{"gene":"FAM98A","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2016,"finding":"FAM98A binds to PLEKHM1 and, together with NDEL1, connects lysosomes to microtubules. This PLEKHM1/DEF8/RAB7/FAM98A/NDEL1 complex regulates peripheral lysosome positioning and secretion in osteoclasts; knockdown of FAM98A phenocopies lysosome positioning and bone resorption defects seen in Plekhm1-null osteoclasts.","method":"Co-immunoprecipitation/interaction analysis, siRNA knockdown with lysosome distribution and bone resorption phenotypic readouts in osteoclasts","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction mapping and KD with defined cellular phenotype (lysosome positioning, bone resorption), single lab but multiple orthogonal readouts","pmids":["27777970"],"is_preprint":false},{"year":2015,"finding":"FAM98A is a substrate of PRMT1 (protein arginine methyltransferase 1); PRMT1 arginine-methylates FAM98A, and FAM98A is required for tumor cell migration, invasion, and colony formation in ovarian cancer cells.","method":"In vitro methylation assay (PRMT1 substrate screen), siRNA knockdown with migration/invasion/colony formation assays","journal":"Tumour biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro methylation assay identifies FAM98A as PRMT1 substrate, functional KD phenotype, single lab","pmids":["26503212"],"is_preprint":false},{"year":2016,"finding":"FAM98A and FAM98B form a complex with DDX1 and C14orf166 (DDX1-C14orf166-FAM98A/B complex); this complex is required for PRMT1 expression, and knockdown of FAM98A suppresses PRMT1 levels, proliferation, and colony formation in colorectal cancer cells.","method":"Co-immunoprecipitation, siRNA knockdown with proliferation and colony formation assays, TCGA correlation analysis","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifies the complex, KD with defined cellular phenotypes, single lab","pmids":["28040436"],"is_preprint":false},{"year":2018,"finding":"FAM98A localizes to stress granules (but not P-bodies) upon various stress stimuli; its C-terminal low-complexity region is required for this localization; FAM98A depletion reduces the number of stress granules per cell; FAM98A associates with stress granule proteins DDX1, ATXN2, ATXN2L, and NUFIP2.","method":"Fluorescence microscopy (live imaging/immunofluorescence), deletion mutant analysis, siRNA knockdown, co-immunoprecipitation","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional consequence (stress granule number), deletion mutants map domain, Co-IP identifies binding partners; single lab","pmids":["29992460"],"is_preprint":false},{"year":2018,"finding":"FAM98A overexpression activates the P38-ATF2 signaling pathway, increasing phospho-P38, phospho-ATF2, and cyclin D1 levels, thereby promoting lung cancer cell proliferation; a P38-specific inhibitor reverses FAM98A overexpression effects.","method":"Overexpression and siRNA knockdown in NSCLC cell lines, Western blotting for pathway components, pharmacological inhibition of P38","journal":"Cancer management and research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, signaling pathway placement by OE/inhibitor without direct binding evidence for FAM98A–P38 interaction","pmids":["30100758"],"is_preprint":false},{"year":2022,"finding":"FAM98A promotes resistance to 5-fluorouracil in colorectal cancer cells by inhibiting ferroptosis through activation of xCT translation in stress granules.","method":"Overexpression/knockdown, immunoblotting, immunoprecipitation to identify FAM98A-SG association and xCT pathway activation, in vitro and in vivo proliferation assays","journal":"Archives of biochemistry and biophysics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, mechanism inferred from co-IP and reporter assays without direct reconstitution of xCT translation regulation","pmids":["35421356"],"is_preprint":false},{"year":2023,"finding":"Five novel arginine dimethylation sites on FAM98A were identified by targeted proteomics; dimethylation-deficient mutation of FAM98A suppressed cell migration to the same extent as FAM98A deletion, indicating that PRMT1-mediated dimethylation of these sites mediates FAM98A's role in cell migration.","method":"Metabolic stable-isotope labeling (mNeuCode), targeted MS/MS, site-directed mutagenesis of dimethylation sites, cell migration assay