{"gene":"PHF5A","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2017,"finding":"PHF5A, as a component of the SF3b subcomplex, forms part of the branch point adenosine binding pocket together with SF3B1. Mutations in PHF5A-Y36, SF3B1-K1071, SF3B1-R1074, and SF3B1-V1078 confer resistance to splicing modulators (pladienolide, herboxidiene, spliceostatin), and cryo-EM analysis of the Bact spliceosome complex shows these resistance mutations cluster in a pocket surrounding the branch point adenosine, suggesting competitive inhibition. PHF5A-Y36C has minimal effect on basal splicing but inhibits the global action of splicing modulators.","method":"Resistance mutation mapping, RNA-seq, crystal structure of human PHF5A, cryo-EM spliceosome Bact complex analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure, cryo-EM structural analysis, mutagenesis, and RNA-seq all in one study with rigorous controls","pmids":["28541300"],"is_preprint":false},{"year":2013,"finding":"PHF5A facilitates recognition of exons with unusual C-rich 3' splice sites in thousands of essential genes. In glioblastoma stem cells (GSCs), PHF5A knockdown inhibits splicing of these genes, leading to cell cycle arrest and loss of viability selectively in cancer cells but not in untransformed neural stem cells, astrocytes, or fibroblasts. PHF5A interacts with the U2 snRNP complex and ATP-dependent helicases.","method":"Genome-wide RNAi screen, RNA-seq, siRNA knockdown in patient-derived GSCs, in vivo xenograft tumor formation assay, pharmacologic U2 snRNP inhibition","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genome-wide screen, RNA-seq, KD with defined cellular phenotype, in vivo validation), replicated across multiple cell types","pmids":["23651857"],"is_preprint":false},{"year":2019,"finding":"PHF5A can be acetylated at lysine 29 (K29) in response to multiple cellular stresses (including nutrient starvation and reduced Acetyl-CoA), dependent on the acetyltransferase p300. PHF5A K29 acetylation strengthens interactions among U2 snRNP components and alters global pre-mRNA splicing patterns. Hyperacetylation of PHF5A induces alternative splicing that stabilizes KDM3A mRNA and promotes its protein expression, promoting stress resistance and colorectal carcinogenesis.","method":"Mass spectrometry identification of acetylation sites, p300 knockout/knockdown, Co-IP, RNA-seq, Western blot, functional rescue experiments","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — identified writer (p300), mapped modification site (K29), showed functional consequences on splicing and downstream target (KDM3A) with multiple orthogonal methods","pmids":["31054974"],"is_preprint":false},{"year":2016,"finding":"Phf5a stabilizes the Paf1 transcriptional elongation complex (PAF1C) and controls RNA polymerase II elongation on pluripotency loci in embryonic stem cells (ESCs). Depletion of Phf5a in ESCs causes hallmarks of differentiation. Phf5a also controls differentiation of adult myoblasts.","method":"shRNA-mediated depletion in mouse ESCs, ChIP-seq for RNA Pol II, Co-IP for PAF1C components, transcriptome analysis, myoblast differentiation assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP-seq, KD with defined transcriptional and differentiation phenotype, multiple cell types tested","pmids":["27749823"],"is_preprint":false},{"year":2008,"finding":"PHF5A acts as a bridge protein between ATP-dependent helicases (EP400 and DDX1) and splicing factors with arginine-serine (RS)-rich domains (U2AF1 and SFRS5). The N-terminal part of PHF5A mediates interaction with EP400 and DDX1, while the C-terminal region mediates interaction with U2AF1 and SFRS5. EP400 and DDX1 interact with U2AF1 and SFRS5 only indirectly via PHF5A. PHF5A-GFP localizes predominantly to the nucleus and co-localizes with U2AF1 and SFRS5 in nuclear speckles.","method":"Yeast two-hybrid, yeast three-hybrid, domain deletion mapping, PHF5A-GFP fusion localization in NIH3T3 cells, co-immunoprecipitation in GC-4spc spermatocyte cells","journal":"Cytogenetic and genome research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid and three-hybrid with domain mapping, in vivo Co-IP, direct localization by fluorescence imaging, multiple interaction partners validated","pmids":["18758164"],"is_preprint":false},{"year":2018,"finding":"PHF5A is required for SF3b spliceosome stability and links the SF3b complex to histones. The PHF5A-SF3b complex modulates alternative splicing of apoptotic signaling genes; PHF5A ablation increases expression of a short truncated FASTK protein that facilitates Fas-mediated apoptosis. PHF5A loss suppresses breast cancer cell proliferation, migration, and tumor formation.","method":"In vivo CRISPR screen, siRNA/shRNA knockdown, RT-PCR for alternative splicing events, Western blot for SF3B components, Co-IP for histone interaction, cell proliferation/migration/apoptosis assays, xenograft tumor formation","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR screen, Co-IP for complex stabilization, splice isoform identification with functional consequence, multiple cancer cell lines and in vivo validation","pmids":["29700004"],"is_preprint":false},{"year":2021,"finding":"Phf5a/Sf3b14b regulates the DNA repair step (NHEJ) of class switch recombination (CSR) by stabilizing the p400 histone chaperone complex at immunoglobulin switch regions. This stabilization promotes deposition of H2A variants H2AX and H2A.Z that are critical for the early DNA damage response and NHEJ, respectively. Loss of Phf5a impairs AID-induced recombination but does not perturb DNA breaks or somatic hypermutation.","method":"siRNA-based loss-of-function screen, ChIP assay, histone deposition assays, I-SceI-induced DSB repair assay, CSR assay in B cells","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA screen with mechanistic follow-up, ChIP for chromatin factor recruitment, epistasis with p400 and H2A variants, orthogonal DSB repair assay","pmids":["33938017"],"is_preprint":false},{"year":2021,"finding":"SIRT7 decrotonylates PHF5A at lysine 25 (K25). Decrotonylation of PHF5A K25 decreases CDK2 expression through retained-intron-induced abnormal alternative splicing, thereby accelerating fibroblast senescence. SIRT7 expression is increased in senescent fibroblasts and aged tissues.","method":"Mass spectrometry crotonylome profiling, SIRT7 knockdown/overexpression, Western blot for PHF5A modifications, RT-PCR for CDK2 splicing isoforms, senescence assays","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS identification of modification site, SIRT7 as eraser identified, functional splicing consequence shown, but single lab with limited orthogonal validation of the SIRT7-PHF5A direct enzymatic relationship","pmids":["34604215"],"is_preprint":false},{"year":2020,"finding":"In pancreatic cancer stem cells, PAF1 interacts with PHF5A and DDX3 to form a sub-complex that binds the promoter region of NANOG and regulates stemness genes. The PAF1-PHF5A interaction is independent of the canonical PAF1 complex function. Levels of PAF1-PHF5A co-localization are increased in human pancreatic tumor specimens.","method":"Co-immunoprecipitation, mass spectrometry, ChIP-seq, RNA-seq, CRISPR/Cas9 PAF1 depletion, tumor sphere formation assays, orthotopic xenograft model","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with MS confirmation, ChIP-seq for promoter binding, functional depletion experiments, single lab","pmids":["32781084"],"is_preprint":false},{"year":2003,"finding":"Ini (the rat/mouse ortholog of PHF5A) localizes to the nucleus of HeLa cells and binds to the proximal connexin43 (Cx43) promoter as shown by electrophoretic mobility shift assay (EMSA). Overexpression of Ini enhances estrogen-induced up-regulation of the cx43 gene in a dose-dependent manner by stimulating the AF-1 (but not AF-2) transcriptional activating function of estrogen receptor alpha (ERα).","method":"EMSA, transient transfection with ERα cDNA, reporter assays, antisense construct experiments, subcellular localization in HeLa cells","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA for direct DNA binding, reporter assays for transcriptional function, AF-1 vs AF-2 dissection, single lab with multiple orthogonal methods","pmids":["12810571"],"is_preprint":false},{"year":2023,"finding":"KMT2A (histone methyltransferase) physically associates with a PHF5A-PHF14-HMG20A-RAI1 protein subcomplex in pancreatic cancer stem cells and epigenetically regulates their self-renewal capacity, cell viability, and in vivo tumorigenicity. Targeting the complex with a KMT2A-WDR5 inhibitor attenuates these cancer stem cell properties.","method":"Co-immunoprecipitation, mass spectrometry, KMT2A-WDR5 inhibitor treatment, tumor sphere formation assays, in vivo tumorigenicity assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with MS identification of complex members, functional inhibitor experiments, in vivo validation, single lab","pmids":["37709746"],"is_preprint":false},{"year":2023,"finding":"PHF5A phosphorylation at Y36 by the TrkA-ERK1/2-ABL1 kinase cascade promotes the interaction between CEP250 and Nek2A in a spliceosome-independent manner at centrosomes, leading to premature centrosome separation. PHF5A is enriched at centrosomes. pY36-PHF5A promotes microtubule remodeling and regulates cell proliferation and migration. This cascade is hyperactivated in medulloblastoma.","method":"Phosphorylation site mapping, centrosome fractionation/localization, Co-IP for CEP250-Nek2A interaction, kinase inhibitor experiments, cell proliferation/migration assays, medulloblastoma cell senescence assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — identified kinase cascade (writers: TrkA-ERK1/2-ABL1), mapped phosphorylation site (Y36), showed spliceosome-independent function at centrosome, Co-IP for downstream interaction, single lab","pmids":["36759599"],"is_preprint":false},{"year":2023,"finding":"PHF5A regulates alternative splicing of DOCK5 to generate a specific oncogenic DOCK5 variant in head and neck squamous cell carcinoma. PHF5A knockdown or overexpression correspondingly alters the level of the DOCK5 variant. PHF5A activates the p38 MAPK pathway, and p38 MAPK inhibition reverses the oncogenic effects of PHF5A on proliferation, migration, and invasion.","method":"qRT-PCR for DOCK5 splice variant, siRNA/overexpression experiments, Western blot for p38 MAPK pathway components, in vitro functional assays, in vivo xenograft model","journal":"Biology direct","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — causal relationship between PHF5A and splice variant confirmed by gain- and loss-of-function, pathway inhibitor rescue experiment, in vivo validation, single lab","pmids":["37434235"],"is_preprint":false},{"year":2023,"finding":"In glioblastoma, loss-of-function PHF5A variants cause altered SF3B complex function: transcriptome sequencing in subject-derived fibroblasts with PHF5A LOF variants revealed alternative promoter use and downregulation of genes involved in cell-cycle regulation. Feedback mechanisms in fibroblasts maintain normal levels of SF3B components (SF3B1-3, SF3B6), and SF3B complex formation was unaffected in 2 subject cell lines, suggesting cell-type-specific pathomechanism rather than simple haploinsufficiency.","method":"Subject-derived fibroblast studies, transcriptome sequencing (RNA-seq), Western blot for SF3B complex components, functional SF3B complex formation assay","journal":"Genetics in medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptome sequencing with patient-derived cells, direct protein level measurements, complex formation assay, but limited to fibroblasts and single study","pmids":["37422718"],"is_preprint":false},{"year":2023,"finding":"In gastric cancer cells, PHF5A knockdown leads to decreased protein stability of FOS through SKP2 (E3 ubiquitin ligase)-mediated ubiquitination. PHF5A silencing promotes VEGFA ubiquitination by interacting with MDM2, thereby reducing VEGFA protein expression. ESCC cell viability and migration promoted by PHF5A are dependent on intact VEGFA and PI3K/AKT signaling.","method":"Co-immunoprecipitation for PHF5A-MDM2 interaction, ubiquitination assays, Western blot, siRNA knockdown, rescue experiments with VEGFA overexpression, in vivo xenograft","journal":"Journal of translational medicine / Biology direct","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP for protein interactions and ubiquitination assays shown but mechanistic link between PHF5A splicing function and protein stability is indirect; two separate papers with partially overlapping claims from single labs","pmids":["36609277","38429756"],"is_preprint":false},{"year":2024,"finding":"PHF5A knockdown in melanoma cells causes massive splicing defects in tumor-relevant genes and increases apoptosis via Fas- and unfolded protein response (UPR)-mediated apoptosis pathways, selectively in melanoma cells but not in fibroblasts.","method":"siRNA knockdown, RNA-seq for splicing changes, apoptosis assays, pathway inhibitor experiments","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq for splicing changes, defined apoptotic pathway (Fas- and UPR-mediated), cell-type specificity demonstrated, single lab","pmids":["39212334"],"is_preprint":false},{"year":2002,"finding":"The C. elegans ortholog of PHF5A (phf-5) is essential for morphogenetic development. phf-5 RNAi causes lethal phenotype in embryonic morphogenetic phase and in young larvae but not in adults. Expression is muscle-specific (pharynx, body wall muscles, anal muscles) during late development.","method":"Transgenic phf-5::yfp reporter, RNAi knockdown phenotype analysis in C. elegans","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNAi loss-of-function with specific developmental phenotype and direct localization by reporter imaging, ortholog study in model organism","pmids":["12359262"],"is_preprint":false},{"year":2025,"finding":"Neural crest (NC)-specific DLC1 partners with the SF3B1-PHF5A splicing complex to determine avian trunk NC cell fate by regulating splicing of NC specifiers SOX9 and SNAI2 pre-mRNAs. Mechanistically, SF3B1-PHF5A binds intronic branch site (BS) sequences of multiple factors, while DLC1 interacts with a specific motif near the BS sequences of SOX9 and SNAI2, conferring functional specificity. DLC1 increases NC cell vulnerability to splicing modulator pladienolide B by reducing SF3B1-PHF5A binding capacity to shorter introns with weaker polypyrimidine tracts.","method":"Avian NC cell functional assays, RNA splicing analysis (RT-PCR, RNA-seq), protein interaction studies, pladienolide B treatment with splicing readout","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional splicing assays in vivo, direct BS sequence binding demonstrated, pharmacological validation with splicing modulator, single lab","pmids":["40691464"],"is_preprint":false},{"year":2025,"finding":"Spliceostatin family compounds covalently bind PHF5A at Cys26 of its ZnCys4 zinc finger, while preserving Zn2+ coordination. QM/MM simulations identify that distortion of the ZnCys4 coordination sphere weakens the Zn-Cys26 bond, enabling water-Cys26 exchange and generating a reactive nucleophilic thiolate. Covalent bond formation is accelerated by an Asp34-Lys29 proton relay that activates the epoxide leaving group of spliceostatins.","method":"Classical and QM/MM molecular dynamics simulations, free-energy calculations","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational prediction only (QM/MM MD simulations), no experimental biochemical validation in this study; preprint","pmids":["bio_10.1101_2025.09.17.676740"],"is_preprint":true},{"year":2020,"finding":"CHD4 interacts with PHF5A in non-small cell lung cancer cells, and knockdown of CHD4 decreases PHF5A protein levels and reduces activation of the RhoA/ROCK signaling pathway. This CHD4-PHF5A interaction is proposed to mediate promotion of NSCLC cell proliferation and migration.","method":"Western blot for protein levels, co-expression analysis, siRNA/overexpression functional assays, xenograft tumor model","journal":"BMC cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — protein level changes shown by Western blot but direct Co-IP of CHD4-PHF5A interaction not clearly demonstrated in the abstract; single lab, indirect mechanistic evidence","pmids":["32228507"],"is_preprint":false},{"year":2022,"finding":"PHF5A is involved in maintaining cancer stem-like phenotype in non-small cell lung cancer (NSCLC); PHF5A knockdown in cancer stem-like cells (CSLCs) results in diminished stemness phenotypes and reduced HDAC8 expression. Inhibition of HDAC activity also affects stemness maintenance, suggesting PHF5A acts upstream of HDAC8 in this context.","method":"siRNA knockdown, Western blot, qRT-PCR, oncosphere-forming assay, HDAC inhibitor treatment","journal":"Annals of clinical and laboratory science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — KD with defined phenotype but no direct interaction evidence between PHF5A and HDAC8; single lab, single institution","pmids":["35777798"],"is_preprint":false},{"year":2019,"finding":"PHF5A knockdown inhibits migration and invasion of hepatocellular carcinoma (HCC) cells and downregulates NF-κB signaling activity. Blocking NF-κB signaling weakens the stimulatory effect of PHF5A on cell migration and invasion.","method":"Wound healing assay, Transwell invasion assay, luciferase reporter assay for NF-κB, Western blot, qPCR, siRNA knockdown","journal":"BioMed research international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional KD with pathway reporter assay, but no direct molecular interaction between PHF5A and NF-κB components demonstrated; single lab","pmids":["30766880"],"is_preprint":false}],"current_model":"PHF5A is a highly conserved zinc-finger PHD-domain protein and essential component of the SF3b spliceosomal subcomplex that recognizes the branch point adenosine during pre-mRNA splicing; it is post-translationally regulated by acetylation (at K29, by p300), decrotonylation (at K25, by SIRT7), and phosphorylation (at Y36, by the TrkA-ERK1/2-ABL1 cascade), which modulate its splicing activity, its interactions within U2 snRNP, and a spliceosome-independent role in centrosome separation; PHF5A additionally stabilizes the PAF1 transcriptional elongation complex and controls RNA Pol II elongation at pluripotency loci, and regulates NHEJ-mediated DNA repair by stabilizing the p400 histone chaperone complex to promote H2AX and H2A.Z deposition at DNA damage sites."},"narrative":{"mechanistic_narrative":"PHF5A is a highly conserved zinc-finger PHD-domain protein that functions as an essential component of the SF3b spliceosomal subcomplex, where together with SF3B1 it helps form the binding pocket that recognizes the intronic branch point adenosine during pre-mRNA splicing [PMID:28541300]. Structural and resistance-mutation mapping place PHF5A-Y36 and adjacent SF3B1 residues at this pocket, the site at which splicing modulators (pladienolide, herboxidiene, spliceostatin) act, with modulator-resistance mutations clustering there [PMID:28541300]; spliceostatin compounds engage the protein covalently at Cys26 of its ZnCys4 zinc finger [PMID:bio_10.1101_2025.09.17.676740]. Through this splicing activity PHF5A enables recognition of exons bearing unusual C-rich 3' splice sites in thousands of essential genes, a dependency that renders cancer cells selectively vulnerable to its loss while sparing untransformed cells [PMID:23651857, PMID:39212334]. PHF5A stabilizes the SF3b complex and links it to histones, and controls alternative splicing of apoptotic and cell-cycle regulators including FASTK and the senescence-linked CDK2 transcript [PMID:29700004, PMID:34604215]. Its splicing output is tuned by post-translational modifications: p300-dependent K29 acetylation strengthens U2 snRNP interactions and reshapes splicing under stress to stabilize KDM3A and drive carcinogenesis [PMID:31054974], while SIRT7-mediated K25 decrotonylation alters CDK2 splicing to accelerate fibroblast senescence [PMID:34604215]. Beyond splicing, PHF5A acts as a bridging adaptor between ATP-dependent helicases (EP400, DDX1) and RS-domain splicing factors (U2AF1, SFRS5) [PMID:18758164], stabilizes the PAF1 transcriptional elongation complex to control RNA Pol II elongation at pluripotency loci [PMID:27749823], and supports NHEJ-mediated DNA repair by stabilizing the p400 histone chaperone complex to deposit H2AX and H2A.Z at switch regions during class switch recombination [PMID:33938017]. A spliceosome-independent role at centrosomes is activated by Y36 phosphorylation via the TrkA-ERK1/2-ABL1 cascade, which promotes CEP250-Nek2A interaction and premature centrosome separation [PMID:36759599]. Loss-of-function PHF5A variants produce a cell-type-specific transcriptional phenotype consistent with altered SF3B function rather than simple haploinsufficiency [PMID:37422718].","teleology":[{"year":2002,"claim":"Establishing that the PHF5A ortholog is developmentally essential framed it as a core cellular factor rather than an accessory protein.","evidence":"Transgenic reporter and RNAi loss-of-function in C. elegans","pmids":["12359262"],"confidence":"Medium","gaps":["Molecular function not defined in this study","Muscle-specific expression pattern not mechanistically linked to a pathway"]},{"year":2003,"claim":"Early work asked whether the protein had a nuclear/transcriptional role, finding it could bind a promoter and modulate ERα transcriptional activity.","evidence":"EMSA, reporter assays, and ERα co-transfection in HeLa cells (ortholog Ini)","pmids":["12810571"],"confidence":"Medium","gaps":["Direct DNA-binding role superseded by later splicing-centric models","No structural basis for promoter binding"]},{"year":2008,"claim":"To define how PHF5A connects machineries, it was shown to bridge ATP-dependent helicases to RS-domain splicing factors, establishing an adaptor architecture.","evidence":"Yeast two/three-hybrid, domain-deletion mapping, Co-IP, and GFP localization to nuclear speckles","pmids":["18758164"],"confidence":"High","gaps":["Indirect interactions not resolved structurally","Stoichiometry within the complex unknown"]},{"year":2013,"claim":"A genome-wide screen answered what splicing substrates depend on PHF5A, revealing recognition of C-rich 3' splice sites in essential genes and a cancer-selective vulnerability.","evidence":"Genome-wide RNAi screen, RNA-seq, siRNA in patient-derived GSCs, xenograft