{"gene":"AGO2","run_date":"2026-06-09T22:02:42","timeline":{"discoveries":[{"year":2006,"finding":"AGO2 (and AGO1) associate with promoter DNA in cells treated with antigene RNAs (agRNAs) complementary to transcription start sites, mediating transcriptional gene silencing in the nucleus; inhibiting AGO1 or AGO2 expression reverses both transcriptional and post-transcriptional silencing.","method":"Chromatin immunoprecipitation, RNAi knockdown of AGO1/AGO2, synthetic agRNA transfection","journal":"Nature structural & molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and knockdown rescue, single lab, two orthogonal methods","pmids":["16936728"],"is_preprint":false},{"year":2012,"finding":"AGO2 (miRNA-free form) is targeted for selective autophagy-mediated degradation via the receptor NDP52; autophagy is required for continued miRNA loading onto AGO2 and for miRNA homeostasis.","method":"Genetic knockdown of NDP52/autophagy components, biochemical fractionation, functional miRNA activity assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal loss-of-function with defined phenotype, multiple orthogonal methods, independently supported","pmids":["23143396"],"is_preprint":false},{"year":2014,"finding":"AGO2 forms a complex with Rad51, and this interaction is enhanced by ionizing radiation; AGO2 catalytic activity and small RNA-binding capability are required for Rad51 accumulation at DSB sites and for homologous recombination repair. DSB resection and RPA/Mre11 loading are unaffected by AGO2 depletion.","method":"Co-immunoprecipitation, ionizing radiation treatment, AGO2 knockdown/catalytic mutants, HR repair assays","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, catalytic mutant validation, multiple functional readouts in a single rigorous study","pmids":["24662483"],"is_preprint":false},{"year":2016,"finding":"saRNA-loaded AGO2 guides assembly of the RNA-induced transcriptional activation (RITA) complex (containing AGO2, RHA, and CTR9/PAF1 complex component) at target promoters, interacting with RNA polymerase II to stimulate transcription initiation and elongation, accompanied by histone H2B monoubiquitination.","method":"Co-immunoprecipitation, mass spectrometry, chromatin immunoprecipitation, RNA polymerase II interaction assays","journal":"Cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS and ChIP, single lab, multiple orthogonal methods","pmids":["26902284"],"is_preprint":false},{"year":2016,"finding":"KRAS-MEK signaling controls AGO2 localization to multivesicular endosomes (MVEs) and exosomal secretion; phosphorylation of AGO2 on serine 387 (downstream of MEK) prevents AGO2-MVE interactions and reduces AGO2 secretion into exosomes, thereby controlling miRNA levels in exosomes.","method":"Isogenic cell lines, MEK/Akt inhibitors, AGO2 phospho-mutant constructs, fractionation, exosome isolation","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — phospho-mutant validation, chemical inhibition, multiple orthogonal approaches in one study","pmids":["27117408"],"is_preprint":false},{"year":2016,"finding":"KRAS directly binds AGO2 via its N-terminal domain interacting with the Switch II region of KRAS, independent of nucleotide (GDP/GTP) state; AGO2 and KRAS co-sediment and co-localize at the endoplasmic reticulum; oncogenic KRAS attenuates AGO2-mediated gene silencing and requires AGO2 for maximal mutant KRAS expression and cellular transformation.","method":"Co-immunoprecipitation mass spectrometry, subcellular fractionation, co-localization, AGO2-/- cells, domain interaction mapping","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding mapped by domain, AGO2 knockout cells, multiple orthogonal methods","pmids":["26854235"],"is_preprint":false},{"year":2014,"finding":"SETDB1 (H3K9 methyltransferase) cooperates with AGO2 in agRNA-induced transcriptional gene silencing of the androgen receptor promoter; agRNA drives AGO2 recruitment to the promoter first, followed by SETDB1 recruitment; SETDB1 associates with SIN3-HDAC complex and EZH2, leading to trimethyl-H3K9 enrichment at the targeted promoter. DNA methylation is not significantly changed.","method":"Chromatin immunoprecipitation, knockdown of SETDB1/AGO2, co-immunoprecipitation, bisulfite sequencing","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and Co-IP, single lab, multiple chromatin marks assessed","pmids":["25183519"],"is_preprint":false},{"year":2013,"finding":"Hsp90 cochaperones p23 and FKBP4 physically interact with hAGO2 and are required for efficient RNAi; p23 and FKBP4 interact with hAGO2 before small RNA loading; RISC loading occurs in the cytoplasm rather than in RNA granules.","method":"Co-immunoprecipitation, RNAi knockdown of cochaperones, RISC loading assays, subcellular fractionation","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, functional knockdown, single lab","pmids":["23741051"],"is_preprint":false},{"year":2014,"finding":"MOV10 (RNA helicase) associates with FMRP and AGO2; MOV10 has a dual function—facilitating microRNA-mediated translation repression for some mRNAs and preventing AGO2 function on others; FMRP prevents MOV10-mediated microRNA suppression on a subset of mRNAs where FMRP and MOV10 bind in close proximity.","method":"Co-immunoprecipitation, RNA immunoprecipitation, iCLIP, AGO2 functional assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-IP and iCLIP, direct interaction assays, single lab","pmids":["25464849"],"is_preprint":false},{"year":2015,"finding":"eIF1A directly interacts with the MID domain of AGO2 (confirmed by NMR and biochemical assays); this interaction promotes AGO2 activities in RNAi and Dicer-independent miR-451 biogenesis; alanine mutation of eIF1A Lys56 impairs RNAi in human cells and zebrafish.","method":"NMR, co-immunoprecipitation, alanine mutagenesis, zebrafish rescue experiments, RNAi activity assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure plus mutagenesis plus in vivo rescue, multiple orthogonal methods","pmids":["26018492"],"is_preprint":false},{"year":2015,"finding":"Ago2 nuclear distribution is cell type- and tissue context-dependent; Ago2 localizes primarily as a nuclear protein in primary human keratinocytes and corresponding organotypic cultures, as well as in skin and cervical tissues, but not in continuous cell lines or larynx tissue.","method":"Immunofluorescence confocal microscopy, subcellular fractionation, tissue microarray immunohistochemistry","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — localization by microscopy and fractionation across multiple tissue types, single lab","pmids":["26699195"],"is_preprint":false},{"year":2018,"finding":"AGO2 is acetylated by p300/CBP at K720, K493, and K355; deacetylation is performed by HDAC7; acetylation at K493/K720 (but not K355) specifically enhances pre-miR-19b1 recruitment to form the miRNA precursor deposit complex (miPDC) and promotes miR-19b maturation via recognition of the UGUGUG motif in the terminal loop of pre-miR-19b1.","method":"Mass spectrometry, site-directed mutagenesis (K→R), co-immunoprecipitation, AGO2 acetylation assays with p300/CBP and HDAC7","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PTM identification by MS, mutagenesis validation, single lab","pmids":["30305728"],"is_preprint":false},{"year":2018,"finding":"Hepatic Ago2-mediated RNA silencing regulates miRNAs (miR-802, miR-103/107, miR-148a/152) and suppresses metabolic genes (Hnf1β, Cav1, Ampka1); liver-specific Ago2 deletion enhances mitochondrial oxidation and ATP consumption linked to mRNA translation, causing AMPK activation and improving obesity-associated metabolic dysfunction.","method":"Liver-specific Ago2 knockout mice, metabolic phenotyping, miRNA profiling, AMPK activity assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO with defined molecular and metabolic phenotypes, multiple orthogonal readouts","pmids":["30201950"],"is_preprint":false},{"year":2018,"finding":"AGO2 promotes telomerase activity and stimulates the association between TERT and TERC; AGO2 depletion results in shorter telomeres and reduced proliferation; AGO2 interacts with TERC and with a newly identified small RNA (terc-sRNA) arising from the H/ACA box of TERC; overexpression of terc-sRNA alone is sufficient to enhance telomerase activity.","method":"AGO2 gain- and loss-of-function, TERT/TERC interaction assays, telomere length measurement, RNA immunoprecipitation","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional knockdown/overexpression with multiple defined readouts, single lab","pmids":["30591524"],"is_preprint":false},{"year":2019,"finding":"FAM120A is an AGO2-interacting RNA-binding protein (identified by immunoprecipitation-MS) that binds poly(G) sequences in 3'-UTRs; FAM120A co-binding with AGO2 on target mRNAs prevents AGO2-mediated target degradation, sequestering miRNA-mediated repression.","method":"Co-immunoprecipitation mass spectrometry, iCLIP, luciferase reporter assays","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS, iCLIP, reporter validation, single lab","pmids":["31289130"],"is_preprint":false},{"year":2019,"finding":"High-throughput SELEX/binding assays reveal quantitative rules for AGO2 RISC target binding and cleavage: RISC tolerates insertions up to 7 nt opposite the central guide region; specific guide:target mismatches can enhance cleavage rate; quantitative in vitro models predict knockdown in cellular systems.","method":"High-throughput in vitro binding assay (RBNS), single-turnover cleavage assays, mouse AGO2 RISC reconstitution","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with systematic mutagenesis, validated in cellular system","pmids":["31324449"],"is_preprint":false},{"year":2020,"finding":"Thirteen heterozygous missense mutations in AGO2 found in patients with neurological developmental disorders each impair shRNA-mediated silencing; mechanistic consequences are either impaired RISC formation or increased AGO2-mRNA target binding associated with decreased phosphorylation of a C-terminal serine cluster involved in mRNA target release, increased dendritic P-body formation, and global transcriptome alterations.","method":"Patient-derived fibroblasts, shRNA silencing assays, AGO2 phosphorylation analysis, transcriptomics, P-body imaging","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple patient mutations, functional silencing assay, phosphorylation analysis, multiple orthogonal readouts","pmids":["33199684"],"is_preprint":false},{"year":2020,"finding":"Musashi-1 (MSI1) translocates to the cytoplasm under stress and forms a complex with AGO2; this MSI1/AGO2 complex stabilizes or destabilizes target mRNAs by binding to their 3'-UTR or coding sequence; disruption of the MSI1/AGO2 interaction (via C-terminal MSI1 overexpression) reduces stress-induced tumor progression.","method":"Co-immunoprecipitation, mass spectrometry, recombinant protein pulldown, RNA-IP, confocal microscopy, GBM xenograft","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified interaction confirmed by pulldown and RNA-IP, functional in vivo validation, single lab","pmids":["31903115"],"is_preprint":false},{"year":2021,"finding":"YTHDF1 interacts with AGO2 via its YTH domain; YTHDF1 promotes P-body formation through liquid-liquid phase separation and recruits AGO2 for miRNA-mediated mRNA degradation; deletion of YTHDF1 causes P-bodies to convert from liquid to gel/solid AGO2/RNA patches, delaying mRNA degradation.","method":"Co-immunoprecipitation, immunofluorescence, 4SU-TT-seq, CRISPR knockout, FRAP, in vitro