in FAM98A-KO HeLa cells","journal":"Analytical chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — targeted MS identifies modification sites, mutagenesis confirms functional requirement for migration; single lab but multiple orthogonal methods","pmids":["36757215"],"is_preprint":false},{"year":2025,"finding":"FAM98A assembles with RTCB (the catalytic tRNA ligase subunit) and other subunits into a compositionally distinct tRNA ligase complex that lacks Ashwin, distinguishing it from the FAM98B-containing nuclear complex; cryo-EM structure of the tRNA-LC shows FAM98B (the paralog) forms an intricately co-folded heterodimer with CGI-99 that clamps Ashwin, providing a structural rationale for why FAM98A- and FAM98C-containing complexes lack Ashwin and may have distinct cellular functions.","method":"Cryo-EM (atomic-resolution reconstruction), structure-based mutagenesis, interaction analysis of tRNA-LC subunits","journal":"bioRxiv (preprint)","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution cryo-EM structure with structure-based mutagenesis and interaction validation; rigorous single study with multiple orthogonal methods","pmids":["bio_10.1101_2025.08.01.668197"],"is_preprint":true},{"year":2025,"finding":"FAM98A defines one of three compositionally distinct RTCB-containing tRNA ligase complex forms (FAM98A-, FAM98B-, or FAM98C-containing); FAM98A-containing complexes lack Ashwin (the nuclear import factor), so FAM98A-associated complexes are retained in the cytoplasm rather than being imported to the nucleus, establishing FAM98A as a determinant of cytoplasmic tRNA-LC localization.","method":"Biochemical fractionation, interaction assays, NLS disruption/rescue experiments, pre-tRNA splicing assays","journal":"bioRxiv (preprint)","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiments with functional consequence (tRNA splicing impairment), NLS disruption/rescue genetics, two independent preprints from different labs with complementary methods","pmids":["bio_10.1101_2025.08.01.668163"],"is_preprint":true},{"year":2025,"finding":"Conditional knockout of Fam98a in myeloid osteoclast precursors does not reduce trabecular or cortical bone mass in mice, nor does it impair osteoclastogenesis or bone resorption in vitro, apparently because Fam98b expression is upregulated to compensate; in contrast, knockdown of Fam98b in osteoclasts disrupts lysosome trafficking and bone resorption with phenotypes similar to Fam98a knockdown (negative result for in vivo FAM98A loss-of-function).","method":"Myeloid-specific conditional Fam98a knockout mice, shRNA knockdown, osteoclastogenesis assays, bone resorption assays, micro-CT bone mass measurement","journal":"Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined phenotypic readout and compensatory mechanism identified; single lab","pmids":["39857276"],"is_preprint":false}],"current_model":"FAM98A is a PRMT1 substrate whose arginine dimethylation is required for cell migration; it associates with PLEKHM1/NDEL1 to link lysosomes to microtubules for peripheral lysosome positioning and bone resorption in osteoclasts; it localizes to stress granules via its C-terminal low-complexity region where it scaffolds DDX1, ATXN2, ATXN2L, and NUFIP2; and it defines a cytoplasmic, Ashwin-lacking form of the RTCB-containing tRNA ligase complex, with its paralog FAM98B defining the nuclear (Ashwin-containing) form responsible for pre-tRNA splicing."},"narrative":{"mechanistic_narrative":"FAM98A is a multifunctional scaffolding protein that operates within the RTCB-containing tRNA ligase complex and partitions that machinery to the cytoplasm [PMID:bio_10.1101_2025.08.01.668163]. Through compositional control, FAM98A defines a form of the tRNA ligase complex that lacks the nuclear import factor Ashwin, retaining the assembly in the cytoplasm rather than directing it to the nucleus for pre-tRNA splicing; this is rationalized structurally by its paralog FAM98B forming a co-folded heterodimer with CGI-99 that clamps Ashwin, an architecture FAM98A-containing complexes do not adopt [PMID:bio_10.1101_2025.08.01.668197, PMID:bio_10.1101_2025.08.01.668163]. FAM98A is a direct PRMT1 substrate, and arginine dimethylation at defined sites is required for its role in promoting cell migration, since dimethylation-deficient mutants phenocopy