validation","pmids":["23651857"],"confidence":"High","gaps":["Basis for cancer-cell selectivity not fully resolved","Mechanism of C-rich splice-site recognition not structurally defined"]},{"year":2016,"claim":"Work in ESCs extended PHF5A beyond splicing, showing it stabilizes the PAF1 elongation complex to control Pol II elongation at pluripotency loci.","evidence":"shRNA depletion, RNA Pol II ChIP-seq, reciprocal Co-IP, differentiation assays in ESCs and myoblasts","pmids":["27749823"],"confidence":"High","gaps":["How splicing and elongation roles are coordinated unknown","Direct vs indirect PAF1C stabilization not dissected"]},{"year":2017,"claim":"Structural studies resolved where PHF5A sits in the spliceosome, placing it in the branch-point adenosine pocket and explaining splicing-modulator resistance mutations.","evidence":"Human PHF5A crystal structure, cryo-EM Bact spliceosome analysis, resistance-mutation mapping, RNA-seq","pmids":["28541300"],"confidence":"High","gaps":["Catalytic contribution of PHF5A vs SF3B1 to branch-point recognition not separated","Effect of Y36C on basal splicing minimal but mechanism unexplained"]},{"year":2018,"claim":"PHF5A was shown to be required for SF3b stability and to link the complex to histones, coupling splicing of apoptotic genes to tumor phenotypes.","evidence":"In vivo CRISPR screen, Co-IP for histone interaction, RT-PCR splice isoform analysis, xenografts","pmids":["29700004"],"confidence":"High","gaps":["Nature of the PHF5A-histone link not structurally defined","Breadth of apoptotic splicing targets beyond FASTK unknown"]},{"year":2019,"claim":"Identification of p300-dependent K29 acetylation answered how splicing output is dynamically tuned by metabolic and stress signals.","evidence":"MS site mapping, p300 KO/KD, Co-IP, RNA-seq, rescue experiments","pmids":["31054974"],"confidence":"High","gaps":["Deacetylase for K29 not identified","Genome-wide scope of acetylation-driven splicing changes incompletely mapped"]},{"year":2020,"claim":"PHF5A was placed in a non-canonical PAF1-DDX3 sub-complex that binds the NANOG promoter, linking it to cancer stemness independent of canonical PAF1C function.","evidence":"Reciprocal Co-IP with MS, ChIP-seq, RNA-seq, CRISPR depletion, orthotopic xenografts in pancreatic cancer stem cells","pmids":["32781084"],"confidence":"Medium","gaps":["Single lab; direct vs scaffold role at NANOG promoter not separated","Relationship to canonical splicing function unclear"]},{"year":2021,"claim":"Two studies expanded PHF5A regulation and function: SIRT7-mediated K25 decrotonylation tuning CDK2 splicing in senescence, and p400 stabilization driving H2A-variant deposition in NHEJ during class switch recombination.","evidence":"Crotonylome MS and SIRT7 manipulation with senescence assays; siRNA screen, ChIP, histone deposition and DSB-repair assays in B cells","pmids":["34604215","33938017"],"confidence":"Medium","gaps":["Direct SIRT7-PHF5A enzymatic relationship validated in a single lab","How a splicing factor stabilizes a chromatin chaperone complex mechanistically unresolved"]},{"year":2023,"claim":"Multiple studies defined a spliceosome-independent centrosomal role (Y36 phosphorylation promoting CEP250-Nek2A and centrosome separation), additional complex partnerships (KMT2A/PHF14/HMG20A/RAI1), and a cell-type-specific LOF pathomechanism in disease.","evidence":"Phospho-site mapping and centrosome fractionation; Co-IP/MS for the KMT2A subcomplex; transcriptome sequencing and complex-formation assays in subject-derived fibroblasts","pmids":["36759599","37709746","37422718","37434235"],"confidence":"Medium","gaps":["Centrosomal mechanism single-lab; structural basis of pY36 action unknown","Disease pathomechanism studied only in fibroblasts"]},{"year":2025,"claim":"Tissue-specific specificity factors (DLC1) were shown to direct SF3B1-PHF5A branch-site binding to particular pre-mRNAs, and simulations proposed the chemical basis of covalent spliceostatin engagement at Cys26.","evidence":"Avian NC splicing assays with pladienolide B; QM/MM MD simulations (preprint)","pmids":["40691464","bio_10.1101_2025.09.17.676740"],"confidence":"Medium","gaps":["Cys26 covalent mechanism is computational only, no biochemical validation","Generality of context-specific cofactor recruitment beyond SOX9/SNAI2 unknown"]},{"year":null,"claim":"How PHF5A's distinct activities — branch-point splicing, transcriptional elongation, DNA-repair chromatin deposition, and centrosomal regulation — are partitioned and coordinated within a cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model integrating splicing vs non-splicing roles","PTM crosstalk (K25, K29, Y36) not jointly studied","No high-resolution structure of PHF5A in its non-spliceosomal complexes"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,17]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,5,6]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,9]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[4]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,2,5]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,8]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[6]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[11]}],"complexes":["SF3b spliceosomal subcomplex","U2 snRNP","PAF1 complex","p400 histone chaperone complex"],"partners":["SF3B1","U2AF1","SFRS5","EP400","DDX1","PAF1","DDX3","KMT2A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7RTV0","full_name":"PHD finger-like domain-containing protein 5A","aliases":["Splicing factor 3B-associated 14 kDa protein","SF3b14b"],"length_aa":110,"mass_kda":12.4,"function":"Component of the 17S U2 SnRNP complex of the spliceosome, a large ribonucleoprotein complex that removes introns from transcribed pre-mRNAs (PubMed:12234937, PubMed:27720643, PubMed:28541300, PubMed:32494006, PubMed:34822310). The 17S U2 SnRNP complex (1) directly participates in early spliceosome assembly and (2) mediates recognition of the intron branch site during pre-mRNA splicing by promoting the selection of the pre-mRNA branch-site adenosine, the nucleophile for the first step of splicing (PubMed:12234937, PubMed:32494006, PubMed:34822310). Within the 17S U2 SnRNP complex, PHF5A is part of the SF3B subcomplex, which is required for 'A' complex assembly formed by the stable binding of U2 snRNP to the branchpoint sequence in pre-mRNA (PubMed:12234937, PubMed:27720643). Sequence independent binding of SF3A and SF3B subcomplexes upstream of the branch site is essential, it may anchor U2 snRNP to the pre-mRNA (PubMed:12234937). Also acts as a component of the minor spliceosome, which is involved in the splicing of U12-type introns in pre-mRNAs (PubMed:15146077, PubMed:33509932). Also involved in elongation by RNA polymerase II as part of the PAF1 complex (PAF1C) (By similarity). PAF1C is required for maintenance of embryonic stem cell (ESC) self-renewal and cellular reprogramming of stem cells (By similarity). Maintains pluripotency by recruiting and stabilizing PAF1C on pluripotency genes loci, and by regulating the expression of the pluripotency genes (By similarity). Regulates the deposition of elongation-associated histone modifications, including dimethylated histone H3 'Lys-79' (H3K79me2) and trimethylated histone H3 'Lys-36' (H3K36me3), on PAF1C targets, self-renewal and pluripotency genes (By similarity). Regulates RNA polymerase II promoter-proximal pause release of the PAF1C targets and self-renewal genes, and the levels of elongating ('Ser-2' phosphorylated) RNA polymerase II in their gene bodies (By similarity). Regulates muscle specification in adult stem cells by stabilizing PAF1C in chromatin to promote myogenic differentiation (By similarity). Acts as a transcriptional regulator by binding to the GJA1/Cx43 promoter and enhancing its up-regulation by ESR1/ER-alpha (By similarity)","subcellular_location":"Nucleus; Nucleus speckle","url":"https://www.uniprot.org/uniprotkb/Q7RTV0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PHF5A","classification":"Common Essential","n_dependent_lines":1208,"n_total_lines":1208,"dependency_fraction":1.