phase separation","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping, FRAP, CRISPR KO, in vitro phase separation, single lab","pmids":["34821414"],"is_preprint":false},{"year":2021,"finding":"Trim71 represses AGO2 mRNA translation in mouse embryonic stem cells; blocking this repression leads to a post-transcriptional increase of mature let-7 miRNAs, resulting in let-7-dependent stemness defects and accelerated differentiation.","method":"Trim71 knockdown/overexpression, let-7 miRNA quantification, pluripotency assays, polysome profiling","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with defined molecular pathway, multiple phenotypic readouts, single lab","pmids":["33599613"],"is_preprint":false},{"year":2023,"finding":"AGO2 in mitochondria of cardiomyocytes activates translation of electron transport chain subunits by recruiting TUFM (mitochondrial translation elongation factor); malonylation of AGO2 reduces its import into mitochondria in diabetic cardiomyopathy; this malonylation is regulated by a cytoplasmic short isoform of SIRT3 acting as a demalonylase.","method":"Mitochondrial fractionation, Co-IP of AGO2 with TUFM, adeno-associated virus delivery, post-translational modification analysis, echocardiography","journal":"Circulation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, PTM analysis, AAV rescue in vivo, single lab","pmids":["38126189"],"is_preprint":false},{"year":2023,"finding":"In quiescent mouse splenocytes, AGO2 localizes almost exclusively to the nucleus; AGO2 nuclear accumulation is regulated by the Pi3K-AKT-mTOR pathway and is promoted when mTOR signaling is low (quiescence); in the nucleus, AGO2 binds young mobile transposons co-transcriptionally and represses their expression via its catalytic (slicer) domain.","method":"Subcellular fractionation, AGO2 localization imaging, mTOR pathway inhibition, AGO2 catalytic mutants, AGO2 ChIP/CLIP on transposons","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods, catalytic mutant validation, pathway epistasis, rigorous mechanistic dissection","pmids":["37985687"],"is_preprint":false},{"year":2024,"finding":"Nuclear AGO2 activates transcription of ANKRD1 (ankyrin repeat domain-containing protein 1) in failing hearts; nuclear (but not cytosolic) AGO2 overexpression exacerbates cardiac dysfunction; ANKRD1 nuclear import drives pathological MYH7 activation and cardiac remodeling; blocking ANKRD1 nuclear import (ivermectin or ANPep peptide) improves cardiac performance.","method":"AAV9-mediated AGO2 delivery, nuclear/cytosolic fractionation, TAC mouse model, chromatin assays, echocardiography","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — compartment-specific overexpression with defined downstream target, in vivo rescue, single lab","pmids":["38475992"],"is_preprint":false},{"year":2017,"finding":"AGO2 competes with IRF3 for binding to CBP/p300 in the nucleus; H5N1 viral infection reduces nuclear AGO2 distribution, relieving competition and promoting IRF3-CBP association and IFN-β transcription; AGO2 does not block IRF3 phosphorylation, nuclear translocation, or DNA binding.","method":"Co-immunoprecipitation, nuclear fractionation, H5N1 infection, IRF3-CBP interaction assays","journal":"Frontiers in cellular and infection microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP mapping specific interaction, infection model, negative controls for phosphorylation/translocation, single lab","pmids":["28589097"],"is_preprint":false},{"year":2014,"finding":"The AGO2 PAZ domain selectively binds ribonucleotides (except adenosine) and poorly recognizes deoxyribonucleotides; the PAZ domain has an inherent lack of binding to adenine nucleotides, explaining selective trimming of 3'-adenylated miRNAs; stronger PAZ domain binders correlate with higher in vivo gene silencing efficacy.","method":"Biophysical binding assays (isothermal titration calorimetry), nucleotide analogue modifications, in vivo gene silencing assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro binding characterization, single lab, no mutagenesis","pmids":["24788663"],"is_preprint":false},{"year":2007,"finding":"Disruption of Ago2 (Eif2c2) in mice causes embryonic lethality early in development after the implantation stage; Ago2 is not required for maintenance of DNA methylation at imprinted genes, centromeric repeats, or Xist, suggesting developmental defects are caused at the post-transcriptional (miRNA-protein complex) rather than transcriptional level.","method":"Ago2 gene knockout mice, bisulfite sequencing for DNA methylation, developmental phenotyping","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined phenotype and mechanistic exclusion of DNA methylation pathway, replicated in context of prior reports","pmids":["17418524"],"is_preprint":false},{"year":2018,"finding":"Antagonistic and cooperative interactions between AGO2 and Pumilio proteins (PUM1/PUM2) on 3'-UTRs regulate mRNA targets; PUM binding near AGO2 sites can counteract miRNA-guided repression (antagonism) or cooperate to enhance AGO2 occupancy; this interaction is not explained by steric hindrance, suggesting an allosteric or indirect mechanism.","method":"CLIP-seq (transcriptome-wide AGO2 binding upon PUM knockdown), luciferase reporter assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CLIP-seq and reporter assay validation, single lab","pmids":["30333515"],"is_preprint":false}],"current_model":"AGO2 is the catalytic core of the RNA-induced silencing complex (RISC), performing endonucleolytic cleavage of target mRNAs guided by loaded small RNAs (miRNAs/siRNAs); its activity is regulated by multiple post-translational modifications (phosphorylation at S387 by MEK, acetylation by p300/CBP/HDAC7, malonylation by cytoplasmic SIRT3), by chaperone-mediated loading (Hsp90/p23/FKBP4), and by autophagy-dependent degradation via NDP52; AGO2 subcellular localization (cytoplasm vs. nucleus vs. mitochondria) is dynamically controlled by the Pi3K-AKT-mTOR pathway and determines distinct functional outputs—cytoplasmic RISC-mediated mRNA silencing, nuclear transcriptional regulation and transposon repression (via catalytic slicer activity), and mitochondrial translation activation via TUFM recruitment; AGO2 also engages KRAS at the ER, promotes telomerase activity through TERT-TERC association, facilitates homologous recombination by recruiting Rad51 to double-strand breaks, and participates in transcriptional activation via the RITA complex at promoters."},"narrative":{"mechanistic_narrative":"AGO2 is the catalytic core of RNA-induced silencing, using loaded small RNAs to direct sequence-specific recognition and endonucleolytic slicing of target mRNAs, with quantitative target-binding and cleavage rules dictated by guide:target complementarity and tolerance for central-region insertions [PMID:31324449], and with the PAZ domain governing selective recognition of 3' nucleotides [PMID:24788663]. Productive RISC assembly requires cytoplasmic chaperone-assisted loading: the Hsp90 cochaperones p23 and FKBP4 engage AGO2 prior to small-RNA loading [PMID:23741051], eIF1A binds the MID domain to promote RNAi and Dicer-independent miR-451 biogenesis [PMID:26018492], and autophagy via the receptor NDP52 selectively degrades miRNA-free AGO2 to sustain miRNA loading and homeostasis [PMID:23143396]. AGO2 silencing activity is further tuned by post-translational modification and by RNA-binding cofactors that redirect target fate—p300/CBP acetylation and HDAC7 deacetylation control pre-miR-19b maturation [PMID:30305728], while FAM120A, MOV10/FMRP, Pumilio proteins, and Musashi-1 modulate or override miRNA-guided repression on subsets of transcripts [PMID:31289130, PMID:25464849, PMID:30333515, PMID:31903115], and YTHDF1 recruits AGO2 into phase-separated P-bodies for mRNA degradation [PMID:34821414]. Beyond cytoplasmic silencing, AGO2 localization is dynamically partitioned by the PI3K-AKT-mTOR pathway: under low mTOR signaling it accumulates in the nucleus where its slicer activity represses young transposons co-transcriptionally [PMID:37985687], and it also participates in transcriptional gene silencing at promoters together with SETDB1 [PMID:16936728, PMID:25183519], saRNA-guided transcriptional activation through the RITA complex and RNA polymerase II [PMID:26902284], homologous-recombination repair by recruiting Rad51 to double-strand breaks [PMID:24662483], telomerase stimulation via TERT-TERC association [PMID:30591524], and mitochondrial translation activation of electron-transport-chain subunits through TUFM recruitment [PMID:38126189]. KRAS-MEK signaling links AGO2 to oncogenic output by directly binding AGO2 at the ER and through S387 phosphorylation that controls AGO2 partitioning into multivesicular endosomes and exosomal miRNA export [PMID:26854235, PMID:27117408]. AGO2 is essential for development, with knockout causing post-implantation embryonic lethality attributable to post-transcriptional rather than DNA-methylation defects [PMID:17418524], and heterozygous missense mutations that impair silencing or target release cause a neurological developmental disorder [PMID:33199684].","teleology":[{"year":2006,"claim":"Established that AGO2 acts beyond cytoplasmic mRNA cleavage by associating with promoter DNA to mediate transcriptional gene silencing, raising the question of how a slicer functions in the nucleus.","evidence":"ChIP and AGO1/AGO2 knockdown rescue with synthetic agRNAs in cells","pmids":["16936728"],"confidence":"Medium","gaps":["Did not define how AGO2 is recruited to chromatin","Did not establish the chromatin effectors downstream of promoter-bound AGO2"]},{"year":2007,"claim":"Determined that AGO2 is essential for early mammalian development and that its requirement is post-transcriptional, excluding a DNA-methylation maintenance role.","evidence":"Ago2 knockout mice with developmental phenotyping and bisulfite sequencing","pmids":["17418524"],"confidence":"High","gaps":["Did not identify the specific miRNA targets driving lethality","Did not address tissue-specific functions masked by early lethality"]},{"year":2013,"claim":"Defined how RISC is assembled, showing Hsp90 cochaperones p23 and FKBP4 engage AGO2 before small-RNA loading in the cytoplasm.","evidence":"Reciprocal Co-IP, cochaperone knockdown, RISC loading assays, fractionation","pmids":["23741051"],"confidence":"Medium","gaps":["Did not resolve the structural transitions during loading","Single-lab study without independent confirmation"]},{"year":2012,"claim":"Linked AGO2 turnover to miRNA homeostasis by showing miRNA-free AGO2 is cleared by NDP52-mediated selective autophagy, which is required for continued loading.","evidence":"Knockdown of NDP52/autophagy components, fractionation, miRNA activity assays","pmids":["23143396"],"confidence":"High","gaps":["Did not define how NDP52 distinguishes loaded from unloaded AGO2","Did not quantify the kinetics of the loading/degradation cycle"]},{"year":2014,"claim":"Expanded AGO2's nuclear roles to genome maintenance and chromatin silencing, demonstrating Rad51 recruitment for HR repair and cooperation with SETDB1 for H3K9-methylation-based transcriptional silencing.","evidence":"Co-IP, ionizing radiation, catalytic mutants, HR/ChIP assays (two studies)","pmids":["24662483","25183519"],"confidence":"High","gaps":["Did not identify the small RNAs guiding AGO2 to DSBs or promoters","Did not establish whether slicing of a target is required at break sites"]},{"year":2014,"claim":"Characterized PAZ-domain nucleotide