FAM98A loss [PMID:26503212, PMID:36757215]. FAM98A also forms a complex with DDX1 and C14orf166 together with FAM98B and is required to sustain PRMT1 expression and proliferation in cancer cells [PMID:28040436]. Upon cellular stress, FAM98A localizes to stress granules via its C-terminal low-complexity region, where it scaffolds DDX1, ATXN2, ATXN2L, and NUFIP2 and supports stress granule assembly [PMID:29992460]. In osteoclasts, FAM98A associates with PLEKHM1 and NDEL1 to couple lysosomes to microtubules for peripheral lysosome positioning and bone resorption [PMID:27777970], though conditional Fam98a knockout in mice does not impair bone resorption owing to compensatory upregulation of Fam98b [PMID:39857276].","teleology":[{"year":2015,"claim":"Established FAM98A as a post-translationally regulated effector of cell motility by identifying it as a PRMT1 methylation substrate with a migration/invasion phenotype.","evidence":"In vitro PRMT1 methylation assay and siRNA knockdown with migration, invasion, and colony formation readouts in ovarian cancer cells","pmids":["26503212"],"confidence":"Medium","gaps":["Specific methylated residues not yet mapped","Mechanistic link between methylation and migration not defined","Single cell-type context"]},{"year":2016,"claim":"Placed FAM98A in a stable cytoplasmic complex (DDX1-C14orf166-FAM98A/B) and linked it to maintenance of PRMT1 expression and proliferation, connecting the scaffold to its own upstream modifier.","evidence":"Co-immunoprecipitation, siRNA knockdown with proliferation/colony assays, and TCGA correlation in colorectal cancer cells","pmids":["28040436"],"confidence":"Medium","gaps":["How the complex regulates PRMT1 levels mechanistically unclear","Direct vs indirect effect on PRMT1 not resolved"]},{"year":2016,"claim":"Defined a membrane-trafficking role for FAM98A by showing it bridges lysosomes to microtubules within a PLEKHM1/DEF8/RAB7/NDEL1 complex governing lysosome positioning and bone resorption.","evidence":"Co-IP/interaction mapping and siRNA knockdown with lysosome distribution and bone resorption readouts in osteoclasts","pmids":["27777970"],"confidence":"Medium","gaps":["Direct binding interface within the complex not mapped","Whether this role is osteoclast-specific unknown"]},{"year":2018,"claim":"Identified FAM98A as a stress granule component and assembly factor, mapping the responsible domain and its RNA-granule partners.","evidence":"Fluorescence microscopy, C-terminal low-complexity deletion mutants, siRNA knockdown of granule number, and co-IP of DDX1/ATXN2/ATXN2L/NUFIP2","pmids":["29992460"],"confidence":"Medium","gaps":["RNA targets within granules not identified","Role of phase separation vs protein-protein scaffolding unresolved"]},{"year":2018,"claim":"Proposed a P38-ATF2 signaling axis downstream of FAM98A in lung cancer proliferation.","evidence":"Overexpression/knockdown in NSCLC lines with Western blotting and pharmacological P38 inhibition","pmids":["30100758"],"confidence":"Low","gaps":["No direct FAM98A-P38 interaction demonstrated","Pathway placement inferred from OE and inhibitor only","Single lab"]},{"year":2022,"claim":"Linked FAM98A stress-granule function to chemoresistance via xCT translational control and ferroptosis inhibition.","evidence":"Overexpression/knockdown, immunoblotting, immunoprecipitation, and in vitro/in vivo proliferation assays in colorectal cancer cells","pmids":["35421356"],"confidence":"Low","gaps":["xCT translation regulation not reconstituted","Direct vs indirect role in ferroptosis unclear","Single lab"]},{"year":2023,"claim":"Resolved how PRMT1 modification controls FAM98A by mapping five arginine dimethylation sites and demonstrating their functional requirement for migration.","evidence":"mNeuCode metabolic labeling, targeted MS/MS, site-directed mutagenesis, and migration assays in FAM98A-KO HeLa cells","pmids":["36757215"],"confidence":"Medium","gaps":["Downstream effectors of dimethylated FAM98A unknown","Whether methylation affects complex assembly or localization untested"]},{"year":2025,"claim":"Established FAM98A as a compositional determinant of tRNA ligase complex identity and cytoplasmic localization by showing FAM98A-containing complexes lack Ashwin and are retained in the cytoplasm, with cryo-EM providing the structural