{"gene":"NAT10","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2014,"finding":"NAT10 acetyltransferase activity mediates nuclear shape rescue in laminopathic cells via microtubule reorganization; chemical inhibition of NAT10 with Remodelin improves nuclear architecture in lamin A/C-depleted and HGPS patient cells.","method":"Chemical genetics (Remodelin), siRNA knockdown, genetic rescue, cellular morphology assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — chemical + genetic target identification with orthogonal methods in multiple cell models, replicated across laminopathy contexts","pmids":["24786082"],"is_preprint":false},{"year":2009,"finding":"NAT10 localizes predominantly to the nucleolus in interphase and concentrates in the mitotic midbody during telophase; the N-terminal domain (residues 549–834) mediates this localization. NAT10 depletion causes defects in nucleolar assembly, cytokinesis, decreased acetylated α-tubulin, and G2/M cell cycle arrest, indicating a role in microtubule acetylation and cell division.","method":"Subcellular fractionation, GFP-fusion live imaging, domain deletion mutants, siRNA knockdown, flow cytometry","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization imaging with functional domain mapping and loss-of-function phenotypic readouts","pmids":["19303003"],"is_preprint":false},{"year":2016,"finding":"NAT10 acetylates p53 at K120 and promotes Mdm2 degradation via its intrinsic E3 ligase activity, thereby stabilizing p53 and activating p53-mediated cell cycle control and apoptosis. After DNA damage, NAT10 translocates from the nucleolus to the nucleoplasm.","method":"Immunoprecipitation, in vitro acetylation assay, ubiquitination assay, siRNA knockdown, site-directed mutagenesis, immunofluorescence","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assays with mutagenesis plus cellular epistasis, single lab with multiple orthogonal methods","pmids":["26882543"],"is_preprint":false},{"year":2022,"finding":"NAT10 acetylates the kinesin motor protein Eg5 at K771, stabilizing Eg5 and promoting its centrosome loading. NAT10 depletion causes monopolar and asymmetrical spindle formation, chromosome misalignment and mitotic catastrophe; K771 acetylation is required for Eg5 motor function.","method":"Co-immunoprecipitation, in vitro acetyltransferase assay, K771-Ac specific antibody, live-cell imaging, rescue with acetylation-mimetic mutant (K771Q), CRISPR/siRNA knockdown","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro acetylation reconstitution, site-specific antibody, mutagenesis rescue, and live imaging, multiple orthogonal methods in one study","pmids":["35210604"],"is_preprint":false},{"year":2018,"finding":"NAT10 nuclear localization is mediated by two nucleolar localization signals (NuLS) at residues 68–75 and 989–1018. A deletion mutant lacking residues 989–1018 translocates to cytoplasm; cytoplasmic/membranous NAT10 co-localizes with α-tubulin and promotes α-tubulin acetylation and microtubule stabilization, enhancing HCC cell migration and invasion.","method":"GFP-NAT10 deletion constructs, live imaging, immunofluorescence, migration/invasion assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping with GFP fusions and functional migration assays, single lab","pmids":["29634924"],"is_preprint":false},{"year":2019,"finding":"NAT10/Kre33 participates in acetylation and processing of 18S rRNA and assembly of the 40S ribosomal subunit in yeast and humans, representing its core function in ribosome biogenesis.","method":"Review synthesizing structural and functional studies on Kre33/NAT10 including acetylation assays and rRNA processing experiments","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — review citing primary experimental data from multiple labs on enzymatic activities","pmids":["31491951"],"is_preprint":false},{"year":2022,"finding":"PARP1 PARylates NAT10 on three conserved lysine residues (K1016, K1017, K1020) within its C-terminal nucleolar localization signal after DNA damage. This PARylation is required for NAT10 translocation from nucleolus to nucleoplasm. PARylated NAT10 then co-localizes and interacts with MORC2 and acetylates MORC2 at K767, contributing to the DNA damage response.","method":"CRISPR-Cas9 KO, in vitro PARylation assay, mutagenesis (K3A mutant), immunofluorescence, co-IP, clonogenic survival assay","journal":"Cell communication and signaling","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro PARylation assay with site mutagenesis, CRISPR KO validation, and functional DNA damage readout in one study","pmids":["35986334"],"is_preprint":false},{"year":2017,"finding":"NAT10 interacts with mutant p53 and counteracts Mdm2 action to increase mutant p53 protein levels in HCC cells, promoting proliferation.","method":"Immunoprecipitation, western blot, RNA interference, cell growth assay","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and KD with functional readout, single lab, no in vitro reconstitution","pmids":["28859621"],"is_preprint":false},{"year":2023,"finding":"NAT10 catalyzes ac4C modification on KSHV PAN lncRNA, stabilizing it and triggering viral lytic reactivation. NAT10 also acetylates IFI16 mRNA, enhancing its stability and translation, leading to inflammasome activation. Mutagenesis of ac4C sites in PAN RNA abolishes these effects.","method":"ac4C sequencing, mutagenesis of ac4C sites in KSHV genome, NAT10 knockdown, virion production assay, RNA stability assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — site-directed mutagenesis of ac4C sites in viral genome context plus NAT10 KD, multiple orthogonal methods","pmids":["37816771"],"is_preprint":false},{"year":2024,"finding":"NAT10 is lactylated by α-tubulin acetyltransferase 1 (ATAT1) at a critical domain, enhancing NAT10 RNA acetyltransferase activity and increasing ac4C modification of tRNASer-CGA-1-1, which boosts translation efficiency of KSHV viral lytic genes and promotes viral reactivation.","method":"Mass spectrometry, mutagenesis, tRNA ac4C modification assays, virion production assay, KSHV lytic gene translation efficiency measurement","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PTM identification by MS with mutagenesis and functional viral reactivation readout, single lab","pmids":["38879723"],"is_preprint":false},{"year":2023,"finding":"Lysine 2-hydroxyisobutyrylation (Khib) at K823 of NAT10 enhances its interaction with deubiquitinase USP39, increasing NAT10 protein stability. NAT10 in turn promotes metastasis by stabilizing NOTCH3 mRNA in an ac4C-dependent manner.","method":"Systemic Khib proteome profiling, CRISPR/Cas9 functional screening, Co-IP, mutagenesis, mRNA stability assay, acRIP","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — proteome-scale Khib mapping integrated with CRISPR screening plus mechanistic Co-IP and mutagenesis validation","pmids":["36882514"],"is_preprint":false},{"year":2023,"finding":"NAT10 binds and stabilizes AHNAK mRNA via ac4C modification to protect it from exonuclease-mediated decay, and AHNAK-mediated DNA damage repair is required for NAT10-induced cisplatin resistance in bladder cancer. NFκB p65 directly binds the NAT10 promoter to activate its transcription upon cisplatin treatment.","method":"acRIP-seq, RNA stability assay, ChIP, knockdown/overexpression with in vitro and in vivo cisplatin resistance assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — acRIP-seq plus ChIP and functional rescue, single lab","pmids":["36939377"],"is_preprint":false},{"year":2023,"finding":"NAT10-mediated ac4C modification of tRNAs reduces their abundance when NAT10 is depleted, decreasing translation efficiency of mRNAs enriched for ac4C-modified tRNA-decoded codons; EGFR is identified as a key downstream target regulated at the translational level through this tRNA ac4C mechanism.","method":"Ribosome profiling, tRNA ac4C profiling, NAT10 depletion, ESCA cell lines and mouse models","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ribosome profiling plus tRNA modification analysis, single lab, mechanistic link established","pmids":["37463108"],"is_preprint":false},{"year":2023,"finding":"Maternal NAT10/Nat10 is essential for oocyte meiotic prophase I progression and oocyte maturation by sculpting the maternal transcriptome through ac4C deposition on CCR4-NOT complex transcripts, enabling timely degradation of poly(A)-tailed mRNAs.","method":"Genetic knockout, poly(A) tail length assay (HA-PAT), transcriptomics, ac4C-seq","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic evidence from mouse KO plus multiple sequencing methods, functionally coherent mechanistic pathway","pmids":["37349316"],"is_preprint":false},{"year":2024,"finding":"NAT10 forms liquid-liquid phase separation condensates via a C-terminal intrinsically disordered region; within these condensates NAT10 interacts with splicing factor SRSF2, acetylates SRSF2 to increase its stability, and acetylated SRSF2 promotes YTHDF1 exon 4 skipping, producing a short tumor-promoting YTHDF1 transcript.","method":"Phase separation assays, Co-IP, in vitro acetylation, domain deletion, RNA splicing analysis, patient organoids","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phase separation characterization, Co-IP, and acetylation assay, single lab, multiple orthogonal methods","pmids":["39024555"],"is_preprint":false},{"year":2024,"finding":"PCBP1/2 and TDP43 function as RNA-binding protein adaptors that tether NAT10 to mRNA substrates and determine ac4C site selection; knockdown of these adaptors reduces mRNA acetylation abundance and ablates cytidine-rich ac4C motifs.","method":"Co-IP, knockdown, acRIP-seq, mass spectrometry","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and functional depletion with acRIP-seq, single lab","pmids":["39556689"],"is_preprint":false},{"year":2024,"finding":"NAT10 resolves nucleolar R-loops through two parallel mechanisms: (1) its RecD helicase domain (RHD) directly unwinds R-loops in vitro and in cells; (2) its acetyltransferase activity acetylates DDX21 at K236 and K573, enhancing DDX21 helicase activity to unwind