selectivity, explaining selective 3'-end trimming and correlating binding strength with silencing efficacy.","evidence":"ITC binding assays with nucleotide analogues and in vivo silencing assays","pmids":["24788663"],"confidence":"Medium","gaps":["No mutagenesis to confirm contact residues","Did not connect end recognition to RISC turnover in cells"]},{"year":2015,"claim":"Resolved direct cofactor control of catalysis by mapping eIF1A binding to the MID domain and showing it promotes RNAi and Dicer-independent miR-451 biogenesis.","evidence":"NMR, Co-IP, alanine mutagenesis, zebrafish rescue, RNAi assays","pmids":["26018492"],"confidence":"High","gaps":["Did not define how eIF1A binding couples to slicing chemistry","Scope of eIF1A-dependent miRNAs not delineated"]},{"year":2015,"claim":"Showed that AGO2 nuclear versus cytoplasmic distribution is cell-type and tissue dependent, reframing its functional output as compartment-determined.","evidence":"Immunofluorescence, fractionation, tissue microarray IHC across tissues","pmids":["26699195"],"confidence":"Medium","gaps":["Did not identify the signal driving tissue-specific nuclear localization","Correlative localization without functional consequence"]},{"year":2016,"claim":"Connected AGO2 to oncogenic KRAS signaling, showing direct ER binding to KRAS and MEK-driven S387 phosphorylation that governs exosomal miRNA export.","evidence":"Co-IP/MS, domain mapping, AGO2-/- cells, phospho-mutants, exosome isolation (two studies)","pmids":["26854235","27117408"],"confidence":"High","gaps":["Did not establish how KRAS binding mechanistically attenuates silencing","Did not define the kinase acting directly on S387 versus pathway intermediates"]},{"year":2016,"claim":"Established AGO2 as a transcriptional activator through saRNA-guided assembly of the RITA complex with RNA polymerase II.","evidence":"Co-IP/MS, ChIP, RNA Pol II interaction assays","pmids":["26902284"],"confidence":"Medium","gaps":["Did not resolve how saRNA selects activating versus silencing outcomes","Single-lab study without independent confirmation"]},{"year":2018,"claim":"Identified PTM and RNA-binding cofactors that tune AGO2 fate, including acetylation-controlled pre-miR-19b maturation and Pumilio antagonism/cooperation on shared 3'-UTRs.","evidence":"MS, K→R mutagenesis, Co-IP, CLIP-seq, reporter assays (two studies)","pmids":["30305728","30333515"],"confidence":"Medium","gaps":["Mechanism of Pumilio-AGO2 allostery undefined","Did not establish in vivo relevance of individual acetylation sites"]},{"year":2018,"claim":"Revealed physiological consequences of AGO2 silencing in metabolism and extended its activity to non-canonical targets, with hepatic Ago2 suppressing metabolic genes and AGO2 stimulating telomerase via TERT-TERC.","evidence":"Liver-specific Ago2 knockout, metabolic phenotyping, miRNA profiling; telomerase and telomere-length assays (two studies)","pmids":["30201950","30591524"],"confidence":"High","gaps":["Did not establish whether telomerase stimulation requires slicer activity","Did not connect metabolic and telomere roles mechanistically"]},{"year":2019,"claim":"Defined quantitative rules for RISC target recognition and cleavage and identified FAM120A as a cofactor that protects mRNAs from AGO2 degradation.","evidence":"High-throughput in vitro binding/cleavage with reconstituted RISC; IP-MS, iCLIP, reporter assays (two studies)","pmids":["31324449","31289130"],"confidence":"High","gaps":["In vitro rules not exhaustively validated across endogenous transcriptomes","FAM120A protective mechanism at the RISC level unresolved"]},{"year":2020,"claim":"Linked AGO2 dysfunction to human disease by showing heterozygous missense mutations impair silencing or target release and cause a neurological developmental disorder.","evidence":"Patient fibroblasts, shRNA silencing assays, phosphorylation analysis, transcriptomics, P-body imaging","pmids":["33199684"],"confidence":"High","gaps":["Did not establish the neuronal targets driving pathology","Did not define the kinase controlling the C-terminal serine cluster"]},{"year":2021,"claim":"Connected AGO2 to phase separation and translational control, showing YTHDF1 recruits AGO2 into liquid P-bodies for mRNA degradation and Trim71 represses AGO2 translation to control let-7 and stemness.","evidence":"Co-IP, FRAP, CRISPR KO, in vitro phase separation; polysome profiling and pluripotency assays (two studies)","pmids":["34821414","33599613"],"confidence":"Medium","gaps":["Did not establish whether phase state is causal versus correlative for degradation","Single-lab studies for each mechanism"]},{"year":2023,"claim":"Resolved how mTOR signaling partitions AGO2 to the nucleus for slicer-dependent transposon repression and identified mitochondrial AGO2 activating ETC translation via TUFM.","evidence":"Fractionation, mTOR inhibition, catalytic mutants, ChIP/CLIP on transposons; mitochondrial Co-IP with TUFM, PTM analysis, AAV rescue (two studies)","pmids":["37985687","38126189"],"confidence":"High","gaps":["Did not define the import machinery delivering AGO2 to mitochondria","Did not establish whether mitochondrial AGO2 uses small RNA guides"]},{"year":2024,"claim":"Demonstrated a compartment-specific pathological output, with nuclear AGO2 activating ANKRD1 transcription to drive cardiac dysfunction.","evidence":"AAV9 compartment-targeted AGO2, fractionation, TAC mouse model, chromatin assays, echocardiography","pmids":["38475992"],"confidence":"Medium","gaps":["Did not define the guide RNA or mechanism of ANKRD1 promoter activation","Single-lab in vivo study"]},{"year":null,"claim":"How AGO2 is selectively trafficked among cytoplasm, nucleus, ER, multivesicular endosomes, and mitochondria, and how each localization couples to a distinct molecular activity, remains unresolved.","evidence":"No single study integrates the localization-determining signals with compartment-specific functional outputs","pmids":[],"confidence":"Medium","gaps":["Import/export machinery for nuclear and mitochondrial AGO2 unknown","Whether non-cytoplasmic functions all require slicer activity and small-RNA guides is unresolved","Integration of PTM code (phosphorylation, acetylation, malonylation) with localization decisions is incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[15,2,21,24]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[13,14,24,15]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,0,22]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7,21]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,10,21,23]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[20]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[5]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,11,15,7]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,3,6,22]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,4]}],"complexes":["RISC","RITA complex"],"partners":["KRAS","RAD51","TUFM","FAM120A","MOV10","MSI1","YTHDF1","EIF1A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UKV8","full_name":"Protein argonaute-2","aliases":["Argonaute RISC catalytic component 2","Eukaryotic translation initiation factor 2C 2","eIF-2C 2","eIF2C 2","PAZ Piwi domain protein","PPD","Protein slicer"],"length_aa":859,"mass_kda":97.2,"function":"Required for RNA-mediated gene silencing (RNAi) by the RNA-induced silencing complex (RISC). The 'minimal RISC' appears to include AGO2 bound to a short guide RNA such as a microRNA (miRNA) or short interfering RNA (siRNA). These guide RNAs direct RISC to complementary mRNAs that are targets for RISC-mediated gene silencing. The precise mechanism of gene silencing depends on the degree of complementarity between the miRNA or siRNA and its target. Binding of RISC to a perfectly complementary mRNA generally results in silencing due to endonucleolytic cleavage of the mRNA specifically by AGO2. Binding of RISC to a partially complementary mRNA results in silencing through inhibition of translation, and this is independent of endonuclease activity. May inhibit translation initiation by binding to the 7-methylguanosine cap, thereby preventing the recruitment of the translation initiation factor eIF4-E. May also inhibit translation initiation via interaction with EIF6, which itself binds to the 60S ribosomal subunit and prevents its association with the 40S ribosomal subunit. The inhibition of translational initiation leads to the accumulation of the affected mRNA in cytoplasmic processing bodies (P-bodies), where mRNA degradation may subsequently occur. In some cases RISC-mediated translational repression is also observed for miRNAs that perfectly match the 3' untranslated region (3'-UTR). Can also up-regulate the translation of specific mRNAs under certain growth conditions. Binds to the AU element of the 3'-UTR of the TNF mRNA and up-regulates translation under conditions of serum starvation. Also required for transcriptional gene silencing (TGS), in which short RNAs known as antigene RNAs or agRNAs direct the transcriptional repression of complementary promoter regions (Microbial infection) Upon Sars-CoV-2 infection, associates with viral miRNA-like small RNA, CoV2-miR-O7a, and may repress mRNAs, such as BATF2, to evade the IFN response","subcellular_location":"Cytoplasm, P-body; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9UKV8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/AGO2","classification":"Not Classified","n_dependent_lines":25,"n_total_lines":1208,"dependency_fraction":0.020695364238410598},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000123908","cell_line_id":"CID001213","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"big_aggregates","grade":2}],"interactors":[{"gene":"TNRC6B","stoichiometry":10.0},{"gene":"AGO1","stoichiometry":4.0},{"gene":"TNRC6A","stoichiometry":4.0},{"gene":"COPS6","stoichiometry":0.2},{"gene":"FKBP5","stoichiometry":0.2},{"gene":"TNRC6C","stoichiometry":0.2},{"gene":"AGO3","stoichiometry":0.2},{"gene":"CNDP2","stoichiometry":0.2},{"gene":"NELFA","stoichiometry":0.2},{"gene":"MIF","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001213","total_profiled":1310},"omim":[{"mim_id":"621249","title":"ARB2 COTRANSCRIPTIONAL REGULATOR A; ARB2A","url":"https://www.omim.org/entry/621249"},{"mim_id":"619458","title":"METHYL-CpG-BINDING DOMAIN PROTEIN 6; MBD6","url":"https://www.omim.org/entry/619458"},{"mim_id":"619335","title":"GRANULE-ASSOCIATED RAC AND RHOG EFFECTOR 1; GARRE1","url":"https://www.omim.org/entry/619335"},{"mim_id":"619149","title":"LESSEL-KREIENKAMP SYNDROME; LESKRES","url":"https://www.omim.org/entry/619149"},{"mim_id":"616972","title":"MICRO RNA 490; MIR490","url":"https://www.omim.org/entry/616972"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytoplasmic bodies","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/AGO2"},"hgnc":{"alias_symbol":["hAGO2","Q10","LINC00980"],"prev_symbol":["EIF2C2","CASC7"]},"alphafold":{"accession":"Q9UKV8","domains":[{"cath_id":"-","chopping":"44-225_365-400","consensus_level":"medium","plddt":93.5127,"start":44,"end":400},{"cath_id":"2.170.260.10","chopping":"228-347","consensus_level":"medium","plddt":93.1901,"start":228,"end":347},{"cath_id":"3.40.50.2300","chopping":"445-570","consensus_level":"high","plddt":97.078,"start":445,"end":570},{"cath_id":"3.30.420.10","chopping":"576-819_835-851","consensus_level":"medium","plddt":95.5857,"start":576,"end":851}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKV8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKV8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKV8-F1-predicted_aligned_error_v6.png","plddt_mean":92.