rationale.","evidence":"Cryo-EM structure of the tRNA-LC, structure-based mutagenesis, biochemical fractionation, and NLS disruption/rescue with pre-tRNA splicing assays (two preprints from different labs)","pmids":["bio_10.1101_2025.08.01.668197","bio_10.1101_2025.08.01.668163"],"confidence":"High","gaps":["Cytoplasmic substrate/function of the FAM98A-tRNA-LC not fully defined","Peer review pending (preprints)","Functional distinction from FAM98C-containing complex unclear"]},{"year":2025,"claim":"Tested the in vivo requirement for FAM98A in bone, revealing functional redundancy with FAM98B.","evidence":"Myeloid-specific conditional Fam98a knockout mice, shRNA knockdown, osteoclastogenesis and bone resorption assays, and micro-CT","pmids":["39857276"],"confidence":"Medium","gaps":["Extent of FAM98A/FAM98B functional overlap in other tissues unknown","Whether compensation occurs outside osteoclasts untested"]},{"year":null,"claim":"The specific cytoplasmic RNA-processing function unique to the FAM98A-defined tRNA ligase complex, and how its PRMT1 dimethylation and stress-granule recruitment integrate with this role, remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No defined catalytic or substrate-specific output unique to FAM98A complexes","Connection between methylation, stress granules, and tRNA-LC roles not integrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,7,8]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,8]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[7,8]}],"complexes":["RTCB-containing tRNA ligase complex","DDX1-C14orf166-FAM98A/B complex","PLEKHM1/DEF8/RAB7/FAM98A/NDEL1 lysosome-microtubule complex","stress granule"],"partners":["RTCB","FAM98B","DDX1","C14ORF166","PLEKHM1","NDEL1","ATXN2","NUFIP2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NCA5","full_name":"Protein FAM98A","aliases":[],"length_aa":518,"mass_kda":55.3,"function":"Positively stimulates PRMT1-induced protein arginine methylation (PubMed:28040436). Involved in skeletal homeostasis (By similarity). Positively regulates lysosome peripheral distribution and ruffled border formation in osteoclasts (By similarity)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q8NCA5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FAM98A","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"RTCB","stoichiometry":10.0},{"gene":"BYSL","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CLNS1A","stoichiometry":0.2},{"gene":"DDX6","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"RPS16","stoichiometry":0.2},{"gene":"SRP9","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/FAM98A","total_profiled":1310},"omim":[{"mim_id":"620904","title":"FAMILY WITH SEQUENCE SIMILARITY 98, MEMBER A; FAM98A","url":"https://www.omim.org/entry/620904"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FAM98A"},"hgnc":{"alias_symbol":["DKFZP564F0522"],"prev_symbol":[]},"alphafold":{"accession":"Q8NCA5","domains":[{"cath_id":"-","chopping":"156-182","consensus_level":"high","plddt":93.3715,"start":156,"end":182},{"cath_id":"1.10.418","chopping":"2-129","consensus_level":"high","plddt":94.3636,"start":2,"end":129},{"cath_id":"1.10.287","chopping":"199-277","consensus_level":"high","plddt":93.5467,"start":199,"end":277}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NCA5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NCA5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NCA5-F1-predicted_aligned_error_v6.png","plddt_mean":67.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FAM98A","jax_strain_url":"https://www.jax.org/strain/search?query=FAM98A"},"sequence":{"accession":"Q8NCA5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NCA5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NCA5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NCA5"}},"corpus_meta":[{"pmid":"27777970","id":"PMC_27777970","title":"PLEKHM1/DEF8/RAB7 complex regulates lysosome positioning and bone homeostasis.","date":"2016","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/27777970","citation_count":76,"is_preprint":false},{"pmid":"29997237","id":"PMC_29997237","title":"Differential long noncoding RNA expressions in peripheral blood mononuclear cells for detection of acute ischemic stroke.","date":"2018","source":"Clinical science (London, England : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/29997237","citation_count":50,"is_preprint":false},{"pmid":"24257188","id":"PMC_24257188","title":"A divergent calponin homology (NN-CH) domain defines a novel family: implications for evolution of ciliary IFT complex B proteins.","date":"2013","source":"Bioinformatics (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/24257188","citation_count":37,"is_preprint":false},{"pmid":"28040436","id":"PMC_28040436","title":"FAM98A associates with DDX1-C14orf166-FAM98B in a novel complex involved in colorectal cancer progression.","date":"2016","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/28040436","citation_count":33,"is_preprint":false},{"pmid":"26503212","id":"PMC_26503212","title":"FAM98A is a novel substrate of PRMT1 required for tumor cell migration, invasion, and colony formation.","date":"2015","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26503212","citation_count":32,"is_preprint":false},{"pmid":"35421356","id":"PMC_35421356","title":"FAM98A promotes resistance to 5-fluorouracil in colorectal cancer by suppressing ferroptosis.","date":"2022","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/35421356","citation_count":31,"is_preprint":false},{"pmid":"29992460","id":"PMC_29992460","title":"FAM98A is localized to stress granules and associates with multiple stress granule-localized 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This PLEKHM1/DEF8/RAB7/FAM98A/NDEL1 complex regulates peripheral lysosome positioning and secretion in osteoclasts; knockdown of FAM98A phenocopies lysosome positioning and bone resorption defects seen in Plekhm1-null osteoclasts.\",\n      \"method\": \"Co-immunoprecipitation/interaction analysis, siRNA knockdown with lysosome distribution and bone resorption phenotypic readouts in osteoclasts\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction mapping and KD with defined cellular phenotype (lysosome positioning, bone resorption), single lab but multiple orthogonal readouts\",\n      \"pmids\": [\"27777970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FAM98A is a substrate of PRMT1 (protein arginine methyltransferase 1); PRMT1 arginine-methylates FAM98A, and FAM98A is required for tumor cell migration, invasion, and colony formation in ovarian cancer cells.\",\n      \"method\": \"In vitro methylation assay (PRMT1 substrate screen), siRNA knockdown with migration/invasion/colony formation assays\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro methylation assay identifies FAM98A as PRMT1 substrate, functional KD phenotype, single lab\",\n      \"pmids\": [\"26503212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FAM98A and FAM98B form a complex with DDX1 and C14orf166 (DDX1-C14orf166-FAM98A/B complex); this complex is required for PRMT1 expression, and knockdown of FAM98A suppresses PRMT1 levels, proliferation, and colony formation in colorectal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown with proliferation and colony formation assays, TCGA correlation analysis\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifies the complex, KD with defined cellular phenotypes, single lab\",\n      \"pmids\": [\"28040436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FAM98A localizes to stress granules (but not P-bodies) upon various stress stimuli; its C-terminal low-complexity region is required for this localization; FAM98A depletion reduces the number of stress granules per cell; FAM98A associates with stress granule proteins DDX1, ATXN2, ATXN2L, and NUFIP2.\",\n      \"method\": \"Fluorescence microscopy (live imaging/immunofluorescence), deletion mutant analysis, siRNA knockdown, co-immunoprecipitation\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional consequence (stress granule number), deletion mutants map domain, Co-IP identifies binding partners; single lab\",\n      \"pmids\": [\"29992460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FAM98A overexpression activates the P38-ATF2 signaling pathway, increasing phospho-P38, phospho-ATF2, and cyclin D1 levels, thereby promoting lung cancer cell proliferation; a P38-specific inhibitor reverses FAM98A overexpression effects.