nucleolar R-loops. NAT10 depletion causes nucleolar R-loop accumulation and DNA damage.","method":"In vitro helicase assay, Co-IP, GST pull-down, mass spectrometry, CRISPR-Cas9 KO, immunofluorescence with RNase H treatment, domain deletion mutants","journal":"Cell communication and signaling","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro helicase reconstitution, site-specific acetylation by MS with mutagenesis (2KR/2KQ), and functional rescue, multiple orthogonal methods","pmids":["39394182"],"is_preprint":false},{"year":2022,"finding":"NAT10 and DDX21 physically interact with RNase H1 and enhance its endoribonuclease cleavage rate in vitro. Reduction of NAT10 and DDX21 decreases PS-ASO activity, impairs pre-rRNA processing, and increases R-loop levels in cells.","method":"BioID proximity labeling, biochemical Co-IP, in vitro RNase H1 cleavage assay, knockdown","journal":"Nucleic acid therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro enzymatic assay plus proximity labeling and cellular knockdown, single lab","pmids":["35852833"],"is_preprint":false},{"year":2025,"finding":"NAT10 accumulates at DNA double-strand break (DSB) sites and executes ac4C modification on RNAs at DNA:RNA hybrids in a PARP1-dependent manner, enhancing the stability of DNA:RNA hybrids and promoting homologous recombination repair. Cryo-EM structure of NAT10–remodelin complex was determined at 2.9 Å, revealing a C2 symmetric architecture.","method":"Laser micro-irradiation, ChIP, cryo-EM structure determination, hepatocyte-specific KO mouse, xenograft and PDX tumor models","journal":"Drug resistance updates","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure plus in vivo KO and chromatin-level functional validation, multiple orthogonal methods","pmids":["40132530"],"is_preprint":false},{"year":2023,"finding":"ac4C RNA accumulates at DNA lesions in UV-microirradiated cells within 2–45 min; however, NAT10 does not itself accumulate at damaged sites and NAT10 depletion does not affect ac4C recruitment to DNA lesions. The recruitment of ac4C RNA to damaged chromatin is PARP-dependent (blocked by olaparib).","method":"UV microirradiation, immunofluorescence, PARP inhibitor treatment, NAT10 depletion","journal":"Epigenetics & chromatin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — negative result for NAT10 direct recruitment rigorously established, PARP dependence demonstrated, single lab","pmids":["37322549"],"is_preprint":false},{"year":2022,"finding":"NAT10-mediated ac4C modification stabilizes HAAPIR piRNA-targeted Tfec mRNA, increasing TFEC expression which transcriptionally activates the pro-apoptotic gene BIK, promoting cardiomyocyte apoptosis during ischemia/reperfusion. HAAPIR piRNA directly interacts with NAT10 to enhance this ac4C acetylation.","method":"RNA immunoprecipitation, ac4C assays, HAAPIR deletion mouse model, ischemia/reperfusion model, apoptosis assay","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mouse model plus RIP and ac4C validation, single lab","pmids":["35138696"],"is_preprint":false},{"year":2022,"finding":"NAT10 depletion in neutrophils causes decay of ULK1 mRNA (an ac4C target) and reduced ULK1 expression, leading to enhanced STING-IRF3 signaling and NLRP3 inflammasome activation, driving neutrophil pyroptosis in sepsis.","method":"Neutrophil-specific NAT10 overexpression mouse model, acRIP, RNA decay assay, STING pathway analysis","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic model plus mechanistic pathway validation, single lab","pmids":["36068299"],"is_preprint":false},{"year":2024,"finding":"NAT10 promotes adipogenesis by mediating ac4C modification of KLF9 mRNA to enhance its stability, which activates the CEBPA/B-PPARG pathway; AAV-mediated NAT10 knockdown in adipose tissue inhibits adipose expansion in high-fat diet mice.","method":"acRIP-seq, RNA-seq, acRIP-PCR, dual-luciferase assay, AAV knockdown in vivo, Remodelin treatment","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — acRIP-seq with in vivo AAV KD and luciferase validation, single lab","pmids":["40123006"],"is_preprint":false},{"year":2024,"finding":"NAT10 promotes liver lipogenesis by mediating ac4C modification of Srebf1 and Scap mRNAs, stabilizing them and activating lipogenic gene transcription; AAV-mediated NAT10 knockdown in mouse liver reduces lipogenesis.","method":"acRIP-PCR, NAT10-RIP-PCR, AAV knockdown, dot blot, Oil Red O staining, Remodelin treatment","journal":"Lipids in health and disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP validation of ac4C targets plus in vivo AAV KD, single lab","pmids":["39529018"],"is_preprint":false},{"year":2024,"finding":"NAT10 facilitates acetylation of NPM1, which enhances NPM1-dependent transcription of PD-L1; Remodelin reduces NPM1 acetylation and decreases PD-L1 expression. NAT10 was identified as the NPM1 acetyltransferase by Co-IP and mass spectrometry.","method":"Co-immunoprecipitation, mass spectrometry, knockdown/inhibitor assays, PD-L1 expression measurement","journal":"Molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with MS identification, functional knockdown, single lab","pmids":["38243170"],"is_preprint":false},{"year":2024,"finding":"NAT10 mediates ac4C modification of Kmt5a (SET domain-containing protein 5a) mRNA to enhance its translation efficiency; cardiac-specific NAT10 KO reduces Kmt5a protein without changing its mRNA, activates p53 signaling, and causes cardiomyocyte apoptosis and heart failure. Kmt5a knockdown recapitulates the NAT10-null phenotype and Kmt5a overexpression rescues it.","method":"Cardiac-specific KO, ribosome footprint sequencing combined with RNA-seq, Kmt5a rescue by overexpression","journal":"Journal of the American Heart Association","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with ribosome profiling plus rescue experiment, multiple orthogonal methods, clear mechanistic chain","pmids":["39392166"],"is_preprint":false},{"year":2024,"finding":"NAT10 promotes cardiomyocyte ferroptosis during I/R injury by mediating ac4C modification of Mybbp1a mRNA, increasing MYBBP1A stability, which activates p53 and represses SLC7A11 transcription. P53 in turn transcriptionally activates NAT10, forming a positive feedback loop.","method":"Cardiac-specific NAT10 KO/overexpression, acRIP, mRNA stability assay, Mybbp1a knockdown rescue, ferroptosis inhibitor Fer-1","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mouse model plus acRIP and pathway rescue, single lab","pmids":["38583415"],"is_preprint":false},{"year":2025,"finding":"NAT10 enhances ac4C modification of CCL2 and CXCL1 mRNAs to stabilize them, promoting macrophage and neutrophil recruitment and accelerating renal inflammation in acute kidney injury; conditional NAT10 KO attenuates and conditional KI exacerbates renal inflammation.","method":"Conditional KO/KI mouse models, ac4C-RIP-seq, RNA-seq, CCL2/CXCL1 neutralizing antibodies, AAV9 silencing, pharmacological inhibition","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO and KI genetic models plus acRIP-seq and pharmacological validation, multiple orthogonal approaches","pmids":["40261924"],"is_preprint":false},{"year":2025,"finding":"NAT10 ac4C-modifies GAS5 lncRNA to regulate its stability in NSCLC; GAS5 in turn stabilizes p53 by binding MYBBP1A and facilitating MYBBP1A-p53 interaction, enhancing p53-mediated IRF1 transcription and type I interferon signaling.","method":"RNA-binding assay, Co-IP, NAT10 acRIP, overexpression/knockdown functional assays","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ac4C modification of lncRNA established by acRIP, with Co-IP for protein interactions, single lab","pmids":["38762546"],"is_preprint":false},{"year":2025,"finding":"During T cell activation, NAT10 is upregulated and its ac4C modification of Myc mRNA increases MYC protein translation efficiency, enabling rapid T cell expansion; conditional deletion of Nat10 in T cells causes cell cycle arrest and impaired expansion in an LCMV infection model.","method":"Conditional T-cell-specific Nat10 KO, ribosome profiling, translation efficiency assay, LCMV infection model","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with ribosome profiling and in vivo infection model, mechanistic chain established","pmids":["40045031"],"is_preprint":false},{"year":2024,"finding":"NAT10 mediates ac4C modification of TGFβ1 mRNA by physically interacting with RNA-binding protein PTBP1, enhancing TGFβ1 mRNA stability and promoting TGFβ/SMAD signaling-driven liver fibrosis and cellular senescence.","method":"acRIP-seq, RNA immunoprecipitation, NAT10 overexpression/KO in hepatic stellate cells, CCl4 mouse model, Remodelin treatment","journal":"Genome medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — acRIP-seq with RIP validation and in vivo model, single lab","pmids":["40817062"],"is_preprint":false},{"year":2024,"finding":"LINC00623 binds NAT10 and recruits deubiquitinase USP39 to block ubiquitination-dependent NAT10 degradation, stabilizing NAT10 protein and thereby sustaining oncogenic mRNA ac4C modification in pancreatic cancer.","method":"RNA pulldown, RNA immunoprecipitation, Co-IP, ubiquitination assay, rescue experiments","journal":"Journal of hematology & oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA pulldown, Co-IP, and ubiquitination assay, single lab","pmids":["35978332"],"is_preprint":false},{"year":2024,"finding":"RNPS1 inhibits ubiquitination-mediated NAT10 degradation by E3 ligase ZSWIM6 through direct protein–protein interaction, maintaining NAT10 protein levels and tRNA ac4C modifications that support translation of oncogenic gene sets in HNSCC.","method":"Co-IP, ubiquitination assay, TRMC-seq (novel tRNA ac4C sequencing), translation efficiency measurement","journal":"International journal of oral science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay with novel sequencing method, single lab","pmids":["38246918"],"is_preprint":false}],"current_model":"NAT10 is a bifunctional nucleolar acetyltransferase (also containing a RecD helicase domain) that (1) catalyzes N4-acetylcytidine (ac4C) modification on tRNAs, rRNAs, and mRNAs to enhance their stability and translation efficiency, with substrate selection assisted by RNA-binding protein adaptors PCBP1/2 and TDP43; (2) acetylates protein substrates including p53 (K120), Eg5 (K771), SRSF2, DDX21 (K236/K573), MORC2 (K767), and NPM1 to regulate cell division, DNA damage response, R-loop resolution, and immune checkpoints; (3) is regulated by PARP1-mediated PARylation at K1016/K1017/K1020 that drives its DNA-damage-induced nucleoplasmic translocation, and by Khib at K823 (via ATAT1) and lactylation that modulate its stability and activity; and (4) controls nuclear architecture in laminopathic cells via microtubule reorganization, making it a central epitranscriptomic and acetyltransferase hub in ribosome biogenesis, mitosis, DNA repair, cardiac physiology, immune responses, and cancer."