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SF3B1","stoichiometry":4.0},{"gene":"COMMD6","stoichiometry":0.2},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"RBM39","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PHF5A","total_profiled":1310},"omim":[{"mim_id":"617846","title":"PHD FINGER PROTEIN 5A; 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Mutations in PHF5A-Y36, SF3B1-K1071, SF3B1-R1074, and SF3B1-V1078 confer resistance to splicing modulators (pladienolide, herboxidiene, spliceostatin), and cryo-EM analysis of the Bact spliceosome complex shows these resistance mutations cluster in a pocket surrounding the branch point adenosine, suggesting competitive inhibition. PHF5A-Y36C has minimal effect on basal splicing but inhibits the global action of splicing modulators.\",\n      \"method\": \"Resistance mutation mapping, RNA-seq, crystal structure of human PHF5A, cryo-EM spliceosome Bact complex analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure, cryo-EM structural analysis, mutagenesis, and RNA-seq all in one study with rigorous controls\",\n      \"pmids\": [\"28541300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PHF5A facilitates recognition of exons with unusual C-rich 3' splice sites in thousands of essential genes. In glioblastoma stem cells (GSCs), PHF5A knockdown inhibits splicing of these genes, leading to cell cycle arrest and loss of viability selectively in cancer cells but not in untransformed neural stem cells, astrocytes, or fibroblasts. PHF5A interacts with the U2 snRNP complex and ATP-dependent helicases.\",\n      \"method\": \"Genome-wide RNAi screen, RNA-seq, siRNA knockdown in patient-derived GSCs, in vivo xenograft tumor formation assay, pharmacologic U2 snRNP inhibition\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genome-wide screen, RNA-seq, KD with defined cellular phenotype, in vivo validation), replicated across multiple cell types\",\n      \"pmids\": [\"23651857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PHF5A can be acetylated at lysine 29 (K29) in response to multiple cellular stresses (including nutrient starvation and reduced Acetyl-CoA), dependent on the acetyltransferase p300. PHF5A K29 acetylation strengthens interactions among U2 snRNP components and alters global pre-mRNA splicing patterns. Hyperacetylation of PHF5A induces alternative splicing that stabilizes KDM3A mRNA and promotes its protein expression, promoting stress resistance and colorectal carcinogenesis.\",\n      \"method\": \"Mass spectrometry identification of acetylation sites, p300 knockout/knockdown, Co-IP, RNA-seq, Western blot, functional rescue experiments\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — identified writer (p300), mapped modification site (K29), showed functional consequences on splicing and downstream target (KDM3A) with multiple orthogonal methods\",\n      \"pmids\": [\"31054974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Phf5a stabilizes the Paf1 transcriptional elongation complex (PAF1C) and controls RNA polymerase II elongation on pluripotency loci in embryonic stem cells (ESCs). Depletion of Phf5a in ESCs causes hallmarks of differentiation. Phf5a also controls differentiation of adult myoblasts.\",\n      \"method\": \"shRNA-mediated depletion in mouse ESCs, ChIP-seq for RNA Pol II, Co-IP for PAF1C components, transcriptome analysis, myoblast differentiation assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP-seq, KD with defined transcriptional and differentiation phenotype, multiple cell types tested\",\n      \"pmids\": [\"27749823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PHF5A acts as a bridge protein between ATP-dependent helicases (EP400 and DDX1) and splicing factors with arginine-serine (RS)-rich domains (U2AF1 and SFRS5). The N-terminal part of PHF5A mediates interaction with EP400 and DDX1, while the C-terminal region mediates interaction with U2AF1 and SFRS5. EP400 and DDX1 interact with U2AF1 and SFRS5 only indirectly via PHF5A. PHF5A-GFP localizes predominantly to the nucleus and co-localizes with U2AF1 and SFRS5 in nuclear speckles.\",\n      \"method\": \"Yeast two-hybrid, yeast three-hybrid, domain deletion mapping, PHF5A-GFP fusion localization in NIH3T3 cells, co-immunoprecipitation in GC-4spc spermatocyte cells\",\n      \"journal\": \"Cytogenetic and genome research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid and three-hybrid with domain mapping, in vivo Co-IP, direct localization by fluorescence imaging, multiple interaction partners validated\",\n      \"pmids\": [\"18758164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PHF5A is required for SF3b spliceosome stability and links the SF3b complex to histones. The PHF5A-SF3b complex modulates alternative splicing of apoptotic signaling genes; PHF5A ablation increases expression of a short truncated FASTK protein that facilitates Fas-mediated apoptosis. PHF5A loss suppresses breast cancer cell proliferation, migration, and tumor formation.\",\n      \"method\": \"In vivo CRISPR screen, siRNA/shRNA knockdown, RT-PCR for alternative splicing events, Western blot for SF3B components, Co-IP for histone interaction, cell proliferation/migration/apoptosis assays, xenograft tumor formation\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR screen, Co-IP for complex stabilization, splice isoform identification with functional consequence, multiple cancer cell lines and in vivo validation\",\n      \"pmids\": [\"29700004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Phf5a/Sf3b14b regulates the DNA repair step (NHEJ) of class switch recombination (CSR) by stabilizing the p400 histone chaperone complex at immunoglobulin switch regions. This stabilization promotes deposition of H2A variants H2AX and H2A.Z that are critical for the early DNA damage response and NHEJ, respectively. Loss of Phf5a impairs AID-induced recombination but does not perturb DNA breaks or somatic hypermutation.\",\n      \"method\": \"siRNA-based loss-of-function screen, ChIP assay, histone deposition assays, I-SceI-induced DSB repair assay, CSR assay in B cells\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA screen with mechanistic follow-up, ChIP for chromatin factor recruitment, epistasis with p400 and H2A variants, orthogonal DSB repair assay\",\n      \"pmids\": [\"33938017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SIRT7 decrotonylates PHF5A at lysine 25 (K25). Decrotonylation of PHF5A K25 decreases CDK2 expression through retained-intron-induced abnormal alternative splicing, thereby accelerating fibroblast senescence. SIRT7 expression is increased in senescent fibroblasts and aged tissues.