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=AGO2","jax_strain_url":"https://www.jax.org/strain/search?query=AGO2"},"sequence":{"accession":"Q9UKV8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UKV8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UKV8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKV8"}},"corpus_meta":[{"pmid":"11771674","id":"PMC_11771674","title":"Biochemical functions of coenzyme Q10.","date":"2001","source":"Journal of the American College of Nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/11771674","citation_count":615,"is_preprint":false},{"pmid":"27117408","id":"PMC_27117408","title":"KRAS-MEK Signaling Controls Ago2 Sorting into Exosomes.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27117408","citation_count":362,"is_preprint":false},{"pmid":"26111777","id":"PMC_26111777","title":"Coenzyme Q10 restores oocyte mitochondrial function and fertility during reproductive aging.","date":"2015","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/26111777","citation_count":348,"is_preprint":false},{"pmid":"17914161","id":"PMC_17914161","title":"Bioenergetic and antioxidant properties of coenzyme Q10: recent developments.","date":"2007","source":"Molecular biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/17914161","citation_count":298,"is_preprint":false},{"pmid":"16936728","id":"PMC_16936728","title":"Involvement of AGO1 and AGO2 in mammalian transcriptional silencing.","date":"2006","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16936728","citation_count":273,"is_preprint":false},{"pmid":"29459830","id":"PMC_29459830","title":"Coenzyme Q10 Supplementation in Aging and Disease.","date":"2018","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/29459830","citation_count":257,"is_preprint":false},{"pmid":"30341421","id":"PMC_30341421","title":"Circular RNA circAGO2 drives cancer progression through facilitating HuR-repressed functions of AGO2-miRNA complexes.","date":"2018","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/30341421","citation_count":250,"is_preprint":false},{"pmid":"23143396","id":"PMC_23143396","title":"Selective autophagy degrades DICER and AGO2 and regulates miRNA activity.","date":"2012","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/23143396","citation_count":213,"is_preprint":false},{"pmid":"24662483","id":"PMC_24662483","title":"Ago2 facilitates Rad51 recruitment and DNA double-strand break repair by homologous recombination.","date":"2014","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/24662483","citation_count":161,"is_preprint":false},{"pmid":"20385818","id":"PMC_20385818","title":"High-risk myeloma is associated with global elevation of miRNAs and overexpression of EIF2C2/AGO2.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/20385818","citation_count":148,"is_preprint":false},{"pmid":"24389208","id":"PMC_24389208","title":"Clinical applications of coenzyme Q10.","date":"2014","source":"Frontiers in bioscience (Landmark edition)","url":"https://pubmed.ncbi.nlm.nih.gov/24389208","citation_count":137,"is_preprint":false},{"pmid":"32933108","id":"PMC_32933108","title":"Disorders of Human Coenzyme Q10 Metabolism: An Overview.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32933108","citation_count":135,"is_preprint":false},{"pmid":"17482884","id":"PMC_17482884","title":"Coenzyme Q10 and statins: biochemical and clinical implications.","date":"2007","source":"Mitochondrion","url":"https://pubmed.ncbi.nlm.nih.gov/17482884","citation_count":134,"is_preprint":false},{"pmid":"31324449","id":"PMC_31324449","title":"High-Throughput Analysis Reveals Rules for Target RNA Binding and Cleavage by AGO2.","date":"2019","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/31324449","citation_count":129,"is_preprint":false},{"pmid":"11351130","id":"PMC_11351130","title":"Ubiquinone (coenzyme q10) and mitochondria in oxidative stress of parkinson's disease.","date":"2001","source":"Biological signals and receptors","url":"https://pubmed.ncbi.nlm.nih.gov/11351130","citation_count":124,"is_preprint":false},{"pmid":"24495877","id":"PMC_24495877","title":"Coenzyme Q10 as a therapy for mitochondrial disease.","date":"2014","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/24495877","citation_count":123,"is_preprint":false},{"pmid":"17094036","id":"PMC_17094036","title":"Human coenzyme Q10 deficiency.","date":"2006","source":"Neurochemical research","url":"https://pubmed.ncbi.nlm.nih.gov/17094036","citation_count":121,"is_preprint":false},{"pmid":"17418524","id":"PMC_17418524","title":"One Argonaute family member, Eif2c2 (Ago2), is essential for development and appears not to be involved in DNA methylation.","date":"2007","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/17418524","citation_count":120,"is_preprint":false},{"pmid":"26902284","id":"PMC_26902284","title":"saRNA-guided Ago2 targets the RITA complex to promoters to stimulate transcription.","date":"2016","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/26902284","citation_count":116,"is_preprint":false},{"pmid":"25126052","id":"PMC_25126052","title":"Coenzyme q10 therapy.","date":"2014","source":"Molecular syndromology","url":"https://pubmed.ncbi.nlm.nih.gov/25126052","citation_count":112,"is_preprint":false},{"pmid":"29980630","id":"PMC_29980630","title":"Coenzyme Q10 deficiencies: pathways in yeast and humans.","date":"2018","source":"Essays in biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29980630","citation_count":108,"is_preprint":false},{"pmid":"15256611","id":"PMC_15256611","title":"Coenzyme Q10 and diabetic endotheliopathy: oxidative stress and the 'recoupling hypothesis'.","date":"2004","source":"QJM : monthly journal of the Association of Physicians","url":"https://pubmed.ncbi.nlm.nih.gov/15256611","citation_count":102,"is_preprint":false},{"pmid":"15911925","id":"PMC_15911925","title":"Coenzyme q10 for prevention of anthracycline-induced cardiotoxicity.","date":"2005","source":"Integrative cancer therapies","url":"https://pubmed.ncbi.nlm.nih.gov/15911925","citation_count":94,"is_preprint":false},{"pmid":"25464849","id":"PMC_25464849","title":"MOV10 and FMRP regulate AGO2 association with microRNA recognition elements.","date":"2014","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/25464849","citation_count":94,"is_preprint":false},{"pmid":"33810539","id":"PMC_33810539","title":"Metabolic Targets of Coenzyme Q10 in Mitochondria.","date":"2021","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/33810539","citation_count":92,"is_preprint":false},{"pmid":"30030365","id":"PMC_30030365","title":"Clinical syndromes associated with Coenzyme Q10 deficiency.","date":"2018","source":"Essays in biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30030365","citation_count":83,"is_preprint":false},{"pmid":"34821414","id":"PMC_34821414","title":"YTHDF1 promotes mRNA degradation via YTHDF1-AGO2 interaction and phase separation.","date":"2021","source":"Cell proliferation","url":"https://pubmed.ncbi.nlm.nih.gov/34821414","citation_count":83,"is_preprint":false},{"pmid":"19531029","id":"PMC_19531029","title":"Biosynthesis and bioproduction of coenzyme Q10 by yeasts and other organisms.","date":"2009","source":"Biotechnology and applied biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19531029","citation_count":82,"is_preprint":false},{"pmid":"32331285","id":"PMC_32331285","title":"Coenzyme Q10: Clinical Applications in Cardiovascular Diseases.","date":"2020","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/32331285","citation_count":78,"is_preprint":false},{"pmid":"23859348","id":"PMC_23859348","title":"Co-enzyme Q10 and idebenone use in Friedreich's ataxia.","date":"2013","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23859348","citation_count":76,"is_preprint":false},{"pmid":"26507454","id":"PMC_26507454","title":"miR-346 and miR-138 competitively regulate hTERT in GRSF1- and AGO2-dependent manners, respectively.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26507454","citation_count":74,"is_preprint":false},{"pmid":"17192765","id":"PMC_17192765","title":"Coenzyme Q10: a review of its promise as a neuroprotectant.","date":"2007","source":"CNS spectrums","url":"https://pubmed.ncbi.nlm.nih.gov/17192765","citation_count":73,"is_preprint":false},{"pmid":"33199684","id":"PMC_33199684","title":"Germline AGO2 mutations impair RNA interference and human neurological development.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33199684","citation_count":70,"is_preprint":false},{"pmid":"21769619","id":"PMC_21769619","title":"Expression of the ribonucleases Drosha, Dicer, and Ago2 in colorectal carcinomas.","date":"2011","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/21769619","citation_count":68,"is_preprint":false},{"pmid":"34129891","id":"PMC_34129891","title":"Coenzyme Q10 supplementation - In ageing and disease.","date":"2021","source":"Mechanisms of ageing and development","url":"https://pubmed.ncbi.nlm.nih.gov/34129891","citation_count":60,"is_preprint":false},{"pmid":"31540029","id":"PMC_31540029","title":"The Paradox of Coenzyme Q10 in Aging.","date":"2019","source":"Nutrients","url":"https://pubmed.ncbi.nlm.nih.gov/31540029","citation_count":60,"is_preprint":false},{"pmid":"34205085","id":"PMC_34205085","title":"Coenzyme Q10 and Cardiovascular Diseases.","date":"2021","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/34205085","citation_count":58,"is_preprint":false},{"pmid":"32164444","id":"PMC_32164444","title":"AGO2 and its partners: a silencing complex, a chromatin modulator, and new features.","date":"2020","source":"Critical reviews in biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/32164444","citation_count":58,"is_preprint":false},{"pmid":"34067632","id":"PMC_34067632","title":"Coenzyme Q10: Clinical Applications beyond Cardiovascular Diseases.","date":"2021","source":"Nutrients","url":"https://pubmed.ncbi.nlm.nih.gov/34067632","citation_count":58,"is_preprint":false},{"pmid":"34064686","id":"PMC_34064686","title":"Coenzyme Q10 and Immune Function: An Overview.","date":"2021","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/34064686","citation_count":57,"is_preprint":false},{"pmid":"30305728","id":"PMC_30305728","title":"Acetylation of AGO2 promotes cancer progression by increasing oncogenic miR-19b biogenesis.","date":"2018","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/30305728","citation_count":56,"is_preprint":false},{"pmid":"28253886","id":"PMC_28253886","title":"Cellular factories for coenzyme Q10 production.","date":"2017","source":"Microbial cell factories","url":"https://pubmed.ncbi.nlm.nih.gov/28253886","citation_count":54,"is_preprint":false},{"pmid":"22174881","id":"PMC_22174881","title":"AGO1 and AGO2 act redundantly in miR408-mediated Plantacyanin regulation.