},"narrative":{"mechanistic_narrative":"NAT10 is a nucleolar bifunctional enzyme that couples N4-acetylcytidine (ac4C) deposition on RNA to protein lysine acetylation, acting as a central hub in ribosome biogenesis, mitosis, the DNA damage response, and gene-expression control across diverse physiological and disease contexts [PMID:31491951, PMID:39394182, PMID:40045031]. Its core RNA function is to write ac4C on tRNAs, rRNA, mRNAs, and lncRNAs, thereby stabilizing transcripts and enhancing their translation efficiency; substrate selection is directed by RNA-binding adaptors PCBP1/2 and TDP43 that tether the enzyme to cytidine-rich motifs [PMID:39556689], and these activities tune the translation of specific targets including EGFR, MYC, and structural/metabolic regulators [PMID:37463108, PMID:40045031]. NAT10 also functions as a protein acetyltransferase: it acetylates p53 at K120 and degrades Mdm2 through an intrinsic E3 ligase activity to stabilize p53 [PMID:26882543], acetylates the kinesin Eg5 at K771 to drive bipolar spindle assembly [PMID:35210604], acetylates DDX21 at K236/K573 and uses its own RecD helicase domain to resolve nucleolar R-loops [PMID:39394182], and acetylates SRSF2 within liquid-liquid phase-separated condensates to redirect splicing [PMID:39024555]. NAT10 localizes predominantly to the nucleolus via two nucleolar localization signals and concentrates at the mitotic midbody, with depletion causing nucleolar assembly defects, cytokinesis failure, and G2/M arrest [PMID:19303003, PMID:29634924]. Its nucleoplasmic relocation upon DNA damage is governed by PARP1-mediated PARylation at K1016/K1017/K1020, enabling MORC2 acetylation and recruitment to DNA:RNA hybrids that promote homologous recombination repair [PMID:35986334, PMID:40132530]. NAT10 protein stability and activity are further modulated by 2-hydroxyisobutyrylation at K823 and lactylation that enhance its acetyltransferase output and protect it from ubiquitin-dependent degradation [PMID:38879723, PMID:36882514]. Through these activities NAT10 governs oocyte maturation, cardiac physiology, adipogenesis, immune responses, and tumor progression [PMID:37349316, PMID:39392166, PMID:40261924, PMID:40045031].","teleology":[{"year":2009,"claim":"Established where NAT10 acts and that it is required for cell division, defining its nucleolar and mitotic localization and linking it to microtubule acetylation.","evidence":"Subcellular fractionation, GFP-fusion imaging, domain deletion, and siRNA knockdown in human cells","pmids":["19303003"],"confidence":"High","gaps":["Direct enzymatic substrate at the midbody not defined","Mechanism linking NAT10 to tubulin acetylation unresolved"]},{"year":2014,"claim":"Showed NAT10 acetyltransferase activity is a druggable node for nuclear architecture, providing the chemical tool Remodelin and a therapeutic rationale in laminopathies.","evidence":"Chemical genetics with Remodelin plus siRNA and genetic rescue in lamin-depleted and HGPS patient cells","pmids":["24786082"],"confidence":"High","gaps":["Molecular target of acetylation driving nuclear shape rescue not pinpointed","Microtubule reorganization mechanism partial"]},{"year":2016,"claim":"Defined NAT10 as a protein acetyltransferase with E3 ligase activity that stabilizes p53, expanding its role beyond RNA to the DNA damage/cell cycle axis.","evidence":"In vitro acetylation and ubiquitination assays, mutagenesis, and immunofluorescence showing nucleolar-to-nucleoplasmic translocation after DNA damage","pmids":["26882543"],"confidence":"High","gaps":["Trigger and machinery for translocation not yet identified","Generality of E3 ligase activity unclear"]},{"year":2017,"claim":"Extended the p53 axis to oncogenic mutant p53, indicating context-dependent pro-tumor outcomes of NAT10 stabilization.","evidence":"Co-IP, knockdown, and growth assays in HCC cells","pmids":["28859621"],"confidence":"Medium","gaps":["No in vitro reconstitution","Acetylation site on mutant p53 not mapped"]},{"year":2019,"claim":"Consolidated NAT10/Kre33 as the conserved enzyme for 18S rRNA acetylation and 40S subunit assembly, defining its core ribosome biogenesis role.","evidence":"Review synthesizing structural and functional rRNA processing/acetylation studies in yeast and human","pmids":["31491951"],"confidence":"Medium","gaps":["Secondary source, not primary data","Quantitative contribution to human ribosome biogenesis not detailed here"]},{"year":2022,"claim":"Resolved how DNA-damage-induced relocation is controlled, showing PARP1 PARylation of the C-terminal NoLS drives nucleoplasmic translocation and MORC2 acetylation.","evidence":"In vitro PARylation assay, K3A mutagenesis, CRISPR KO, co-IP, and clonogenic survival","pmids":["35986334"],"confidence":"High","gaps":["Full set of nucleoplasmic substrates incomplete","Reader of PARylated NAT10 not defined"]},{"year":2022,"claim":"Identified a mitotic protein substrate, showing Eg5 K771 acetylation stabilizes the motor and is required for bipolar spindle assembly.","evidence":"Co-IP, in vitro acetyltransferase assay, site-specific antibody, mutant rescue, and live imaging","pmids":["35210604"],"confidence":"High","gaps":["Deacetylase counteracting K771 not identified","Temporal regulation across mitosis unclear"]},{"year":2022,"claim":"Linked NAT10 to R-loop and rRNA homeostasis through cooperation with DDX21 and RNase H1.","evidence":"BioID, co-IP, in vitro RNase H1 cleavage assay, and knockdown","pmids":["35852833"],"confidence":"Medium","gaps":["Whether stimulation of RNase H1 requires catalytic NAT10 not separated","Single lab"]},{"year":2022,"claim":"Demonstrated ac4C as a physiologic mRNA-stabilizing mark with tissue phenotypes, in cardiomyocyte apoptosis (HAAPIR/Tfec) and neutrophil pyroptosis (ULK1).","evidence":"RIP/acRIP, RNA decay assays, and genetic mouse models (HAAPIR deletion; neutrophil-specific NAT10)","pmids":["35138696","36068299"],"confidence":"Medium","gaps":["Adaptor specifying these mRNA targets not defined","Direct vs indirect effects not fully separated"]},{"year":2023,"claim":"Established PTM-driven control of NAT10 stability and activity via Khib at K823 (USP39 recruitment) feeding into ac4C-dependent NOTCH3 stabilization and metastasis.","evidence":"Khib proteome profiling, CRISPR screening, co-IP, mutagenesis, and mRNA stability assays","pmids":["36882514"],"confidence":"High","gaps":["Khib writer/eraser dynamics on NAT10 not fully mapped","Breadth of downstream ac4C targets unclear"]},{"year":2023,"claim":"Showed NAT10 reprograms translation via tRNA ac4C, decreasing tRNA abundance and codon-biased translation when depleted, with EGFR as a key output.","evidence":"Ribosome profiling, tRNA ac4C profiling, and NAT10 depletion in ESCA models","pmids":["37463108"],"confidence":"Medium","gaps":["Mechanism linking ac4C to tRNA abundance unresolved","Codon-decoding model not directly proven"]},{"year":2023,"claim":"Defined a maternal developmental requirement, with NAT10 ac4C on CCR4-NOT transcripts shaping the maternal transcriptome for oocyte maturation.","evidence":"Genetic knockout, poly(A) tail assays, transcriptomics, and ac4C-seq","pmids":["37349316"],"confidence":"High","gaps":["How ac4C couples to deadenylation machinery mechanistically unclear"]},{"year":2023,"claim":"Extended ac4C to viral and immune RNAs, stabilizing KSHV PAN lncRNA and IFI16 mRNA to drive lytic reactivation and inflammasome activation.","evidence":"ac4C-seq, site mutagenesis in viral genome, knockdown, and RNA stability/virion assays","pmids":["37816771"],"confidence":"High","gaps":["Selectivity for viral vs host transcripts not fully defined"]},{"year":2023,"claim":"Connected NAT10 to therapy resistance, stabilizing AHNAK mRNA for DNA repair and driving cisplatin resistance under NF-κB transcriptional control.","evidence":"acRIP-seq, RNA stability, ChIP, and in vitro/in vivo cisplatin assays","pmids":["36939377"],"confidence":"Medium","gaps":["Single lab","Direct ac4C site contribution to AHNAK stability not mutationally proven"]},{"year":2023,"claim":"Clarified that ac4C RNA, not NAT10 itself, is recruited to DNA lesions in a PARP-dependent manner, refining the model of NAT10's role at damage sites.","evidence":"UV microirradiation, immunofluorescence with PARP inhibition, and NAT10 depletion (negative result)","pmids":["37322549"],"confidence":"Medium","gaps":["Where ac4C marking of damage-associated RNA occurs is unresolved","Apparent tension with later DSB-recruitment findings"]},{"year":2024,"claim":"Showed NAT10 acts within phase-separated condensates to acetylate SRSF2 and reprogram splicing (YTHDF1), revealing a condensate-based mode of action.","evidence":"Phase separation assays, co-IP, in vitro acetylation, domain deletion, and patient organoids","pmids":["39024555"],"confidence":"Medium","gaps":["IDR requirement for catalytic output not fully dissected","Single lab"]},{"year":2024,"claim":"Resolved dual mechanisms of R-loop resolution: direct RecD helicase unwinding plus DDX21 K236/K573 acetylation that boosts DDX21 helicase activity.","evidence":"In vitro helicase assay, GST pull-down, MS, CRISPR KO, RNase H-controlled imaging, and 2KR/2KQ mutagenesis","pmids":["39394182"],"confidence":"High","gaps":["Relative contribution of helicase vs