\",\n      \"method\": \"Mass spectrometry crotonylome profiling, SIRT7 knockdown/overexpression, Western blot for PHF5A modifications, RT-PCR for CDK2 splicing isoforms, senescence assays\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification of modification site, SIRT7 as eraser identified, functional splicing consequence shown, but single lab with limited orthogonal validation of the SIRT7-PHF5A direct enzymatic relationship\",\n      \"pmids\": [\"34604215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In pancreatic cancer stem cells, PAF1 interacts with PHF5A and DDX3 to form a sub-complex that binds the promoter region of NANOG and regulates stemness genes. The PAF1-PHF5A interaction is independent of the canonical PAF1 complex function. Levels of PAF1-PHF5A co-localization are increased in human pancreatic tumor specimens.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, ChIP-seq, RNA-seq, CRISPR/Cas9 PAF1 depletion, tumor sphere formation assays, orthotopic xenograft model\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with MS confirmation, ChIP-seq for promoter binding, functional depletion experiments, single lab\",\n      \"pmids\": [\"32781084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Ini (the rat/mouse ortholog of PHF5A) localizes to the nucleus of HeLa cells and binds to the proximal connexin43 (Cx43) promoter as shown by electrophoretic mobility shift assay (EMSA). Overexpression of Ini enhances estrogen-induced up-regulation of the cx43 gene in a dose-dependent manner by stimulating the AF-1 (but not AF-2) transcriptional activating function of estrogen receptor alpha (ERα).\",\n      \"method\": \"EMSA, transient transfection with ERα cDNA, reporter assays, antisense construct experiments, subcellular localization in HeLa cells\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA for direct DNA binding, reporter assays for transcriptional function, AF-1 vs AF-2 dissection, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"12810571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KMT2A (histone methyltransferase) physically associates with a PHF5A-PHF14-HMG20A-RAI1 protein subcomplex in pancreatic cancer stem cells and epigenetically regulates their self-renewal capacity, cell viability, and in vivo tumorigenicity. Targeting the complex with a KMT2A-WDR5 inhibitor attenuates these cancer stem cell properties.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, KMT2A-WDR5 inhibitor treatment, tumor sphere formation assays, in vivo tumorigenicity assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with MS identification of complex members, functional inhibitor experiments, in vivo validation, single lab\",\n      \"pmids\": [\"37709746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PHF5A phosphorylation at Y36 by the TrkA-ERK1/2-ABL1 kinase cascade promotes the interaction between CEP250 and Nek2A in a spliceosome-independent manner at centrosomes, leading to premature centrosome separation. PHF5A is enriched at centrosomes. pY36-PHF5A promotes microtubule remodeling and regulates cell proliferation and migration. This cascade is hyperactivated in medulloblastoma.\",\n      \"method\": \"Phosphorylation site mapping, centrosome fractionation/localization, Co-IP for CEP250-Nek2A interaction, kinase inhibitor experiments, cell proliferation/migration assays, medulloblastoma cell senescence assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — identified kinase cascade (writers: TrkA-ERK1/2-ABL1), mapped phosphorylation site (Y36), showed spliceosome-independent function at centrosome, Co-IP for downstream interaction, single lab\",\n      \"pmids\": [\"36759599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PHF5A regulates alternative splicing of DOCK5 to generate a specific oncogenic DOCK5 variant in head and neck squamous cell carcinoma. PHF5A knockdown or overexpression correspondingly alters the level of the DOCK5 variant. PHF5A activates the p38 MAPK pathway, and p38 MAPK inhibition reverses the oncogenic effects of PHF5A on proliferation, migration, and invasion.\",\n      \"method\": \"qRT-PCR for DOCK5 splice variant, siRNA/overexpression experiments, Western blot for p38 MAPK pathway components, in vitro functional assays, in vivo xenograft model\",\n      \"journal\": \"Biology direct\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — causal relationship between PHF5A and splice variant confirmed by gain- and loss-of-function, pathway inhibitor rescue experiment, in vivo validation, single lab\",\n      \"pmids\": [\"37434235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In glioblastoma, loss-of-function PHF5A variants cause altered SF3B complex function: transcriptome sequencing in subject-derived fibroblasts with PHF5A LOF variants revealed alternative promoter use and downregulation of genes involved in cell-cycle regulation. Feedback mechanisms in fibroblasts maintain normal levels of SF3B components (SF3B1-3, SF3B6), and SF3B complex formation was unaffected in 2 subject cell lines, suggesting cell-type-specific pathomechanism rather than simple haploinsufficiency.\",\n      \"method\": \"Subject-derived fibroblast studies, transcriptome sequencing (RNA-seq), Western blot for SF3B complex components, functional SF3B complex formation assay\",\n      \"journal\": \"Genetics in medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptome sequencing with patient-derived cells, direct protein level measurements, complex formation assay, but limited to fibroblasts and single study\",\n      \"pmids\": [\"37422718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In gastric cancer cells, PHF5A knockdown leads to decreased protein stability of FOS through SKP2 (E3 ubiquitin ligase)-mediated ubiquitination. PHF5A silencing promotes VEGFA ubiquitination by interacting with MDM2, thereby reducing VEGFA protein expression. ESCC cell viability and migration promoted by PHF5A are dependent on intact VEGFA and PI3K/AKT signaling.\",\n      \"method\": \"Co-immunoprecipitation for PHF5A-MDM2 interaction, ubiquitination assays, Western blot, siRNA knockdown, rescue experiments with VEGFA overexpression, in vivo xenograft\",\n      \"journal\": \"Journal of translational medicine / Biology direct\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP for protein interactions and ubiquitination assays shown but mechanistic link between PHF5A splicing function and protein stability is indirect; two separate papers with partially overlapping claims from single labs\",\n      \"pmids\": [\"36609277\", \"38429756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PHF5A knockdown in melanoma cells causes massive splicing defects in tumor-relevant genes and increases apoptosis via Fas- and unfolded protein response (UPR)-mediated apoptosis pathways, selectively in melanoma cells but not in fibroblasts.\",\n      \"method\": \"siRNA knockdown, RNA-seq for splicing changes, apoptosis assays, pathway inhibitor experiments\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq for splicing changes, defined apoptotic pathway (Fas- and UPR-mediated), cell-type specificity demonstrated, single lab\",\n      \"pmids\": [\"39212334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The C. elegans ortholog of PHF5A (phf-5) is essential for morphogenetic development. phf-5 RNAi causes lethal phenotype in embryonic morphogenetic phase and in young larvae but not in adults. Expression is muscle-specific (pharynx, body wall muscles, anal muscles) during late development.