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22174881","citation_count":51,"is_preprint":false},{"pmid":"31412983","id":"PMC_31412983","title":"LncRNA-CASC7 enhances corticosteroid sensitivity via inhibiting the PI3K/AKT signaling pathway by targeting miR-21 in severe asthma.","date":"2019","source":"Pulmonology","url":"https://pubmed.ncbi.nlm.nih.gov/31412983","citation_count":49,"is_preprint":false},{"pmid":"28762311","id":"PMC_28762311","title":"Therapeutic Potential of Co-enzyme Q10 in Retinal Diseases.","date":"2017","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28762311","citation_count":45,"is_preprint":false},{"pmid":"29571256","id":"PMC_29571256","title":"Hydrogen sulfide upregulated lncRNA CasC7 to reduce neuronal cell apoptosis in spinal cord ischemia-reperfusion injury rat.","date":"2018","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/29571256","citation_count":45,"is_preprint":false},{"pmid":"18957876","id":"PMC_18957876","title":"Effects of ubiquinone (coenzyme Q10) on myopathy in statin users.","date":"2008","source":"Current opinion in lipidology","url":"https://pubmed.ncbi.nlm.nih.gov/18957876","citation_count":45,"is_preprint":false},{"pmid":"33231565","id":"PMC_33231565","title":"miRNA-122-5p stimulates the proliferation and DNA synthesis and inhibits the early apoptosis of human spermatogonial stem cells by targeting CBL and competing with lncRNA CASC7.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/33231565","citation_count":43,"is_preprint":false},{"pmid":"7752819","id":"PMC_7752819","title":"Coenzyme Q10, plasma membrane oxidase and growth control.","date":"1994","source":"Molecular aspects of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/7752819","citation_count":43,"is_preprint":false},{"pmid":"12011263","id":"PMC_12011263","title":"Translocation der(13;21)(q10;q10) in skeletal and extraskeletal mesenchymal chondrosarcoma.","date":"2002","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/12011263","citation_count":43,"is_preprint":false},{"pmid":"35199552","id":"PMC_35199552","title":"Coenzyme Q10 effects in neurological diseases.","date":"2021","source":"Physiological research","url":"https://pubmed.ncbi.nlm.nih.gov/35199552","citation_count":42,"is_preprint":false},{"pmid":"25183519","id":"PMC_25183519","title":"AGO2 and SETDB1 cooperate in promoter-targeted transcriptional silencing of the androgen receptor gene.","date":"2014","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/25183519","citation_count":42,"is_preprint":false},{"pmid":"28273876","id":"PMC_28273876","title":"Biochemical Assessment of Coenzyme Q10 Deficiency.","date":"2017","source":"Journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28273876","citation_count":40,"is_preprint":false},{"pmid":"24169347","id":"PMC_24169347","title":"Strong reduction of AGO2 expression in melanoma and cellular consequences.","date":"2013","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/24169347","citation_count":40,"is_preprint":false},{"pmid":"30661904","id":"PMC_30661904","title":"LncRNA CASC7 inhibits the progression of glioma via regulating Wnt/β-catenin signaling pathway.","date":"2019","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/30661904","citation_count":39,"is_preprint":false},{"pmid":"37627647","id":"PMC_37627647","title":"Primary Coenzyme Q10 Deficiency: An Update.","date":"2023","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/37627647","citation_count":39,"is_preprint":false},{"pmid":"28954383","id":"PMC_28954383","title":"Long non-coding RNA CASC7 inhibits the proliferation and migration of colon cancer cells via inhibiting microRNA-21.","date":"2017","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/28954383","citation_count":38,"is_preprint":false},{"pmid":"26854235","id":"PMC_26854235","title":"KRAS Engages AGO2 to Enhance Cellular Transformation.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/26854235","citation_count":38,"is_preprint":false},{"pmid":"38126189","id":"PMC_38126189","title":"AGO2 Protects Against Diabetic Cardiomyopathy by Activating Mitochondrial Gene Translation.","date":"2023","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/38126189","citation_count":36,"is_preprint":false},{"pmid":"26699195","id":"PMC_26699195","title":"Cell Type- and Tissue Context-dependent Nuclear Distribution of Human Ago2.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26699195","citation_count":34,"is_preprint":false},{"pmid":"11976213","id":"PMC_11976213","title":"Human aging and global function of coenzyme Q10.","date":"2002","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/11976213","citation_count":34,"is_preprint":false},{"pmid":"15734664","id":"PMC_15734664","title":"Statins, cholesterol, Co-enzyme Q10, and Parkinson's disease.","date":"2005","source":"Parkinsonism & related disorders","url":"https://pubmed.ncbi.nlm.nih.gov/15734664","citation_count":34,"is_preprint":false},{"pmid":"33846300","id":"PMC_33846300","title":"Impaired AGO2/miR-185-3p/NRP1 axis promotes colorectal cancer metastasis.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33846300","citation_count":33,"is_preprint":false},{"pmid":"26018492","id":"PMC_26018492","title":"eIF1A augments Ago2-mediated Dicer-independent miRNA biogenesis and RNA interference.","date":"2015","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/26018492","citation_count":33,"is_preprint":false},{"pmid":"30201950","id":"PMC_30201950","title":"Hepatic Ago2-mediated RNA silencing controls energy metabolism linked to AMPK activation and obesity-associated pathophysiology.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30201950","citation_count":33,"is_preprint":false},{"pmid":"23736673","id":"PMC_23736673","title":"Primary coenzyme Q10 (CoQ 10) deficiencies and related nephropathies.","date":"2013","source":"Pediatric nephrology (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/23736673","citation_count":32,"is_preprint":false},{"pmid":"23741051","id":"PMC_23741051","title":"Hsp90 cochaperones p23 and FKBP4 physically interact with hAgo2 and activate RNA interference-mediated silencing in mammalian cells.","date":"2013","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/23741051","citation_count":31,"is_preprint":false},{"pmid":"31324173","id":"PMC_31324173","title":"Quantifying Argonaute 2 (Ago2) expression to stratify breast cancer.","date":"2019","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31324173","citation_count":31,"is_preprint":false},{"pmid":"38783100","id":"PMC_38783100","title":"tRF-33-P4R8YP9LON4VDP inhibits gastric cancer progression via modulating STAT3 signaling pathway in an AGO2-dependent manner.","date":"2024","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/38783100","citation_count":31,"is_preprint":false},{"pmid":"30333515","id":"PMC_30333515","title":"Antagonistic and cooperative AGO2-PUM interactions in regulating mRNAs.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30333515","citation_count":29,"is_preprint":false},{"pmid":"26227789","id":"PMC_26227789","title":"Expression of the microRNA regulators Drosha, Dicer and Ago2 in non-small cell lung carcinomas.","date":"2015","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/26227789","citation_count":29,"is_preprint":false},{"pmid":"19263520","id":"PMC_19263520","title":"Coenzyme Q10 and alpha-tocopherol protect against amitriptyline toxicity.","date":"2009","source":"Toxicology and applied pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/19263520","citation_count":28,"is_preprint":false},{"pmid":"33599613","id":"PMC_33599613","title":"Repressing Ago2 mRNA translation by Trim71 maintains pluripotency through inhibiting let-7 microRNAs.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/33599613","citation_count":28,"is_preprint":false},{"pmid":"36300654","id":"PMC_36300654","title":"Coenzyme Q10 in aging and disease.","date":"2022","source":"Critical reviews in food science and nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/36300654","citation_count":27,"is_preprint":false},{"pmid":"31289130","id":"PMC_31289130","title":"Sequestration of microRNA-mediated target repression by the Ago2-associated RNA-binding protein FAM120A.","date":"2019","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/31289130","citation_count":26,"is_preprint":false},{"pmid":"28589097","id":"PMC_28589097","title":"AGO2 Negatively Regulates Type I Interferon Signaling Pathway by Competition Binding IRF3 with CBP/p300.","date":"2017","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/28589097","citation_count":25,"is_preprint":false},{"pmid":"37985687","id":"PMC_37985687","title":"AGO2 silences mobile transposons in the nucleus of quiescent cells.","date":"2023","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/37985687","citation_count":24,"is_preprint":false},{"pmid":"31015365","id":"PMC_31015365","title":"Pristimerin inhibits glioma progression by targeting AGO2 and PTPN1 expression via miR-542-5p.","date":"2019","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/31015365","citation_count":23,"is_preprint":false},{"pmid":"17442628","id":"PMC_17442628","title":"Coenzyme Q10 in phenylketonuria and mevalonic aciduria.","date":"2007","source":"Mitochondrion","url":"https://pubmed.ncbi.nlm.nih.gov/17442628","citation_count":23,"is_preprint":false},{"pmid":"33881976","id":"PMC_33881976","title":"Coenzyme Q10 Supplement Rescues Postovulatory Oocyte Aging by Regulating SIRT4 Expression.","date":"2022","source":"Current molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/33881976","citation_count":22,"is_preprint":false},{"pmid":"34889164","id":"PMC_34889164","title":"Long non-coding RNA CASC7 suppresses malignant behaviors of breast cancer by regulating miR-21-5p/FASLG axis.","date":"2021","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/34889164","citation_count":21,"is_preprint":false},{"pmid":"25142877","id":"PMC_25142877","title":"Coenzyme Q10 increases cholesterol efflux and inhibits atherosclerosis through microRNAs.","date":"2014","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/25142877","citation_count":21,"is_preprint":false},{"pmid":"28903378","id":"PMC_28903378","title":"AGO2 involves the malignant phenotypes and FAK/PI3K/AKT signaling pathway in hypopharyngeal-derived FaDu cells.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28903378","citation_count":21,"is_preprint":false},{"pmid":"38561074","id":"PMC_38561074","title":"Neuron-targeted liposomal coenzyme Q10 attenuates neuronal ferroptosis after subarachnoid hemorrhage by activating the ferroptosis suppressor protein 1/coenzyme Q10 system.","date":"2024","source":"Acta biomaterialia","url":"https://pubmed.ncbi.nlm.nih.gov/38561074","citation_count":20,"is_preprint":false},{"pmid":"30591524","id":"PMC_30591524","title":"AGO2 promotes telomerase activity and interaction between the telomerase components TERT and TERC.","date":"2018","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/30591524","citation_count":20,"is_preprint":false},{"pmid":"24788663","id":"PMC_24788663","title":"Bioenergetics and gene silencing approaches for unraveling nucleotide recognition by the human EIF2C2/Ago2 PAZ domain.