acetylase arms not quantified"]},{"year":2024,"claim":"Identified the adaptor logic of mRNA substrate selection, showing PCBP1/2 and TDP43 tether NAT10 and define ac4C site motifs.","evidence":"Co-IP, knockdown, acRIP-seq, and mass spectrometry","pmids":["39556689"],"confidence":"Medium","gaps":["Hierarchy among adaptors not established","Single lab"]},{"year":2024,"claim":"Demonstrated lactylation by ATAT1 as an activating PTM that increases NAT10 RNA acetyltransferase output and tRNA ac4C to promote viral translation.","evidence":"Mass spectrometry, mutagenesis, tRNA ac4C and translation efficiency assays","pmids":["38879723"],"confidence":"Medium","gaps":["Lactylation site stoichiometry and reversibility unclear","Single lab"]},{"year":2024,"claim":"Identified additional ubiquitination-stability regulators (LINC00623/USP39; RNPS1 vs ZSWIM6) and a new protein substrate NPM1 controlling PD-L1, broadening NAT10's regulatory and immune roles.","evidence":"RNA pulldown, co-IP, ubiquitination assays, MS, and functional readouts","pmids":["35978332","38246918","38243170"],"confidence":"Medium","gaps":["NPM1 acetylation site not mapped","Interplay among competing E3/DUB regulators unclear"]},{"year":2024,"claim":"Established broad physiologic ac4C-target programs: adipogenesis (KLF9), hepatic lipogenesis (Srebf1/Scap), cardiac homeostasis (Kmt5a, Mybbp1a), and fibrosis (TGFβ1 via PTBP1).","evidence":"acRIP-seq/RIP, ribosome profiling, conditional/cardiac KO and AAV knockdown, and rescue experiments","pmids":["40123006","39529018","39392166","38583415","40817062"],"confidence":"High","gaps":["Tissue-specific adaptor determinants not defined","Overlapping vs distinct target sets across tissues unclear"]},{"year":2025,"claim":"Provided structural and chromatin-level mechanism at DSBs, showing PARP1-dependent NAT10 accumulation and ac4C on DNA:RNA hybrids promotes homologous recombination, with a 2.9 Å cryo-EM NAT10–remodelin structure.","evidence":"Laser micro-irradiation, ChIP, cryo-EM, hepatocyte-specific KO, and xenograft/PDX models","pmids":["40132530"],"confidence":"High","gaps":["Reconciliation with prior report that NAT10 does not accumulate at lesions needed","Hybrid-stabilizing mechanism at atomic detail incomplete"]},{"year":2025,"claim":"Defined immune-cell and inflammatory roles, with MYC mRNA ac4C enabling T cell expansion and CCL2/CXCL1 ac4C driving renal inflammation.","evidence":"Conditional/T-cell-specific KO and KI, ribosome profiling, acRIP-seq, neutralizing antibodies, and infection/AKI models","pmids":["40045031","40261924"],"confidence":"High","gaps":["Signals upregulating NAT10 during activation not fully defined","Cell-type-specific target selection mechanism unclear"]},{"year":null,"claim":"How NAT10 integrates its competing RNA-acetylase, protein-acetylase, E3-ligase, and helicase activities into context-specific outputs, and how PTMs and adaptors jointly select substrates in vivo, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model coordinating ac4C vs protein acetylation","Deacetylases/erasers for most NAT10 protein substrates unidentified","Quantitative rules governing adaptor-directed ac4C site choice unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[5,8,12,13,16]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,3,14,16,24]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[2,3,5,16]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[15,20,28]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[16]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[1,4,6,16]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[2,6]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,4]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[5,12,13,15]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[12,25,29]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[6,16,18]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,2,3]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,21,27,29]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[14,24]}],"complexes":[],"partners":["PARP1","MORC2","DDX21","SRSF2","PCBP1","TDP43","USP39","PTBP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H0A0","full_name":"RNA cytidine acetyltransferase","aliases":["18S rRNA cytosine acetyltransferase","N-acetyltransferase 10","N-acetyltransferase-like protein","hALP"],"length_aa":1025,"mass_kda":115.7,"function":"RNA cytidine acetyltransferase that catalyzes the formation of N(4)-acetylcytidine (ac4C) modification on mRNAs, 18S rRNA and tRNAs (PubMed:25411247, PubMed:25653167, PubMed:30449621, PubMed:35679869). Catalyzes ac4C modification of a broad range of mRNAs, enhancing mRNA stability and translation (PubMed:30449621, PubMed:35679869). mRNA ac4C modification is frequently present within wobble cytidine sites and promotes translation efficiency (PubMed:30449621). Mediates the formation of ac4C at position 1842 in 18S rRNA (PubMed:25411247). May also catalyze the formation of ac4C at position 1337 in 18S rRNA (By similarity). Required for early nucleolar cleavages of precursor rRNA at sites A0, A1 and A2 during 18S rRNA synthesis (PubMed:25411247, PubMed:25653167). Catalyzes the formation of ac4C in serine and leucine tRNAs (By similarity). Requires the tRNA-binding adapter protein THUMPD1 for full tRNA acetyltransferase activity but not for 18S rRNA acetylation (PubMed:25653167). In addition to RNA acetyltransferase activity, also able to acetylate lysine residues of proteins, such as histones, microtubules, p53/TP53 and MDM2, in vitro (PubMed:14592445, PubMed:17631499, PubMed:19303003, PubMed:26882543, PubMed:27993683, PubMed:30165671). The relevance of the protein lysine acetyltransferase activity is however unsure in vivo (PubMed:30449621). Activates telomerase activity by stimulating the transcription of TERT, and may also regulate telomerase function by affecting the balance of telomerase subunit assembly, disassembly, and localization (PubMed:14592445, PubMed:18082603). Involved in the regulation of centrosome duplication by acetylating CENATAC during mitosis, promoting SASS6 proteasome degradation (PubMed:31722219). Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome (PubMed:34516797)","subcellular_location":"Nucleus, nucleolus; Midbody","url":"https://www.uniprot.org/uniprotkb/Q9H0A0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/NAT10","classification":"Common Essential","n_dependent_lines":1190,"n_total_lines":1208,"dependency_fraction":0.9850993377483444},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"FKBP5","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NAT10","total_profiled":1310},"omim":[{"mim_id":"621074","title":"MITOTIC DEACETYLASE-ASSOCIATED SANT DOMAIN PROTEIN; MIDEAS","url":"https://www.omim.org/entry/621074"},{"mim_id":"621031","title":"POLYMERASE I, RNA, SUBUNIT E; POLR1E","url":"https://www.omim.org/entry/621031"},{"mim_id":"620142","title":"CENTROSOMAL AT-AC SPLICING FACTOR; CENATAC","url":"https://www.omim.org/entry/620142"},{"mim_id":"616664","title":"SMALL NUCLEOLAR RNA, C/D BOX, 13; SNORD13","url":"https://www.omim.org/entry/616664"},{"mim_id":"616662","title":"THUMP DOMAIN PROTEIN 1, NAT10 ACETYLTRANSFERASE ADAPTOR; THUMPD1","url":"https://www.omim.org/entry/616662"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoli","reliability":"Enhanced"},{"location":"Midbody","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NAT10"},"hgnc":{"alias_symbol":["hALP","FLJ10774","FLJ12179","NET43","KIAA1709","Kre33"],"prev_symbol":[]},"alphafold":{"accession":"Q9H0A0","domains":[{"cath_id":"3.40.50,3.40.50","chopping":"9-215","consensus_level":"high","plddt":82.9287,"start":9,"end":215},{"cath_id":"3.40.50.300","chopping":"231-440_457-466","consensus_level":"high","plddt":82.8001,"start":231,"end":466},{"cath_id":"3.40.630","chopping":"498-583_629-659_684-707","consensus_level":"medium","plddt":83.751,"start":498,"end":707},{"cath_id":"-","chopping":"803-916","consensus_level":"high","plddt":86.4166,"start":803,"end":916}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H0A0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H0A0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H0A0-F1-predicted_aligned_error_v6.png","plddt_mean":78.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NAT10","jax_strain_url":"https://www.jax.org/strain/search?query=NAT10"},"sequence":{"accession":"Q9H0A0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H0A0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H0A0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H0A0"}},"corpus_meta":[{"pmid":"24786082","id":"PMC_24786082","title":"Chemical inhibition of NAT10 corrects defects of laminopathic cells.","date":"2014","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/24786082","citation_count":321,"is_preprint":false},{"pmid":"36939377","id":"PMC_36939377","title":"NAT10 Drives Cisplatin Chemoresistance by Enhancing ac4C-Associated DNA Repair in Bladder Cancer.","date":"2023","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/36939377","citation_count":174,"is_preprint":false},{"pmid":"26882543","id":"PMC_26882543","title":"NAT10 regulates p53 activation through acetylating p53 at K120 and ubiquitinating Mdm2.","date":"2016","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/26882543","citation_count":168,"is_preprint":false},{"pmid":"35522942","id":"PMC_35522942","title":"NAT10-mediated mRNA N4-acetylcytidine modification promotes bladder cancer progression.","date":"2022","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35522942","citation_count":149,"is_preprint":false},{"pmid":"19303003","id":"PMC_19303003","title":"NAT10, a nucleolar protein, localizes to the midbody and regulates cytokinesis and acetylation of microtubules.","date":"2009","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/19303003","citation_count":140,"is_preprint":false},{"pmid":"36882514","id":"PMC_36882514","title":"Lysine 2-hydroxyisobutyrylation of NAT10 promotes cancer metastasis in an ac4C-dependent manner.","date":"2023","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/36882514","citation_count":139,"is_preprint":false},{"pmid":"36522719","id":"PMC_36522719","title":"Acetyltransferase