\",\n      \"method\": \"Transgenic phf-5::yfp reporter, RNAi knockdown phenotype analysis in C. elegans\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNAi loss-of-function with specific developmental phenotype and direct localization by reporter imaging, ortholog study in model organism\",\n      \"pmids\": [\"12359262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Neural crest (NC)-specific DLC1 partners with the SF3B1-PHF5A splicing complex to determine avian trunk NC cell fate by regulating splicing of NC specifiers SOX9 and SNAI2 pre-mRNAs. Mechanistically, SF3B1-PHF5A binds intronic branch site (BS) sequences of multiple factors, while DLC1 interacts with a specific motif near the BS sequences of SOX9 and SNAI2, conferring functional specificity. DLC1 increases NC cell vulnerability to splicing modulator pladienolide B by reducing SF3B1-PHF5A binding capacity to shorter introns with weaker polypyrimidine tracts.\",\n      \"method\": \"Avian NC cell functional assays, RNA splicing analysis (RT-PCR, RNA-seq), protein interaction studies, pladienolide B treatment with splicing readout\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional splicing assays in vivo, direct BS sequence binding demonstrated, pharmacological validation with splicing modulator, single lab\",\n      \"pmids\": [\"40691464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Spliceostatin family compounds covalently bind PHF5A at Cys26 of its ZnCys4 zinc finger, while preserving Zn2+ coordination. QM/MM simulations identify that distortion of the ZnCys4 coordination sphere weakens the Zn-Cys26 bond, enabling water-Cys26 exchange and generating a reactive nucleophilic thiolate. Covalent bond formation is accelerated by an Asp34-Lys29 proton relay that activates the epoxide leaving group of spliceostatins.\",\n      \"method\": \"Classical and QM/MM molecular dynamics simulations, free-energy calculations\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational prediction only (QM/MM MD simulations), no experimental biochemical validation in this study; preprint\",\n      \"pmids\": [\"bio_10.1101_2025.09.17.676740\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CHD4 interacts with PHF5A in non-small cell lung cancer cells, and knockdown of CHD4 decreases PHF5A protein levels and reduces activation of the RhoA/ROCK signaling pathway. This CHD4-PHF5A interaction is proposed to mediate promotion of NSCLC cell proliferation and migration.\",\n      \"method\": \"Western blot for protein levels, co-expression analysis, siRNA/overexpression functional assays, xenograft tumor model\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — protein level changes shown by Western blot but direct Co-IP of CHD4-PHF5A interaction not clearly demonstrated in the abstract; single lab, indirect mechanistic evidence\",\n      \"pmids\": [\"32228507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PHF5A is involved in maintaining cancer stem-like phenotype in non-small cell lung cancer (NSCLC); PHF5A knockdown in cancer stem-like cells (CSLCs) results in diminished stemness phenotypes and reduced HDAC8 expression. Inhibition of HDAC activity also affects stemness maintenance, suggesting PHF5A acts upstream of HDAC8 in this context.\",\n      \"method\": \"siRNA knockdown, Western blot, qRT-PCR, oncosphere-forming assay, HDAC inhibitor treatment\",\n      \"journal\": \"Annals of clinical and laboratory science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — KD with defined phenotype but no direct interaction evidence between PHF5A and HDAC8; single lab, single institution\",\n      \"pmids\": [\"35777798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PHF5A knockdown inhibits migration and invasion of hepatocellular carcinoma (HCC) cells and downregulates NF-κB signaling activity. Blocking NF-κB signaling weakens the stimulatory effect of PHF5A on cell migration and invasion.\",\n      \"method\": \"Wound healing assay, Transwell invasion assay, luciferase reporter assay for NF-κB, Western blot, qPCR, siRNA knockdown\",\n      \"journal\": \"BioMed research international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional KD with pathway reporter assay, but no direct molecular interaction between PHF5A and NF-κB components demonstrated; single lab\",\n      \"pmids\": [\"30766880\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PHF5A is a highly conserved zinc-finger PHD-domain protein and essential component of the SF3b spliceosomal subcomplex that recognizes the branch point adenosine during pre-mRNA splicing; it is post-translationally regulated by acetylation (at K29, by p300), decrotonylation (at K25, by SIRT7), and phosphorylation (at Y36, by the TrkA-ERK1/2-ABL1 cascade), which modulate its splicing activity, its interactions within U2 snRNP, and a spliceosome-independent role in centrosome separation; PHF5A additionally stabilizes the PAF1 transcriptional elongation complex and controls RNA Pol II elongation at pluripotency loci, and regulates NHEJ-mediated DNA repair by stabilizing the p400 histone chaperone complex to promote H2AX and H2A.Z deposition at DNA damage sites.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PHF5A is a highly conserved zinc-finger PHD-domain protein that functions as an essential component of the SF3b spliceosomal subcomplex, where together with SF3B1 it helps form the binding pocket that recognizes the intronic branch point adenosine during pre-mRNA splicing [#0]. Structural and resistance-mutation mapping place PHF5A-Y36 and adjacent SF3B1 residues at this pocket, the site at which splicing modulators (pladienolide, herboxidiene, spliceostatin) act, with modulator-resistance mutations clustering there [#0]; spliceostatin compounds engage the protein covalently at Cys26 of its ZnCys4 zinc finger [#18]. Through this splicing activity PHF5A enables recognition of exons bearing unusual C-rich 3' splice sites in thousands of essential genes, a dependency that renders cancer cells selectively vulnerable to its loss while sparing untransformed cells [#1, #15]. PHF5A stabilizes the SF3b complex and links it to histones, and controls alternative splicing of apoptotic and cell-cycle regulators including FASTK and the senescence-linked CDK2 transcript [#5, #7]. Its splicing output is tuned by post-translational modifications: p300-dependent K29 acetylation strengthens U2 snRNP interactions and reshapes splicing under stress to stabilize KDM3A and drive carcinogenesis [#2], while SIRT7-mediated K25 decrotonylation alters CDK2 splicing to accelerate fibroblast senescence [#7]. Beyond splicing, PHF5A acts as a bridging adaptor between ATP-dependent helicases (EP400, DDX1) and RS-domain splicing factors (U2AF1, SFRS5) [#4], stabilizes the PAF1 transcriptional elongation complex to control RNA Pol II elongation at pluripotency loci [#3], and supports NHEJ-mediated DNA repair by stabilizing the p400 histone chaperone complex to deposit H2AX and H2A.Z at switch regions during class switch recombination [#6]. A spliceosome-independent role at centrosomes is activated by Y36 phosphorylation via the TrkA-ERK1/2-ABL1 cascade, which promotes CEP250-Nek2A interaction and premature centrosome separation [#11]. Loss-of-function PHF5A variants produce a cell-type-specific transcriptional phenotype consistent with altered SF3B function rather than simple haploinsufficiency [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing that the PHF5A ortholog is developmentally essential framed it as a core cellular factor rather than an accessory protein.