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24788663","citation_count":19,"is_preprint":false},{"pmid":"34357552","id":"PMC_34357552","title":"Neuroprotective effects of coenzyme Q10 in Parkinson's model via a novel Q10/miR-149-5p/MMPs pathway.","date":"2021","source":"Metabolic brain disease","url":"https://pubmed.ncbi.nlm.nih.gov/34357552","citation_count":19,"is_preprint":false},{"pmid":"32860492","id":"PMC_32860492","title":"Long non-coding RNA CASC7 is associated with the pathogenesis of heart failure via modulating the expression of miR-30c.","date":"2020","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32860492","citation_count":18,"is_preprint":false},{"pmid":"34205194","id":"PMC_34205194","title":"An Aedes aegypti-Derived Ago2 Knockout Cell Line to Investigate Arbovirus Infections.","date":"2021","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/34205194","citation_count":18,"is_preprint":false},{"pmid":"34879122","id":"PMC_34879122","title":"Targeting coenzyme Q10 synthesis overcomes bortezomib resistance in multiple myeloma.","date":"2022","source":"Molecular omics","url":"https://pubmed.ncbi.nlm.nih.gov/34879122","citation_count":18,"is_preprint":false},{"pmid":"28300636","id":"PMC_28300636","title":"Perinatal protein malnutrition alters expression of miRNA biogenesis genes Xpo5 and Ago2 in mice brain.","date":"2017","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/28300636","citation_count":18,"is_preprint":false},{"pmid":"32829089","id":"PMC_32829089","title":"Protective effects of Coenzyme Q10 against acute pancreatitis.","date":"2020","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/32829089","citation_count":18,"is_preprint":false},{"pmid":"31903115","id":"PMC_31903115","title":"Musashi-1 promotes stress-induced tumor progression through recruitment of AGO2.","date":"2020","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/31903115","citation_count":17,"is_preprint":false},{"pmid":"37667786","id":"PMC_37667786","title":"Coenzyme Q10 Stimulate Reproductive Vatality.","date":"2023","source":"Drug design, development and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/37667786","citation_count":16,"is_preprint":false},{"pmid":"38475992","id":"PMC_38475992","title":"Nuclear AGO2 promotes myocardial remodeling by activating ANKRD1 transcription in failing hearts.","date":"2024","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/38475992","citation_count":15,"is_preprint":false},{"pmid":"25680411","id":"PMC_25680411","title":"IRF7 promotes glioma cell invasion by inhibiting AGO2 expression.","date":"2015","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25680411","citation_count":15,"is_preprint":false},{"pmid":"15167860","id":"PMC_15167860","title":"Coenzyme Q10 and lipid-related gene induction in HeLa cells.","date":"2004","source":"American journal of obstetrics and gynecology","url":"https://pubmed.ncbi.nlm.nih.gov/15167860","citation_count":15,"is_preprint":false},{"pmid":"30537346","id":"PMC_30537346","title":"Multiple receptors converge on H2-Q10 to regulate NK and γδT-cell development.","date":"2019","source":"Immunology and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/30537346","citation_count":15,"is_preprint":false},{"pmid":"32101951","id":"PMC_32101951","title":"LncRNA cancer susceptibility candidate (CASC7) upregulates phosphatase and tensin homolog by downregulating miR-10a to inhibit neuroblastoma cell proliferation.","date":"2020","source":"Neuroreport","url":"https://pubmed.ncbi.nlm.nih.gov/32101951","citation_count":14,"is_preprint":false},{"pmid":"31655860","id":"PMC_31655860","title":"The RNA-RNA base pairing potential of human Dicer and Ago2 proteins.","date":"2019","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/31655860","citation_count":14,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":45954,"output_tokens":6405,"usd":0.116969,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15322,"output_tokens":5462,"usd":0.10658,"stage2_stop_reason":"end_turn"},"total_usd":0.223549,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"AGO2 (and AGO1) associate with promoter DNA in cells treated with antigene RNAs (agRNAs) complementary to transcription start sites, mediating transcriptional gene silencing in the nucleus; inhibiting AGO1 or AGO2 expression reverses both transcriptional and post-transcriptional silencing.\",\n      \"method\": \"Chromatin immunoprecipitation, RNAi knockdown of AGO1/AGO2, synthetic agRNA transfection\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and knockdown rescue, single lab, two orthogonal methods\",\n      \"pmids\": [\"16936728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"AGO2 (miRNA-free form) is targeted for selective autophagy-mediated degradation via the receptor NDP52; autophagy is required for continued miRNA loading onto AGO2 and for miRNA homeostasis.\",\n      \"method\": \"Genetic knockdown of NDP52/autophagy components, biochemical fractionation, functional miRNA activity assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal loss-of-function with defined phenotype, multiple orthogonal methods, independently supported\",\n      \"pmids\": [\"23143396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"AGO2 forms a complex with Rad51, and this interaction is enhanced by ionizing radiation; AGO2 catalytic activity and small RNA-binding capability are required for Rad51 accumulation at DSB sites and for homologous recombination repair. DSB resection and RPA/Mre11 loading are unaffected by AGO2 depletion.\",\n      \"method\": \"Co-immunoprecipitation, ionizing radiation treatment, AGO2 knockdown/catalytic mutants, HR repair assays\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, catalytic mutant validation, multiple functional readouts in a single rigorous study\",\n      \"pmids\": [\"24662483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"saRNA-loaded AGO2 guides assembly of the RNA-induced transcriptional activation (RITA) complex (containing AGO2, RHA, and CTR9/PAF1 complex component) at target promoters, interacting with RNA polymerase II to stimulate transcription initiation and elongation, accompanied by histone H2B monoubiquitination.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, chromatin immunoprecipitation, RNA polymerase II interaction assays\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS and ChIP, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"26902284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KRAS-MEK signaling controls AGO2 localization to multivesicular endosomes (MVEs) and exosomal secretion; phosphorylation of AGO2 on serine 387 (downstream of MEK) prevents AGO2-MVE interactions and reduces AGO2 secretion into exosomes, thereby controlling miRNA levels in exosomes.\",\n      \"method\": \"Isogenic cell lines, MEK/Akt inhibitors, AGO2 phospho-mutant constructs, fractionation, exosome isolation\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phospho-mutant validation, chemical inhibition, multiple orthogonal approaches in one study\",\n      \"pmids\": [\"27117408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KRAS directly binds AGO2 via its N-terminal domain interacting with the Switch II region of KRAS, independent of nucleotide (GDP/GTP) state; AGO2 and KRAS co-sediment and co-localize at the endoplasmic reticulum; oncogenic KRAS attenuates AGO2-mediated gene silencing and requires AGO2 for maximal mutant KRAS expression and cellular transformation.\",\n      \"method\": \"Co-immunoprecipitation mass spectrometry, subcellular fractionation, co-localization, AGO2-/- cells, domain interaction mapping\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct binding mapped by domain, AGO2 knockout cells, multiple orthogonal methods\",\n      \"pmids\": [\"26854235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SETDB1 (H3K9 methyltransferase) cooperates with AGO2 in agRNA-induced transcriptional gene silencing of the androgen receptor promoter; agRNA drives AGO2 recruitment to the promoter first, followed by SETDB1 recruitment; SETDB1 associates with SIN3-HDAC complex and EZH2, leading to trimethyl-H3K9 enrichment at the targeted promoter. DNA methylation is not significantly changed.\",\n      \"method\": \"Chromatin immunoprecipitation, knockdown of SETDB1/AGO2, co-immunoprecipitation, bisulfite sequencing\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and Co-IP, single lab, multiple chromatin marks assessed\",\n      \"pmids\": [\"25183519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Hsp90 cochaperones p23 and FKBP4 physically interact with hAGO2 and are required for efficient RNAi; p23 and FKBP4 interact with hAGO2 before small RNA loading; RISC loading occurs in the cytoplasm rather than in RNA granules.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown of cochaperones, RISC loading assays, subcellular fractionation\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, functional knockdown, single lab\",\n      \"pmids\": [\"23741051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MOV10 (RNA helicase) associates with FMRP and AGO2; MOV10 has a dual function—facilitating microRNA-mediated translation repression for some mRNAs and preventing AGO2 function on others; FMRP prevents MOV10-mediated microRNA suppression on a subset of mRNAs where FMRP and MOV10 bind in close proximity.\",\n      \"method\": \"Co-immunoprecipitation, RNA immunoprecipitation, iCLIP, AGO2 functional assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-IP and iCLIP, direct interaction assays, single lab\",\n      \"pmids\": [\"25464849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"eIF1A directly interacts with the MID domain of AGO2 (confirmed by NMR and biochemical assays); this interaction promotes AGO2 activities in RNAi and Dicer-independent miR-451 biogenesis; alanine mutation of eIF1A Lys56 impairs RNAi in human cells and zebrafish.\",\n      \"method\": \"NMR, co-immunoprecipitation, alanine mutagenesis, zebrafish rescue experiments, RNAi activity assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure plus mutagenesis plus in vivo rescue, multiple orthogonal methods\",\n      \"pmids\": [\"26018492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Ago2 nuclear distribution is cell type- and tissue context-dependent; Ago2 localizes primarily as a nuclear protein in primary human keratinocytes and corresponding organotypic cultures, as well as in skin and cervical tissues, but not in continuous cell lines or larynx tissue.\",\n      \"method\": \"Immunofluorescence confocal microscopy, subcellular fractionation, tissue microarray immunohistochemistry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — localization by microscopy and fractionation across multiple tissue types, single lab\",\n      \"pmids\": [\"26699195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"AGO2 is acetylated by p300/CBP at K720, K493, and K355; deacetylation is performed by HDAC7; acetylation at K493/K720 (but not K355) specifically enhances pre-miR-19b1 recruitment to form the miRNA precursor deposit complex (miPDC) and promotes miR-19b maturation via recognition of the UGUGUG motif in the terminal loop of pre-miR-19b1.\",\n      \"method\": \"Mass spectrometry, site-directed mutagenesis (K→R), co-immunoprecipitation, AGO2 acetylation assays with p300/CBP and HDAC7\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PTM identification by MS, mutagenesis validation, single lab\",\n      \"pmids\": [\"30305728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Hepatic Ago2-mediated RNA silencing regulates miRNAs (miR-802, miR-103/107, miR-148a/152) and suppresses metabolic genes (Hnf1β, Cav1, Ampka1); liver-specific Ago2 deletion enhances mitochondrial oxidation and ATP consumption linked to mRNA translation, causing AMPK activation and improving obesity-associated metabolic dysfunction.\",\n      \"method\": \"Liver-specific Ago2 knockout mice, metabolic phenotyping, miRNA profiling, AMPK activity assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO with defined molecular and metabolic phenotypes, multiple orthogonal readouts\",\n      \"pmids\": [\"30201950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"AGO2 promotes telomerase activity and stimulates the association between TERT and TERC; AGO2 depletion results in shorter telomeres and reduced proliferation; AGO2 interacts with TERC and with a newly identified small RNA (terc-sRNA) arising from the H/ACA box of TERC; overexpression of terc-sRNA alone is sufficient to enhance telomerase activity.