NAT10 regulates the Wnt/β-catenin signaling pathway to promote colorectal cancer progression via ac4C acetylation of KIF23 mRNA.","date":"2022","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/36522719","citation_count":134,"is_preprint":false},{"pmid":"37128278","id":"PMC_37128278","title":"Mechanisms of NAT10 as ac4C writer in diseases.","date":"2023","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/37128278","citation_count":124,"is_preprint":false},{"pmid":"37818745","id":"PMC_37818745","title":"NAT10/ac4C/FOXP1 Promotes Malignant Progression and Facilitates Immunosuppression by Reprogramming Glycolytic Metabolism in Cervical Cancer.","date":"2023","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/37818745","citation_count":121,"is_preprint":false},{"pmid":"37328448","id":"PMC_37328448","title":"N4-Acetylcytidine Drives Glycolysis Addiction in Gastric Cancer via NAT10/SEPT9/HIF-1α Positive Feedback Loop.","date":"2023","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/37328448","citation_count":111,"is_preprint":false},{"pmid":"35138696","id":"PMC_35138696","title":"PIWI-Interacting RNA HAAPIR Regulates Cardiomyocyte Death After Myocardial Infarction by Promoting NAT10-Mediated ac4 C Acetylation of Tfec mRNA.","date":"2022","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/35138696","citation_count":103,"is_preprint":false},{"pmid":"36609449","id":"PMC_36609449","title":"Helicobacter pylori-induced NAT10 stabilizes MDM2 mRNA via RNA acetylation to facilitate gastric cancer progression.","date":"2023","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/36609449","citation_count":95,"is_preprint":false},{"pmid":"35967285","id":"PMC_35967285","title":"NAT10 promotes cell proliferation by acetylating CEP170 mRNA to enhance translation efficiency in multiple myeloma.","date":"2022","source":"Acta pharmaceutica Sinica. B","url":"https://pubmed.ncbi.nlm.nih.gov/35967285","citation_count":90,"is_preprint":false},{"pmid":"36068299","id":"PMC_36068299","title":"NAT10 regulates neutrophil pyroptosis in sepsis via acetylating ULK1 RNA and activating STING pathway.","date":"2022","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/36068299","citation_count":82,"is_preprint":false},{"pmid":"28859621","id":"PMC_28859621","title":"NAT10 is upregulated in hepatocellular carcinoma and enhances mutant p53 activity.","date":"2017","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/28859621","citation_count":74,"is_preprint":false},{"pmid":"37955115","id":"PMC_37955115","title":"NAT10 Is Involved in Cardiac Remodeling Through ac4C-Mediated Transcriptomic Regulation.","date":"2023","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/37955115","citation_count":68,"is_preprint":false},{"pmid":"37816771","id":"PMC_37816771","title":"NAT10-dependent N4-acetylcytidine modification mediates PAN RNA stability, KSHV reactivation, and IFI16-related inflammasome activation.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37816771","citation_count":68,"is_preprint":false},{"pmid":"37463108","id":"PMC_37463108","title":"NAT10-mediated ac4C tRNA modification promotes EGFR mRNA translation and gefitinib resistance in cancer.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/37463108","citation_count":68,"is_preprint":false},{"pmid":"36765042","id":"PMC_36765042","title":"Role of NAT10-mediated ac4C-modified HSP90AA1 RNA acetylation in ER stress-mediated metastasis and lenvatinib resistance in hepatocellular carcinoma.","date":"2023","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/36765042","citation_count":65,"is_preprint":false},{"pmid":"38065232","id":"PMC_38065232","title":"Emerging roles of RNA ac4C modification and NAT10 in mammalian development and human diseases.","date":"2023","source":"Pharmacology & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/38065232","citation_count":63,"is_preprint":false},{"pmid":"37349316","id":"PMC_37349316","title":"Maternal NAT10 orchestrates oocyte meiotic cell-cycle progression and maturation in mice.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37349316","citation_count":61,"is_preprint":false},{"pmid":"35978332","id":"PMC_35978332","title":"The LINC00623/NAT10 signaling axis promotes pancreatic cancer progression by remodeling ac4C modification of mRNA.","date":"2022","source":"Journal of hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35978332","citation_count":58,"is_preprint":false},{"pmid":"37307924","id":"PMC_37307924","title":"NAT10 regulates the LPS-induced inflammatory response via the NOX2-ROS-NF-κB pathway in macrophages.","date":"2023","source":"Biochimica et biophysica acta. 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NAT10 depletion causes defects in nucleolar assembly, cytokinesis, decreased acetylated α-tubulin, and G2/M cell cycle arrest, indicating a role in microtubule acetylation and cell division.\",\n      \"method\": \"Subcellular fractionation, GFP-fusion live imaging, domain deletion mutants, siRNA knockdown, flow cytometry\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization imaging with functional domain mapping and loss-of-function phenotypic readouts\",\n      \"pmids\": [\"19303003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NAT10 acetylates p53 at K120 and promotes Mdm2 degradation via its intrinsic E3 ligase activity, thereby stabilizing p53 and activating p53-mediated cell cycle control and apoptosis. After DNA damage, NAT10 translocates from the nucleolus to the nucleoplasm.\",\n      \"method\": \"Immunoprecipitation, in vitro acetylation assay, ubiquitination assay, siRNA knockdown, site-directed mutagenesis, immunofluorescence\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assays with mutagenesis plus cellular epistasis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"26882543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NAT10 acetylates the kinesin motor protein Eg5 at K771, stabilizing Eg5 and promoting its centrosome loading. NAT10 depletion causes monopolar and asymmetrical spindle formation, chromosome misalignment and mitotic catastrophe; K771 acetylation is required for Eg5 motor function.\",\n      \"method\": \"Co-immunoprecipitation, in vitro acetyltransferase assay, K771-Ac specific antibody, live-cell imaging, rescue with acetylation-mimetic mutant (K771Q), CRISPR/siRNA knockdown\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro acetylation reconstitution, site-specific antibody, mutagenesis rescue, and live imaging, multiple orthogonal methods in one study\",\n      \"pmids\": [\"35210604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NAT10 nuclear localization is mediated by two nucleolar localization signals (NuLS) at residues 68–75 and 989–1018. A deletion mutant lacking residues 989–1018 translocates to cytoplasm; cytoplasmic/membranous NAT10 co-localizes with α-tubulin and promotes α-tubulin acetylation and microtubule stabilization, enhancing HCC cell migration and invasion.\",\n      \"method\": \"GFP-NAT10 deletion constructs, live imaging, immunofluorescence, migration/invasion assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping with GFP fusions and functional migration assays, single lab\",\n      \"pmids\": [\"29634924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NAT10/Kre33 participates in acetylation and processing of 18S rRNA and assembly of the 40S ribosomal subunit in yeast and humans, representing its core function in ribosome biogenesis.\",\n      \"method\": \"Review synthesizing structural and functional studies on Kre33/NAT10 including acetylation assays and rRNA processing experiments\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — review citing primary experimental data from multiple labs on enzymatic activities\",\n      \"pmids\": [\"31491951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PARP1 PARylates NAT10 on three conserved lysine residues (K1016, K1017, K1020) within its C-terminal nucleolar localization signal after DNA damage. This PARylation is required for NAT10 translocation from nucleolus to nucleoplasm. PARylated NAT10 then co-localizes and interacts with MORC2 and acetylates MORC2 at K767, contributing to the DNA damage response.\",\n      \"method\": \"CRISPR-Cas9 KO, in vitro PARylation assay, mutagenesis (K3A mutant), immunofluorescence, co-IP, clonogenic survival assay\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro PARylation assay with site mutagenesis, CRISPR KO validation, and functional DNA damage readout in one study\",\n      \"pmids\": [\"35986334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NAT10 interacts with mutant p53 and counteracts Mdm2 action to increase mutant p53 protein levels in HCC cells, promoting proliferation.\",\n      \"method\": \"Immunoprecipitation, western blot, RNA interference, cell growth assay\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and KD with functional readout, single lab, no in vitro reconstitution\",\n      \"pmids\": [\"28859621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NAT10 catalyzes ac4C modification on KSHV PAN lncRNA, stabilizing it and triggering viral lytic reactivation. NAT10 also acetylates IFI16 mRNA, enhancing its stability and translation, leading to inflammasome activation. Mutagenesis of ac4C sites in PAN RNA abolishes these effects.\",\n      \"method\": \"ac4C sequencing, mutagenesis of ac4C sites in KSHV genome, NAT10 knockdown, virion production assay, RNA stability assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — site-directed mutagenesis of ac4C sites in viral genome context plus NAT10 KD, multiple orthogonal methods\",\n      \"pmids\": [\"37816771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NAT10 is lactylated by α-tubulin acetyltransferase 1 (ATAT1) at a critical domain, enhancing NAT10 RNA acetyltransferase activity and increasing ac4C modification of tRNASer-CGA-1-1, which boosts translation efficiency of KSHV viral lytic genes and promotes viral reactivation.