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked RBM14 to paraspeckle-dependent RNA export, supporting HIV-1 Rev function via NEAT1 integrity.\",\n      \"evidence\": \"Complexome mining, Rev-dependent reporter, RNA quantification, and NEAT1 depletion epistasis\",\n      \"pmids\": [\"25589658\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RBM14-Rev contact not mapped\", \"Generalizability beyond viral export unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided mechanistic detail for RBM14 in NHEJ, showing it controls XRCC4/XLF recruitment and KU release at damage sites.\",\n      \"evidence\": \"Chromatin fractionation, FRAP/immunofluorescence at damage sites, comet and γH2AX assays\",\n      \"pmids\": [\"28426349\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct interactions with NHEJ factors not biochemically resolved\", \"Single-lab data\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated that RBM14's IDR-driven phase separation is essential for embryonic patterning and that knockout causes DNA damage and altered DDR-gene splicing.\",\n      \"evidence\": \"In vitro droplet assays, zebrafish chimeric-IDR rescue, CRISPR knockout mouse, RNA-seq, IP-MS\",\n      \"pmids\": [\"31636951\", \"31794640\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Composition of physiological condensates incompletely defined\", \"Causal link between splicing changes and lethality not fully established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the recruitment logic and biochemical activity of RBM14 at DSBs: PARP/RNAPII-dependent recruitment and direct binding of RNA:DNA hybrids.\",\n      \"evidence\": \"Laser microirradiation kinetics, PARP/RNAPII inhibitors, S9.6 detection, RNA:DNA substrate pulldown\",\n      \"pmids\": [\"32094185\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How hybrid binding promotes repair completion unresolved\", \"Distinction between NHEJ and HR roles at hybrids not delineated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Implicated RBM14 in spindle-pole organization through α-tubulin interaction and modulation of tubulin acetylation in oocytes.\",\n      \"evidence\": \"Oocyte morpholino knockdown, immunofluorescence co-localization, co-IP with α-tubulin\",\n      \"pmids\": [\"33604343\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of acetylation control unknown\", \"Relationship to nuclear functions unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed RBM14 condensates concentrate maternal mRNAs at spindle poles and recruit PARN to drive deadenylation, controlling zygotic genome activation.\",\n      \"evidence\": \"Live imaging, in vitro phase separation, m6A/m5C functional tests, PARN co-IP, zebrafish/mouse depletion, RNA-seq\",\n      \"pmids\": [\"36477743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA modification readers governing recruitment not identified\", \"Asymmetric partitioning mechanism incompletely defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved RBM14's role in homologous recombination, showing it promotes CtIP-dependent resection and RPA/RAD51 loading by binding resected intermediates.\",\n      \"evidence\": \"RPA-coated ssDNA pulldown, CtIP co-IP, RPA/RAD51 recruitment, HR reporter and irradiation sensitivity\",\n      \"pmids\": [\"37559455\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Choice between NHEJ and HR engagement not explained\", \"Single-lab data\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified Ser521 O-GlcNAcylation as a switch controlling RBM14-TRIM33 interaction, OGA stability, and oncogenicity, placing RBM14 in O-GlcNAc homeostasis.\",\n      \"evidence\": \"MS site mapping, S521A mutagenesis, co-IP, ubiquitination and proteasome assays, oncogenic assays\",\n      \"pmids\": [\"38678556\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"O-GlcNAc transferase responsible not defined here\", \"Link to nuclear/splicing functions unexplored\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Added antiviral and splicing-partner dimensions: RBM14 restricts PEDV via p62-autophagy and MAVS/TRAF3 interferon signaling, and competes with NONO to control DLG1 splicing.\",\n      \"evidence\": \"Co-IP, autophagy flux, IFN reporter, viral replication assays; IP/MS and splicing PSI quantification in cancer cells\",\n      \"pmids\": [\"38411947\", \"38341127\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect MAVS engagement unclear\", \"Generalizability of NONO competition across transcripts untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected RBM14's RRM-mediated mRNA stabilization to cancer metabolism, stabilizing HK2 mRNA to drive glycolysis and H3K18 lactylation-dependent metastasis programs.\",\n      \"evidence\": \"RRM1/2 mutagenesis, RIP, mRNA stability and ECAR assays, H3K18la ChIP-seq, metastasis models\",\n      \"pmids\": [\"42062247\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Breadth of stabilized mRNA targets unknown\", \"Specificity of RRM binding not structurally defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Reported USP44-mediated deubiquitination as a stabilizing mechanism protecting RBM14 against radiation-induced damage.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, knockdown and overexpression rescue with γH2AX and viability readouts\",\n      \"pmids\": [\"41299552\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Deubiquitination inferred from co-IP and rescue, not directly reconstituted\", \"Ubiquitination sites on RBM14 not mapped\", \"Largely in vitro\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RBM14's distinct activities—coactivation, splicing, DSB repair, phase-separated condensate formation, and O-GlcNAc homeostasis—are coordinated or partitioned within a single protein, and what determines context-specific engagement, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural model integrating RRM and IDR functions\", \"Determinants of pathway selection at DSBs (NHEJ vs HR) unknown\", \"Cross-talk between PTM control and condensate behavior unexplored\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 16, 24]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 18, 20]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 13]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [18]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [9, 17, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [11, 16, 20]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 18, 23]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [14, 18]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [13, 22]}\n    ],\n    \"complexes\": [\"paraspeckle\"],\n    \"partners\": [\"TRBP\", \"CREBBP\", \"EP300\", \"CtIP\", \"PARN\", \"TRIM33\", \"NONO\", \"USP44\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}