\",\n      \"method\": \"AGO2 gain- and loss-of-function, TERT/TERC interaction assays, telomere length measurement, RNA immunoprecipitation\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdown/overexpression with multiple defined readouts, single lab\",\n      \"pmids\": [\"30591524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FAM120A is an AGO2-interacting RNA-binding protein (identified by immunoprecipitation-MS) that binds poly(G) sequences in 3'-UTRs; FAM120A co-binding with AGO2 on target mRNAs prevents AGO2-mediated target degradation, sequestering miRNA-mediated repression.\",\n      \"method\": \"Co-immunoprecipitation mass spectrometry, iCLIP, luciferase reporter assays\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS, iCLIP, reporter validation, single lab\",\n      \"pmids\": [\"31289130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"High-throughput SELEX/binding assays reveal quantitative rules for AGO2 RISC target binding and cleavage: RISC tolerates insertions up to 7 nt opposite the central guide region; specific guide:target mismatches can enhance cleavage rate; quantitative in vitro models predict knockdown in cellular systems.\",\n      \"method\": \"High-throughput in vitro binding assay (RBNS), single-turnover cleavage assays, mouse AGO2 RISC reconstitution\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with systematic mutagenesis, validated in cellular system\",\n      \"pmids\": [\"31324449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Thirteen heterozygous missense mutations in AGO2 found in patients with neurological developmental disorders each impair shRNA-mediated silencing; mechanistic consequences are either impaired RISC formation or increased AGO2-mRNA target binding associated with decreased phosphorylation of a C-terminal serine cluster involved in mRNA target release, increased dendritic P-body formation, and global transcriptome alterations.\",\n      \"method\": \"Patient-derived fibroblasts, shRNA silencing assays, AGO2 phosphorylation analysis, transcriptomics, P-body imaging\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple patient mutations, functional silencing assay, phosphorylation analysis, multiple orthogonal readouts\",\n      \"pmids\": [\"33199684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Musashi-1 (MSI1) translocates to the cytoplasm under stress and forms a complex with AGO2; this MSI1/AGO2 complex stabilizes or destabilizes target mRNAs by binding to their 3'-UTR or coding sequence; disruption of the MSI1/AGO2 interaction (via C-terminal MSI1 overexpression) reduces stress-induced tumor progression.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, recombinant protein pulldown, RNA-IP, confocal microscopy, GBM xenograft\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified interaction confirmed by pulldown and RNA-IP, functional in vivo validation, single lab\",\n      \"pmids\": [\"31903115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YTHDF1 interacts with AGO2 via its YTH domain; YTHDF1 promotes P-body formation through liquid-liquid phase separation and recruits AGO2 for miRNA-mediated mRNA degradation; deletion of YTHDF1 causes P-bodies to convert from liquid to gel/solid AGO2/RNA patches, delaying mRNA degradation.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, 4SU-TT-seq, CRISPR knockout, FRAP, in vitro phase separation\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping, FRAP, CRISPR KO, in vitro phase separation, single lab\",\n      \"pmids\": [\"34821414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Trim71 represses AGO2 mRNA translation in mouse embryonic stem cells; blocking this repression leads to a post-transcriptional increase of mature let-7 miRNAs, resulting in let-7-dependent stemness defects and accelerated differentiation.\",\n      \"method\": \"Trim71 knockdown/overexpression, let-7 miRNA quantification, pluripotency assays, polysome profiling\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with defined molecular pathway, multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"33599613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AGO2 in mitochondria of cardiomyocytes activates translation of electron transport chain subunits by recruiting TUFM (mitochondrial translation elongation factor); malonylation of AGO2 reduces its import into mitochondria in diabetic cardiomyopathy; this malonylation is regulated by a cytoplasmic short isoform of SIRT3 acting as a demalonylase.\",\n      \"method\": \"Mitochondrial fractionation, Co-IP of AGO2 with TUFM, adeno-associated virus delivery, post-translational modification analysis, echocardiography\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, PTM analysis, AAV rescue in vivo, single lab\",\n      \"pmids\": [\"38126189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In quiescent mouse splenocytes, AGO2 localizes almost exclusively to the nucleus; AGO2 nuclear accumulation is regulated by the Pi3K-AKT-mTOR pathway and is promoted when mTOR signaling is low (quiescence); in the nucleus, AGO2 binds young mobile transposons co-transcriptionally and represses their expression via its catalytic (slicer) domain.\",\n      \"method\": \"Subcellular fractionation, AGO2 localization imaging, mTOR pathway inhibition, AGO2 catalytic mutants, AGO2 ChIP/CLIP on transposons\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods, catalytic mutant validation, pathway epistasis, rigorous mechanistic dissection\",\n      \"pmids\": [\"37985687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Nuclear AGO2 activates transcription of ANKRD1 (ankyrin repeat domain-containing protein 1) in failing hearts; nuclear (but not cytosolic) AGO2 overexpression exacerbates cardiac dysfunction; ANKRD1 nuclear import drives pathological MYH7 activation and cardiac remodeling; blocking ANKRD1 nuclear import (ivermectin or ANPep peptide) improves cardiac performance.\",\n      \"method\": \"AAV9-mediated AGO2 delivery, nuclear/cytosolic fractionation, TAC mouse model, chromatin assays, echocardiography\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — compartment-specific overexpression with defined downstream target, in vivo rescue, single lab\",\n      \"pmids\": [\"38475992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"AGO2 competes with IRF3 for binding to CBP/p300 in the nucleus; H5N1 viral infection reduces nuclear AGO2 distribution, relieving competition and promoting IRF3-CBP association and IFN-β transcription; AGO2 does not block IRF3 phosphorylation, nuclear translocation, or DNA binding.\",\n      \"method\": \"Co-immunoprecipitation, nuclear fractionation, H5N1 infection, IRF3-CBP interaction assays\",\n      \"journal\": \"Frontiers in cellular and infection microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP mapping specific interaction, infection model, negative controls for phosphorylation/translocation, single lab\",\n      \"pmids\": [\"28589097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The AGO2 PAZ domain selectively binds ribonucleotides (except adenosine) and poorly recognizes deoxyribonucleotides; the PAZ domain has an inherent lack of binding to adenine nucleotides, explaining selective trimming of 3'-adenylated miRNAs; stronger PAZ domain binders correlate with higher in vivo gene silencing efficacy.\",\n      \"method\": \"Biophysical binding assays (isothermal titration calorimetry), nucleotide analogue modifications, in vivo gene silencing assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro binding characterization, single lab, no mutagenesis\",\n      \"pmids\": [\"24788663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Disruption of Ago2 (Eif2c2) in mice causes embryonic lethality early in development after the implantation stage; Ago2 is not required for maintenance of DNA methylation at imprinted genes, centromeric repeats, or Xist, suggesting developmental defects are caused at the post-transcriptional (miRNA-protein complex) rather than transcriptional level.\",\n      \"method\": \"Ago2 gene knockout mice, bisulfite sequencing for DNA methylation, developmental phenotyping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined phenotype and mechanistic exclusion of DNA methylation pathway, replicated in context of prior reports\",\n      \"pmids\": [\"17418524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Antagonistic and cooperative interactions between AGO2 and Pumilio proteins (PUM1/PUM2) on 3'-UTRs regulate mRNA targets; PUM binding near AGO2 sites can counteract miRNA-guided repression (antagonism) or cooperate to enhance AGO2 occupancy; this interaction is not explained by steric hindrance, suggesting an allosteric or indirect mechanism.\",\n      \"method\": \"CLIP-seq (transcriptome-wide AGO2 binding upon PUM knockdown), luciferase reporter assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CLIP-seq and reporter assay validation, single lab\",\n      \"pmids\": [\"30333515\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AGO2 is the catalytic core of the RNA-induced silencing complex (RISC), performing endonucleolytic cleavage of target mRNAs guided by loaded small RNAs (miRNAs/siRNAs); its activity is regulated by multiple post-translational modifications (phosphorylation at S387 by MEK, acetylation by p300/CBP/HDAC7, malonylation by cytoplasmic SIRT3), by chaperone-mediated loading (Hsp90/p23/FKBP4), and by autophagy-dependent degradation via NDP52; AGO2 subcellular localization (cytoplasm vs. nucleus vs. mitochondria) is dynamically controlled by the Pi3K-AKT-mTOR pathway and determines distinct functional outputs—cytoplasmic RISC-mediated mRNA silencing, nuclear transcriptional regulation and transposon repression (via catalytic slicer activity), and mitochondrial translation activation via TUFM recruitment; AGO2 also engages KRAS at the ER, promotes telomerase activity through TERT-TERC association, facilitates homologous recombination by recruiting Rad51 to double-strand breaks, and participates in transcriptional activation via the RITA complex at promoters.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"AGO2 is the catalytic core of RNA-induced silencing, using loaded small RNAs to direct sequence-specific recognition and endonucleolytic slicing of target mRNAs, with quantitative target-binding and cleavage rules dictated by guide:target complementarity and tolerance for central-region insertions [#15], and with the PAZ domain governing selective recognition of 3' nucleotides [#24]. Productive RISC assembly requires cytoplasmic chaperone-assisted loading: the Hsp90 cochaperones p23 and FKBP4 engage AGO2 prior to small-RNA loading [#7], eIF1A binds the MID domain to promote RNAi and Dicer-independent miR-451 biogenesis [#9], and autophagy via the receptor NDP52 selectively degrades miRNA-free AGO2 to sustain miRNA loading and homeostasis [#1]. AGO2 silencing activity is further tuned by post-translational modification and by RNA-binding cofactors that redirect target fate—p300/CBP acetylation and HDAC7 deacetylation control pre-miR-19b maturation [#11], while FAM120A, MOV10/FMRP, Pumilio proteins, and Musashi-1 modulate or override miRNA-guided repression on subsets of transcripts [#14, #8, #26, #17], and YTHDF1 recruits AGO2 into phase-separated P-bodies for mRNA degradation [#18]. Beyond cytoplasmic silencing, AGO2 localization is dynamically partitioned by the PI3K-AKT-mTOR pathway: under low mTOR signaling it accumulates in the nucleus where its slicer activity represses young transposons co-transcriptionally [#21], and it also participates in transcriptional gene silencing at promoters together with SETDB1 [#0, #6], saRNA-guided transcriptional activation through the RITA complex and RNA polymerase II [#3], homologous-recombination repair by recruiting Rad51 to double-strand breaks [#2], telomerase stimulation via TERT-TERC association [#13], and mitochondrial translation activation of electron-transport-chain subunits through TUFM recruitment [#20]. KRAS-MEK signaling links AGO2 to oncogenic output by directly binding AGO2 at the ER and through S387 phosphorylation that controls AGO2 partitioning into multivesicular endosomes and exosomal miRNA export [#5, #4]. AGO2 is essential for development, with knockout causing post-implantation embryonic lethality attributable to post-transcriptional rather than DNA-methylation defects [#25], and heterozygous missense mutations that impair silencing or target release cause a neurological developmental disorder [#16].