\",\n      \"method\": \"Mass spectrometry, mutagenesis, tRNA ac4C modification assays, virion production assay, KSHV lytic gene translation efficiency measurement\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PTM identification by MS with mutagenesis and functional viral reactivation readout, single lab\",\n      \"pmids\": [\"38879723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Lysine 2-hydroxyisobutyrylation (Khib) at K823 of NAT10 enhances its interaction with deubiquitinase USP39, increasing NAT10 protein stability. NAT10 in turn promotes metastasis by stabilizing NOTCH3 mRNA in an ac4C-dependent manner.\",\n      \"method\": \"Systemic Khib proteome profiling, CRISPR/Cas9 functional screening, Co-IP, mutagenesis, mRNA stability assay, acRIP\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — proteome-scale Khib mapping integrated with CRISPR screening plus mechanistic Co-IP and mutagenesis validation\",\n      \"pmids\": [\"36882514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NAT10 binds and stabilizes AHNAK mRNA via ac4C modification to protect it from exonuclease-mediated decay, and AHNAK-mediated DNA damage repair is required for NAT10-induced cisplatin resistance in bladder cancer. NFκB p65 directly binds the NAT10 promoter to activate its transcription upon cisplatin treatment.\",\n      \"method\": \"acRIP-seq, RNA stability assay, ChIP, knockdown/overexpression with in vitro and in vivo cisplatin resistance assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — acRIP-seq plus ChIP and functional rescue, single lab\",\n      \"pmids\": [\"36939377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NAT10-mediated ac4C modification of tRNAs reduces their abundance when NAT10 is depleted, decreasing translation efficiency of mRNAs enriched for ac4C-modified tRNA-decoded codons; EGFR is identified as a key downstream target regulated at the translational level through this tRNA ac4C mechanism.\",\n      \"method\": \"Ribosome profiling, tRNA ac4C profiling, NAT10 depletion, ESCA cell lines and mouse models\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ribosome profiling plus tRNA modification analysis, single lab, mechanistic link established\",\n      \"pmids\": [\"37463108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Maternal NAT10/Nat10 is essential for oocyte meiotic prophase I progression and oocyte maturation by sculpting the maternal transcriptome through ac4C deposition on CCR4-NOT complex transcripts, enabling timely degradation of poly(A)-tailed mRNAs.\",\n      \"method\": \"Genetic knockout, poly(A) tail length assay (HA-PAT), transcriptomics, ac4C-seq\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic evidence from mouse KO plus multiple sequencing methods, functionally coherent mechanistic pathway\",\n      \"pmids\": [\"37349316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NAT10 forms liquid-liquid phase separation condensates via a C-terminal intrinsically disordered region; within these condensates NAT10 interacts with splicing factor SRSF2, acetylates SRSF2 to increase its stability, and acetylated SRSF2 promotes YTHDF1 exon 4 skipping, producing a short tumor-promoting YTHDF1 transcript.\",\n      \"method\": \"Phase separation assays, Co-IP, in vitro acetylation, domain deletion, RNA splicing analysis, patient organoids\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phase separation characterization, Co-IP, and acetylation assay, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"39024555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PCBP1/2 and TDP43 function as RNA-binding protein adaptors that tether NAT10 to mRNA substrates and determine ac4C site selection; knockdown of these adaptors reduces mRNA acetylation abundance and ablates cytidine-rich ac4C motifs.\",\n      \"method\": \"Co-IP, knockdown, acRIP-seq, mass spectrometry\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and functional depletion with acRIP-seq, single lab\",\n      \"pmids\": [\"39556689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NAT10 resolves nucleolar R-loops through two parallel mechanisms: (1) its RecD helicase domain (RHD) directly unwinds R-loops in vitro and in cells; (2) its acetyltransferase activity acetylates DDX21 at K236 and K573, enhancing DDX21 helicase activity to unwind nucleolar R-loops. NAT10 depletion causes nucleolar R-loop accumulation and DNA damage.\",\n      \"method\": \"In vitro helicase assay, Co-IP, GST pull-down, mass spectrometry, CRISPR-Cas9 KO, immunofluorescence with RNase H treatment, domain deletion mutants\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro helicase reconstitution, site-specific acetylation by MS with mutagenesis (2KR/2KQ), and functional rescue, multiple orthogonal methods\",\n      \"pmids\": [\"39394182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NAT10 and DDX21 physically interact with RNase H1 and enhance its endoribonuclease cleavage rate in vitro. Reduction of NAT10 and DDX21 decreases PS-ASO activity, impairs pre-rRNA processing, and increases R-loop levels in cells.\",\n      \"method\": \"BioID proximity labeling, biochemical Co-IP, in vitro RNase H1 cleavage assay, knockdown\",\n      \"journal\": \"Nucleic acid therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro enzymatic assay plus proximity labeling and cellular knockdown, single lab\",\n      \"pmids\": [\"35852833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NAT10 accumulates at DNA double-strand break (DSB) sites and executes ac4C modification on RNAs at DNA:RNA hybrids in a PARP1-dependent manner, enhancing the stability of DNA:RNA hybrids and promoting homologous recombination repair. Cryo-EM structure of NAT10–remodelin complex was determined at 2.9 Å, revealing a C2 symmetric architecture.\",\n      \"method\": \"Laser micro-irradiation, ChIP, cryo-EM structure determination, hepatocyte-specific KO mouse, xenograft and PDX tumor models\",\n      \"journal\": \"Drug resistance updates\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure plus in vivo KO and chromatin-level functional validation, multiple orthogonal methods\",\n      \"pmids\": [\"40132530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ac4C RNA accumulates at DNA lesions in UV-microirradiated cells within 2–45 min; however, NAT10 does not itself accumulate at damaged sites and NAT10 depletion does not affect ac4C recruitment to DNA lesions. The recruitment of ac4C RNA to damaged chromatin is PARP-dependent (blocked by olaparib).\",\n      \"method\": \"UV microirradiation, immunofluorescence, PARP inhibitor treatment, NAT10 depletion\",\n      \"journal\": \"Epigenetics & chromatin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — negative result for NAT10 direct recruitment rigorously established, PARP dependence demonstrated, single lab\",\n      \"pmids\": [\"37322549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NAT10-mediated ac4C modification stabilizes HAAPIR piRNA-targeted Tfec mRNA, increasing TFEC expression which transcriptionally activates the pro-apoptotic gene BIK, promoting cardiomyocyte apoptosis during ischemia/reperfusion. HAAPIR piRNA directly interacts with NAT10 to enhance this ac4C acetylation.\",\n      \"method\": \"RNA immunoprecipitation, ac4C assays, HAAPIR deletion mouse model, ischemia/reperfusion model, apoptosis assay\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mouse model plus RIP and ac4C validation, single lab\",\n      \"pmids\": [\"35138696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NAT10 depletion in neutrophils causes decay of ULK1 mRNA (an ac4C target) and reduced ULK1 expression, leading to enhanced STING-IRF3 signaling and NLRP3 inflammasome activation, driving neutrophil pyroptosis in sepsis.\",\n      \"method\": \"Neutrophil-specific NAT10 overexpression mouse model, acRIP, RNA decay assay, STING pathway analysis\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic model plus mechanistic pathway validation, single lab\",\n      \"pmids\": [\"36068299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NAT10 promotes adipogenesis by mediating ac4C modification of KLF9 mRNA to enhance its stability, which activates the CEBPA/B-PPARG pathway; AAV-mediated NAT10 knockdown in adipose tissue inhibits adipose expansion in high-fat diet mice.\",\n      \"method\": \"acRIP-seq, RNA-seq, acRIP-PCR, dual-luciferase assay, AAV knockdown in vivo, Remodelin treatment\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — acRIP-seq with in vivo AAV KD and luciferase validation, single lab\",\n      \"pmids\": [\"40123006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NAT10 promotes liver lipogenesis by mediating ac4C modification of Srebf1 and Scap mRNAs, stabilizing them and activating lipogenic gene transcription; AAV-mediated NAT10 knockdown in mouse liver reduces lipogenesis.\",\n      \"method\": \"acRIP-PCR, NAT10-RIP-PCR, AAV knockdown, dot blot, Oil Red O staining, Remodelin treatment\",\n      \"journal\": \"Lipids in health and disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP validation of ac4C targets plus in vivo AAV KD, single lab\",\n      \"pmids\": [\"39529018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NAT10 facilitates acetylation of NPM1, which enhances NPM1-dependent transcription of PD-L1; Remodelin reduces NPM1 acetylation and decreases PD-L1 expression. NAT10 was identified as the NPM1 acetyltransferase by Co-IP and mass spectrometry.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, knockdown/inhibitor assays, PD-L1 expression measurement\",\n      \"journal\": \"Molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with MS identification, functional knockdown, single lab\",\n      \"pmids\": [\"38243170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NAT10 mediates ac4C modification of Kmt5a (SET domain-containing protein 5a) mRNA to enhance its translation efficiency; cardiac-specific NAT10 KO reduces Kmt5a protein without changing its mRNA, activates p53 signaling, and causes cardiomyocyte apoptosis and heart failure. Kmt5a knockdown recapitulates the NAT10-null phenotype and Kmt5a overexpression rescues it.