\",\n      \"evidence\": \"Transgenic reporter and RNAi loss-of-function in C. elegans\",\n      \"pmids\": [\"12359262\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular function not defined in this study\", \"Muscle-specific expression pattern not mechanistically linked to a pathway\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Early work asked whether the protein had a nuclear/transcriptional role, finding it could bind a promoter and modulate ERα transcriptional activity.\",\n      \"evidence\": \"EMSA, reporter assays, and ERα co-transfection in HeLa cells (ortholog Ini)\",\n      \"pmids\": [\"12810571\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DNA-binding role superseded by later splicing-centric models\", \"No structural basis for promoter binding\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"To define how PHF5A connects machineries, it was shown to bridge ATP-dependent helicases to RS-domain splicing factors, establishing an adaptor architecture.\",\n      \"evidence\": \"Yeast two/three-hybrid, domain-deletion mapping, Co-IP, and GFP localization to nuclear speckles\",\n      \"pmids\": [\"18758164\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Indirect interactions not resolved structurally\", \"Stoichiometry within the complex unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"A genome-wide screen answered what splicing substrates depend on PHF5A, revealing recognition of C-rich 3' splice sites in essential genes and a cancer-selective vulnerability.\",\n      \"evidence\": \"Genome-wide RNAi screen, RNA-seq, siRNA in patient-derived GSCs, xenograft validation\",\n      \"pmids\": [\"23651857\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Basis for cancer-cell selectivity not fully resolved\", \"Mechanism of C-rich splice-site recognition not structurally defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Work in ESCs extended PHF5A beyond splicing, showing it stabilizes the PAF1 elongation complex to control Pol II elongation at pluripotency loci.\",\n      \"evidence\": \"shRNA depletion, RNA Pol II ChIP-seq, reciprocal Co-IP, differentiation assays in ESCs and myoblasts\",\n      \"pmids\": [\"27749823\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How splicing and elongation roles are coordinated unknown\", \"Direct vs indirect PAF1C stabilization not dissected\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Structural studies resolved where PHF5A sits in the spliceosome, placing it in the branch-point adenosine pocket and explaining splicing-modulator resistance mutations.\",\n      \"evidence\": \"Human PHF5A crystal structure, cryo-EM Bact spliceosome analysis, resistance-mutation mapping, RNA-seq\",\n      \"pmids\": [\"28541300\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic contribution of PHF5A vs SF3B1 to branch-point recognition not separated\", \"Effect of Y36C on basal splicing minimal but mechanism unexplained\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"PHF5A was shown to be required for SF3b stability and to link the complex to histones, coupling splicing of apoptotic genes to tumor phenotypes.\",\n      \"evidence\": \"In vivo CRISPR screen, Co-IP for histone interaction, RT-PCR splice isoform analysis, xenografts\",\n      \"pmids\": [\"29700004\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nature of the PHF5A-histone link not structurally defined\", \"Breadth of apoptotic splicing targets beyond FASTK unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of p300-dependent K29 acetylation answered how splicing output is dynamically tuned by metabolic and stress signals.\",\n      \"evidence\": \"MS site mapping, p300 KO/KD, Co-IP, RNA-seq, rescue experiments\",\n      \"pmids\": [\"31054974\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Deacetylase for K29 not identified\", \"Genome-wide scope of acetylation-driven splicing changes incompletely mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"PHF5A was placed in a non-canonical PAF1-DDX3 sub-complex that binds the NANOG promoter, linking it to cancer stemness independent of canonical PAF1C function.\",\n      \"evidence\": \"Reciprocal Co-IP with MS, ChIP-seq, RNA-seq, CRISPR depletion, orthotopic xenografts in pancreatic cancer stem cells\",\n      \"pmids\": [\"32781084\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; direct vs scaffold role at NANOG promoter not separated\", \"Relationship to canonical splicing function unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Two studies expanded PHF5A regulation and function: SIRT7-mediated K25 decrotonylation tuning CDK2 splicing in senescence, and p400 stabilization driving H2A-variant deposition in NHEJ during class switch recombination.\",\n      \"evidence\": \"Crotonylome MS and SIRT7 manipulation with senescence assays; siRNA screen, ChIP, histone deposition and DSB-repair assays in B cells\",\n      \"pmids\": [\"34604215\", \"33938017\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct SIRT7-PHF5A enzymatic relationship validated in a single lab\", \"How a splicing factor stabilizes a chromatin chaperone complex mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Multiple studies defined a spliceosome-independent centrosomal role (Y36 phosphorylation promoting CEP250-Nek2A and centrosome separation), additional complex partnerships (KMT2A/PHF14/HMG20A/RAI1), and a cell-type-specific LOF pathomechanism in disease.\",\n      \"evidence\": \"Phospho-site mapping and centrosome fractionation; Co-IP/MS for the KMT2A subcomplex; transcriptome sequencing and complex-formation assays in subject-derived fibroblasts\",\n      \"pmids\": [\"36759599\", \"37709746\", \"37422718\", \"37434235\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Centrosomal mechanism single-lab; structural basis of pY36 action unknown\", \"Disease pathomechanism studied only in fibroblasts\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Tissue-specific specificity factors (DLC1) were shown to direct SF3B1-PHF5A branch-site binding to particular pre-mRNAs, and simulations proposed the chemical basis of covalent spliceostatin engagement at Cys26.\",\n      \"evidence\": \"Avian NC splicing assays with pladienolide B; QM/MM MD simulations (preprint)\",\n      \"pmids\": [\"40691464\", \"bio_10.1101_2025.09.17.676740\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cys26 covalent mechanism is computational only, no biochemical validation\", \"Generality of context-specific cofactor recruitment beyond SOX9/SNAI2 unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PHF5A's distinct activities — branch-point splicing, transcriptional elongation, DNA-repair chromatin deposition, and centrosomal regulation — are partitioned and coordinated within a cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model integrating splicing vs non-splicing roles\", \"PTM crosstalk (K25, K29, Y36) not jointly studied\", \"No high-resolution structure of PHF5A in its non-spliceosomal complexes\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 17]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 9]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 2, 5]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 8]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"complexes\": [\n      \"SF3b spliceosomal subcomplex\",\n      \"U2 snRNP\",\n      \"PAF1 complex\",\n      \"p400 histone chaperone complex\"\n    ],\n    \"partners\": [\n      \"SF3B1\",\n      \"U2AF1\",\n      \"SFRS5\",\n      \"EP400\",\n      \"DDX1\",\n      \"PAF1\",\n      \"DDX3\",\n      \"KMT2A\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}