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that AGO2 acts beyond cytoplasmic mRNA cleavage by associating with promoter DNA to mediate transcriptional gene silencing, raising the question of how a slicer functions in the nucleus.\",\n      \"evidence\": \"ChIP and AGO1/AGO2 knockdown rescue with synthetic agRNAs in cells\",\n      \"pmids\": [\"16936728\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define how AGO2 is recruited to chromatin\", \"Did not establish the chromatin effectors downstream of promoter-bound AGO2\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Determined that AGO2 is essential for early mammalian development and that its requirement is post-transcriptional, excluding a DNA-methylation maintenance role.\",\n      \"evidence\": \"Ago2 knockout mice with developmental phenotyping and bisulfite sequencing\",\n      \"pmids\": [\"17418524\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the specific miRNA targets driving lethality\", \"Did not address tissue-specific functions masked by early lethality\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined how RISC is assembled, showing Hsp90 cochaperones p23 and FKBP4 engage AGO2 before small-RNA loading in the cytoplasm.\",\n      \"evidence\": \"Reciprocal Co-IP, cochaperone knockdown, RISC loading assays, fractionation\",\n      \"pmids\": [\"23741051\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not resolve the structural transitions during loading\", \"Single-lab study without independent confirmation\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked AGO2 turnover to miRNA homeostasis by showing miRNA-free AGO2 is cleared by NDP52-mediated selective autophagy, which is required for continued loading.\",\n      \"evidence\": \"Knockdown of NDP52/autophagy components, fractionation, miRNA activity assays\",\n      \"pmids\": [\"23143396\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how NDP52 distinguishes loaded from unloaded AGO2\", \"Did not quantify the kinetics of the loading/degradation cycle\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Expanded AGO2's nuclear roles to genome maintenance and chromatin silencing, demonstrating Rad51 recruitment for HR repair and cooperation with SETDB1 for H3K9-methylation-based transcriptional silencing.\",\n      \"evidence\": \"Co-IP, ionizing radiation, catalytic mutants, HR/ChIP assays (two studies)\",\n      \"pmids\": [\"24662483\", \"25183519\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the small RNAs guiding AGO2 to DSBs or promoters\", \"Did not establish whether slicing of a target is required at break sites\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Characterized PAZ-domain nucleotide selectivity, explaining selective 3'-end trimming and correlating binding strength with silencing efficacy.\",\n      \"evidence\": \"ITC binding assays with nucleotide analogues and in vivo silencing assays\",\n      \"pmids\": [\"24788663\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mutagenesis to confirm contact residues\", \"Did not connect end recognition to RISC turnover in cells\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved direct cofactor control of catalysis by mapping eIF1A binding to the MID domain and showing it promotes RNAi and Dicer-independent miR-451 biogenesis.\",\n      \"evidence\": \"NMR, Co-IP, alanine mutagenesis, zebrafish rescue, RNAi assays\",\n      \"pmids\": [\"26018492\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how eIF1A binding couples to slicing chemistry\", \"Scope of eIF1A-dependent miRNAs not delineated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed that AGO2 nuclear versus cytoplasmic distribution is cell-type and tissue dependent, reframing its functional output as compartment-determined.\",\n      \"evidence\": \"Immunofluorescence, fractionation, tissue microarray IHC across tissues\",\n      \"pmids\": [\"26699195\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the signal driving tissue-specific nuclear localization\", \"Correlative localization without functional consequence\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected AGO2 to oncogenic KRAS signaling, showing direct ER binding to KRAS and MEK-driven S387 phosphorylation that governs exosomal miRNA export.\",\n      \"evidence\": \"Co-IP/MS, domain mapping, AGO2-/- cells, phospho-mutants, exosome isolation (two studies)\",\n      \"pmids\": [\"26854235\", \"27117408\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish how KRAS binding mechanistically attenuates silencing\", \"Did not define the kinase acting directly on S387 versus pathway intermediates\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established AGO2 as a transcriptional activator through saRNA-guided assembly of the RITA complex with RNA polymerase II.\",\n      \"evidence\": \"Co-IP/MS, ChIP, RNA Pol II interaction assays\",\n      \"pmids\": [\"26902284\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not resolve how saRNA selects activating versus silencing outcomes\", \"Single-lab study without independent confirmation\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified PTM and RNA-binding cofactors that tune AGO2 fate, including acetylation-controlled pre-miR-19b maturation and Pumilio antagonism/cooperation on shared 3'-UTRs.\",\n      \"evidence\": \"MS, K→R mutagenesis, Co-IP, CLIP-seq, reporter assays (two studies)\",\n      \"pmids\": [\"30305728\", \"30333515\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of Pumilio-AGO2 allostery undefined\", \"Did not establish in vivo relevance of individual acetylation sites\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed physiological consequences of AGO2 silencing in metabolism and extended its activity to non-canonical targets, with hepatic Ago2 suppressing metabolic genes and AGO2 stimulating telomerase via TERT-TERC.\",\n      \"evidence\": \"Liver-specific Ago2 knockout, metabolic phenotyping, miRNA profiling; telomerase and telomere-length assays (two studies)\",\n      \"pmids\": [\"30201950\", \"30591524\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether telomerase stimulation requires slicer activity\", \"Did not connect metabolic and telomere roles mechanistically\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined quantitative rules for RISC target recognition and cleavage and identified FAM120A as a cofactor that protects mRNAs from AGO2 degradation.\",\n      \"evidence\": \"High-throughput in vitro binding/cleavage with reconstituted RISC; IP-MS, iCLIP, reporter assays (two studies)\",\n      \"pmids\": [\"31324449\", \"31289130\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro rules not exhaustively validated across endogenous transcriptomes\", \"FAM120A protective mechanism at the RISC level unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked AGO2 dysfunction to human disease by showing heterozygous missense mutations impair silencing or target release and cause a neurological developmental disorder.\",\n      \"evidence\": \"Patient fibroblasts, shRNA silencing assays, phosphorylation analysis, transcriptomics, P-body imaging\",\n      \"pmids\": [\"33199684\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the neuronal targets driving pathology\", \"Did not define the kinase controlling the C-terminal serine cluster\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected AGO2 to phase separation and translational control, showing YTHDF1 recruits AGO2 into liquid P-bodies for mRNA degradation and Trim71 represses AGO2 translation to control let-7 and stemness.\",\n      \"evidence\": \"Co-IP, FRAP, CRISPR KO, in vitro phase separation; polysome profiling and pluripotency assays (two studies)\",\n      \"pmids\": [\"34821414\", \"33599613\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish whether phase state is causal versus correlative for degradation\", \"Single-lab studies for each mechanism\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved how mTOR signaling partitions AGO2 to the nucleus for slicer-dependent transposon repression and identified mitochondrial AGO2 activating ETC translation via TUFM.\",\n      \"evidence\": \"Fractionation, mTOR inhibition, catalytic mutants, ChIP/CLIP on transposons; mitochondrial Co-IP with TUFM, PTM analysis, AAV rescue (two studies)\",\n      \"pmids\": [\"37985687\", \"38126189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the import machinery delivering AGO2 to mitochondria\", \"Did not establish whether mitochondrial AGO2 uses small RNA guides\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated a compartment-specific pathological output, with nuclear AGO2 activating ANKRD1 transcription to drive cardiac dysfunction.\",\n      \"evidence\": \"AAV9 compartment-targeted AGO2, fractionation, TAC mouse model, chromatin assays, echocardiography\",\n      \"pmids\": [\"38475992\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the guide RNA or mechanism of ANKRD1 promoter activation\", \"Single-lab in vivo study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How AGO2 is selectively trafficked among cytoplasm, nucleus, ER, multivesicular endosomes, and mitochondria, and how each localization couples to a distinct molecular activity, remains unresolved.\",\n      \"evidence\": \"No single study integrates the localization-determining signals with compartment-specific functional outputs\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Import/export machinery for nuclear and mitochondrial AGO2 unknown\", \"Whether non-cytoplasmic functions all require slicer activity and small-RNA guides is unresolved\", \"Integration of PTM code (phosphorylation, acetylation, malonylation) with localization decisions is incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [15, 2, 21, 24]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [13, 14, 24, 15]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 0, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7, 21]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 10, 21, 23]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 11, 15, 7]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 3, 6, 22]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 4]}\n    ],\n    \"complexes\": [\"RISC\", \"RITA complex\"],\n    \"partners\": [\"KRAS\", \"Rad51\", \"TUFM\", \"FAM120A\", \"MOV10\", \"MSI1\", \"YTHDF1\", \"eIF1A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}