\",\n      \"method\": \"Cardiac-specific KO, ribosome footprint sequencing combined with RNA-seq, Kmt5a rescue by overexpression\",\n      \"journal\": \"Journal of the American Heart Association\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with ribosome profiling plus rescue experiment, multiple orthogonal methods, clear mechanistic chain\",\n      \"pmids\": [\"39392166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NAT10 promotes cardiomyocyte ferroptosis during I/R injury by mediating ac4C modification of Mybbp1a mRNA, increasing MYBBP1A stability, which activates p53 and represses SLC7A11 transcription. P53 in turn transcriptionally activates NAT10, forming a positive feedback loop.\",\n      \"method\": \"Cardiac-specific NAT10 KO/overexpression, acRIP, mRNA stability assay, Mybbp1a knockdown rescue, ferroptosis inhibitor Fer-1\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mouse model plus acRIP and pathway rescue, single lab\",\n      \"pmids\": [\"38583415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NAT10 enhances ac4C modification of CCL2 and CXCL1 mRNAs to stabilize them, promoting macrophage and neutrophil recruitment and accelerating renal inflammation in acute kidney injury; conditional NAT10 KO attenuates and conditional KI exacerbates renal inflammation.\",\n      \"method\": \"Conditional KO/KI mouse models, ac4C-RIP-seq, RNA-seq, CCL2/CXCL1 neutralizing antibodies, AAV9 silencing, pharmacological inhibition\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO and KI genetic models plus acRIP-seq and pharmacological validation, multiple orthogonal approaches\",\n      \"pmids\": [\"40261924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NAT10 ac4C-modifies GAS5 lncRNA to regulate its stability in NSCLC; GAS5 in turn stabilizes p53 by binding MYBBP1A and facilitating MYBBP1A-p53 interaction, enhancing p53-mediated IRF1 transcription and type I interferon signaling.\",\n      \"method\": \"RNA-binding assay, Co-IP, NAT10 acRIP, overexpression/knockdown functional assays\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ac4C modification of lncRNA established by acRIP, with Co-IP for protein interactions, single lab\",\n      \"pmids\": [\"38762546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"During T cell activation, NAT10 is upregulated and its ac4C modification of Myc mRNA increases MYC protein translation efficiency, enabling rapid T cell expansion; conditional deletion of Nat10 in T cells causes cell cycle arrest and impaired expansion in an LCMV infection model.\",\n      \"method\": \"Conditional T-cell-specific Nat10 KO, ribosome profiling, translation efficiency assay, LCMV infection model\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with ribosome profiling and in vivo infection model, mechanistic chain established\",\n      \"pmids\": [\"40045031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NAT10 mediates ac4C modification of TGFβ1 mRNA by physically interacting with RNA-binding protein PTBP1, enhancing TGFβ1 mRNA stability and promoting TGFβ/SMAD signaling-driven liver fibrosis and cellular senescence.\",\n      \"method\": \"acRIP-seq, RNA immunoprecipitation, NAT10 overexpression/KO in hepatic stellate cells, CCl4 mouse model, Remodelin treatment\",\n      \"journal\": \"Genome medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — acRIP-seq with RIP validation and in vivo model, single lab\",\n      \"pmids\": [\"40817062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LINC00623 binds NAT10 and recruits deubiquitinase USP39 to block ubiquitination-dependent NAT10 degradation, stabilizing NAT10 protein and thereby sustaining oncogenic mRNA ac4C modification in pancreatic cancer.\",\n      \"method\": \"RNA pulldown, RNA immunoprecipitation, Co-IP, ubiquitination assay, rescue experiments\",\n      \"journal\": \"Journal of hematology & oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA pulldown, Co-IP, and ubiquitination assay, single lab\",\n      \"pmids\": [\"35978332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RNPS1 inhibits ubiquitination-mediated NAT10 degradation by E3 ligase ZSWIM6 through direct protein–protein interaction, maintaining NAT10 protein levels and tRNA ac4C modifications that support translation of oncogenic gene sets in HNSCC.\",\n      \"method\": \"Co-IP, ubiquitination assay, TRMC-seq (novel tRNA ac4C sequencing), translation efficiency measurement\",\n      \"journal\": \"International journal of oral science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay with novel sequencing method, single lab\",\n      \"pmids\": [\"38246918\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NAT10 is a bifunctional nucleolar acetyltransferase (also containing a RecD helicase domain) that (1) catalyzes N4-acetylcytidine (ac4C) modification on tRNAs, rRNAs, and mRNAs to enhance their stability and translation efficiency, with substrate selection assisted by RNA-binding protein adaptors PCBP1/2 and TDP43; (2) acetylates protein substrates including p53 (K120), Eg5 (K771), SRSF2, DDX21 (K236/K573), MORC2 (K767), and NPM1 to regulate cell division, DNA damage response, R-loop resolution, and immune checkpoints; (3) is regulated by PARP1-mediated PARylation at K1016/K1017/K1020 that drives its DNA-damage-induced nucleoplasmic translocation, and by Khib at K823 (via ATAT1) and lactylation that modulate its stability and activity; and (4) controls nuclear architecture in laminopathic cells via microtubule reorganization, making it a central epitranscriptomic and acetyltransferase hub in ribosome biogenesis, mitosis, DNA repair, cardiac physiology, immune responses, and cancer.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NAT10 is a nucleolar bifunctional enzyme that couples N4-acetylcytidine (ac4C) deposition on RNA to protein lysine acetylation, acting as a central hub in ribosome biogenesis, mitosis, the DNA damage response, and gene-expression control across diverse physiological and disease contexts [#5, #16, #29]. Its core RNA function is to write ac4C on tRNAs, rRNA, mRNAs, and lncRNAs, thereby stabilizing transcripts and enhancing their translation efficiency; substrate selection is directed by RNA-binding adaptors PCBP1/2 and TDP43 that tether the enzyme to cytidine-rich motifs [#15], and these activities tune the translation of specific targets including EGFR, MYC, and structural/metabolic regulators [#12, #29]. NAT10 also functions as a protein acetyltransferase: it acetylates p53 at K120 and degrades Mdm2 through an intrinsic E3 ligase activity to stabilize p53 [#2], acetylates the kinesin Eg5 at K771 to drive bipolar spindle assembly [#3], acetylates DDX21 at K236/K573 and uses its own RecD helicase domain to resolve nucleolar R-loops [#16], and acetylates SRSF2 within liquid-liquid phase-separated condensates to redirect splicing [#14]. NAT10 localizes predominantly to the nucleolus via two nucleolar localization signals and concentrates at the mitotic midbody, with depletion causing nucleolar assembly defects, cytokinesis failure, and G2/M arrest [#1, #4]. Its nucleoplasmic relocation upon DNA damage is governed by PARP1-mediated PARylation at K1016/K1017/K1020, enabling MORC2 acetylation and recruitment to DNA:RNA hybrids that promote homologous recombination repair [#6, #18]. NAT10 protein stability and activity are further modulated by 2-hydroxyisobutyrylation at K823 and lactylation that enhance its acetyltransferase output and protect it from ubiquitin-dependent degradation [#9, #10]. Through these activities NAT10 governs oocyte maturation, cardiac physiology, adipogenesis, immune responses, and tumor progression [#13, #25, #27, #29].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established where NAT10 acts and that it is required for cell division, defining its nucleolar and mitotic localization and linking it to microtubule acetylation.\",\n      \"evidence\": \"Subcellular fractionation, GFP-fusion imaging, domain deletion, and siRNA knockdown in human cells\",\n      \"pmids\": [\"19303003\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzymatic substrate at the midbody not defined\", \"Mechanism linking NAT10 to tubulin acetylation unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed NAT10 acetyltransferase activity is a druggable node for nuclear architecture, providing the chemical tool Remodelin and a therapeutic rationale in laminopathies.\",\n      \"evidence\": \"Chemical genetics with Remodelin plus siRNA and genetic rescue in lamin-depleted and HGPS patient cells\",\n      \"pmids\": [\"24786082\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular target of acetylation driving nuclear shape rescue not pinpointed\", \"Microtubule reorganization mechanism partial\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined NAT10 as a protein acetyltransferase with E3 ligase activity that stabilizes p53, expanding its role beyond RNA to the DNA damage/cell cycle axis.\",\n      \"evidence\": \"In vitro acetylation and ubiquitination assays, mutagenesis, and immunofluorescence showing nucleolar-to-nucleoplasmic translocation after DNA damage\",\n      \"pmids\": [\"26882543\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger and machinery for translocation not yet identified\", \"Generality of E3 ligase activity unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended the p53 axis to oncogenic mutant p53, indicating context-dependent pro-tumor outcomes of NAT10 stabilization.\",\n      \"evidence\": \"Co-IP, knockdown, and growth assays in HCC cells\",\n      \"pmids\": [\"28859621\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution\", \"Acetylation site on mutant p53 not mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Consolidated NAT10/Kre33 as the conserved enzyme for 18S rRNA acetylation and 40S subunit assembly, defining its core ribosome biogenesis role.\",\n      \"evidence\": \"Review synthesizing structural and functional rRNA processing/acetylation studies in yeast and human\",\n      \"pmids\": [\"31491951\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Secondary source, not primary data\", \"Quantitative contribution to human ribosome biogenesis not detailed here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved how DNA-damage-induced relocation is controlled, showing PARP1 PARylation of the C-terminal NoLS drives nucleoplasmic translocation and MORC2 acetylation.\",\n      \"evidence\": \"In vitro PARylation assay, K3A mutagenesis, CRISPR KO, co-IP, and clonogenic survival\",\n      \"pmids\": [\"35986334\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of nucleoplasmic substrates incomplete\", \"Reader of PARylated NAT10 not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified a mitotic protein substrate, showing Eg5 K771 acetylation stabilizes the motor and is required for bipolar spindle assembly.\",\n      \"evidence\": \"Co-IP, in vitro acetyltransferase assay, site-specific antibody, mutant rescue, and live imaging\",\n      \"pmids\": [\"35210604\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Deacetylase counteracting K771 not identified\", \"Temporal regulation across mitosis unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked NAT10 to R-loop and rRNA homeostasis through cooperation with DDX21 and RNase H1.\",\n      \"evidence\": \"BioID, co-IP, in vitro RNase H1 cleavage assay, and knockdown\",\n      \"pmids\": [\"35852833\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether stimulation of RNase H1 requires catalytic NAT10 not separated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated ac4C as a physiologic mRNA-stabilizing mark with tissue phenotypes, in cardiomyocyte apoptosis (HAAPIR/Tfec) and neutrophil pyroptosis (ULK1).\",\n      \"evidence\": \"RIP/acRIP, RNA decay assays, and genetic mouse models (HAAPIR deletion; neutrophil-specific NAT10)\",\n      \"pmids\": [\"35138696\", \"36068299\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Adaptor specifying these mRNA targets not defined\", \"Direct vs indirect effects not fully separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established PTM-driven control of NAT10 stability and activity via Khib at K823 (USP39 recruitment) feeding into ac4C-dependent NOTCH3 stabilization and metastasis.\",\n      \"evidence\": \"Khib proteome profiling, CRISPR screening, co-IP, mutagenesis, and mRNA stability assays\",\n      \"pmids\": [\"36882514\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Khib writer/eraser dynamics on NAT10 not fully mapped\", \"Breadth of downstream ac4C targets unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed NAT10 reprograms translation via tRNA ac4C, decreasing tRNA abundance and codon-biased translation when depleted, with EGFR as a key output.\",\n      \"evidence\": \"Ribosome profiling, tRNA ac4C profiling, and NAT10 depletion in ESCA models\",\n      \"pmids\": [\"37463108\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking ac4C to tRNA abundance unresolved\", \"Codon-decoding model not directly proven\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a maternal developmental requirement, with NAT10 ac4C on CCR4-NOT transcripts shaping the maternal transcriptome for oocyte maturation.\",\n      \"evidence\": \"Genetic knockout, poly(A) tail assays, transcriptomics, and ac4C-seq\",\n      \"pmids\": [\"37349316\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ac4C couples to deadenylation machinery mechanistically unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended ac4C to viral and immune RNAs, stabilizing KSHV PAN lncRNA and IFI16 mRNA to drive lytic reactivation and inflammasome activation.\",\n      \"evidence\": \"ac4C-seq, site mutagenesis in viral genome, knockdown, and RNA stability/virion assays\",\n      \"pmids\": [\"37816771\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity for viral vs host transcripts not fully defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected NAT10 to therapy resistance, stabilizing AHNAK mRNA for DNA repair and driving cisplatin resistance under NF-κB transcriptional control.\",\n      \"evidence\": \"acRIP-seq, RNA stability, ChIP, and in vitro/in vivo cisplatin assays\",\n      \"pmids\": [\"36939377\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct ac4C site contribution to AHNAK stability not mutationally proven\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Clarified that ac4C RNA, not NAT10 itself, is recruited to DNA lesions in a PARP-dependent manner, refining the model of NAT10's role at damage sites.\",\n      \"evidence\": \"UV microirradiation, immunofluorescence with PARP inhibition, and NAT10 depletion (negative result)\",\n      \"pmids\": [\"37322549\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Where ac4C marking of damage-associated RNA occurs is unresolved\", \"Apparent tension with later DSB-recruitment findings\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed NAT10 acts within phase-separated condensates to acetylate SRSF2 and reprogram splicing (YTHDF1), revealing a condensate-based mode of action.\",\n      \"evidence\": \"Phase separation assays, co-IP, in vitro acetylation, domain deletion, and patient organoids\",\n      \"pmids\": [\"39024555\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"IDR requirement for catalytic output not fully dissected\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved dual mechanisms of R-loop resolution: direct RecD helicase unwinding plus DDX21 K236/K573 acetylation that boosts DDX21 helicase activity.\",\n      \"evidence\": \"In vitro helicase assay, GST pull-down, MS, CRISPR KO, RNase H-controlled imaging, and 2KR/2KQ mutagenesis\",\n      \"pmids\": [\"39394182\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of helicase vs acetylase arms not quantified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified the adaptor logic of mRNA substrate selection, showing PCBP1/2 and TDP43 tether NAT10 and define ac4C site motifs.\",\n      \"evidence\": \"Co-IP, knockdown, acRIP-seq, and mass spectrometry\",\n      \"pmids\": [\"39556689\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Hierarchy among adaptors not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated lactylation by ATAT1 as an activating PTM that increases NAT10 RNA acetyltransferase output and tRNA ac4C to promote viral translation.\",\n      \"evidence\": \"Mass spectrometry, mutagenesis, tRNA ac4C and translation efficiency assays\",\n      \"pmids\": [\"38879723\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Lactylation site stoichiometry and reversibility unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified additional ubiquitination-stability regulators (LINC00623/USP39; RNPS1 vs ZSWIM6) and a new protein substrate NPM1 controlling PD-L1, broadening NAT10's regulatory and immune roles.\",\n      \"evidence\": \"RNA pulldown, co-IP, ubiquitination assays, MS, and functional readouts\",\n      \"pmids\": [\"35978332\", \"38246918\", \"38243170\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NPM1 acetylation site not mapped\", \"Interplay among competing E3/DUB regulators unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established broad physiologic ac4C-target programs: adipogenesis (KLF9), hepatic lipogenesis (Srebf1/Scap), cardiac homeostasis (Kmt5a, Mybbp1a), and fibrosis (TGFβ1 via PTBP1).\",\n      \"evidence\": \"acRIP-seq/RIP, ribosome profiling, conditional/cardiac KO and AAV knockdown, and rescue experiments\",\n      \"pmids\": [\"40123006\", \"39529018\", \"39392166\", \"38583415\", \"40817062\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific adaptor determinants not defined\", \"Overlapping vs distinct target sets across tissues unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided structural and chromatin-level mechanism at DSBs, showing PARP1-dependent NAT10 accumulation and ac4C on DNA:RNA hybrids promotes homologous recombination, with a 2.9 Å cryo-EM NAT10–remodelin structure.\",\n      \"evidence\": \"Laser micro-irradiation, ChIP, cryo-EM, hepatocyte-specific KO, and xenograft/PDX models\",\n      \"pmids\": [\"40132530\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation with prior report that NAT10 does not accumulate at lesions needed\", \"Hybrid-stabilizing mechanism at atomic detail incomplete\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined immune-cell and inflammatory roles, with MYC mRNA ac4C enabling T cell expansion and CCL2/CXCL1 ac4C driving renal inflammation.\",\n      \"evidence\": \"Conditional/T-cell-specific KO and KI, ribosome profiling, acRIP-seq, neutralizing antibodies, and infection/AKI models\",\n      \"pmids\": [\"40045031\", \"40261924\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals upregulating NAT10 during activation not fully defined\", \"Cell-type-specific target selection mechanism unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NAT10 integrates its competing RNA-acetylase, protein-acetylase, E3-ligase, and helicase activities into context-specific outputs, and how PTMs and adaptors jointly select substrates in vivo, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model coordinating ac4C vs protein acetylation\", \"Deacetylases/erasers for most NAT10 protein substrates unidentified\", \"Quantitative rules governing adaptor-directed ac4C site choice unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [5, 8, 12, 13, 16]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 3, 14, 16, 24]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [2, 3, 5, 16]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [15, 20, 28]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [1, 4, 6, 16]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [5, 12, 13, 15]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [12, 25, 29]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [6, 16, 18]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 21, 27, 29]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [14, 24]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PARP1\", \"MORC2\", \"DDX21\", \"SRSF2\", \"PCBP1\", \"TDP43\", \"USP39\", \"PTBP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}