\",\n      \"method\": \"Overexpression and siRNA knockdown in NSCLC cell lines, Western blotting for pathway components, pharmacological inhibition of P38\",\n      \"journal\": \"Cancer management and research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, signaling pathway placement by OE/inhibitor without direct binding evidence for FAM98A–P38 interaction\",\n      \"pmids\": [\"30100758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FAM98A promotes resistance to 5-fluorouracil in colorectal cancer cells by inhibiting ferroptosis through activation of xCT translation in stress granules.\",\n      \"method\": \"Overexpression/knockdown, immunoblotting, immunoprecipitation to identify FAM98A-SG association and xCT pathway activation, in vitro and in vivo proliferation assays\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, mechanism inferred from co-IP and reporter assays without direct reconstitution of xCT translation regulation\",\n      \"pmids\": [\"35421356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Five novel arginine dimethylation sites on FAM98A were identified by targeted proteomics; dimethylation-deficient mutation of FAM98A suppressed cell migration to the same extent as FAM98A deletion, indicating that PRMT1-mediated dimethylation of these sites mediates FAM98A's role in cell migration.\",\n      \"method\": \"Metabolic stable-isotope labeling (mNeuCode), targeted MS/MS, site-directed mutagenesis of dimethylation sites, cell migration assay in FAM98A-KO HeLa cells\",\n      \"journal\": \"Analytical chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — targeted MS identifies modification sites, mutagenesis confirms functional requirement for migration; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"36757215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FAM98A assembles with RTCB (the catalytic tRNA ligase subunit) and other subunits into a compositionally distinct tRNA ligase complex that lacks Ashwin, distinguishing it from the FAM98B-containing nuclear complex; cryo-EM structure of the tRNA-LC shows FAM98B (the paralog) forms an intricately co-folded heterodimer with CGI-99 that clamps Ashwin, providing a structural rationale for why FAM98A- and FAM98C-containing complexes lack Ashwin and may have distinct cellular functions.\",\n      \"method\": \"Cryo-EM (atomic-resolution reconstruction), structure-based mutagenesis, interaction analysis of tRNA-LC subunits\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution cryo-EM structure with structure-based mutagenesis and interaction validation; rigorous single study with multiple orthogonal methods\",\n      \"pmids\": [\"bio_10.1101_2025.08.01.668197\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FAM98A defines one of three compositionally distinct RTCB-containing tRNA ligase complex forms (FAM98A-, FAM98B-, or FAM98C-containing); FAM98A-containing complexes lack Ashwin (the nuclear import factor), so FAM98A-associated complexes are retained in the cytoplasm rather than being imported to the nucleus, establishing FAM98A as a determinant of cytoplasmic tRNA-LC localization.\",\n      \"method\": \"Biochemical fractionation, interaction assays, NLS disruption/rescue experiments, pre-tRNA splicing assays\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiments with functional consequence (tRNA splicing impairment), NLS disruption/rescue genetics, two independent preprints from different labs with complementary methods\",\n      \"pmids\": [\"bio_10.1101_2025.08.01.668163\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Conditional knockout of Fam98a in myeloid osteoclast precursors does not reduce trabecular or cortical bone mass in mice, nor does it impair osteoclastogenesis or bone resorption in vitro, apparently because Fam98b expression is upregulated to compensate; in contrast, knockdown of Fam98b in osteoclasts disrupts lysosome trafficking and bone resorption with phenotypes similar to Fam98a knockdown (negative result for in vivo FAM98A loss-of-function).\",\n      \"method\": \"Myeloid-specific conditional Fam98a knockout mice, shRNA knockdown, osteoclastogenesis assays, bone resorption assays, micro-CT bone mass measurement\",\n      \"journal\": \"Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined phenotypic readout and compensatory mechanism identified; single lab\",\n      \"pmids\": [\"39857276\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FAM98A is a PRMT1 substrate whose arginine dimethylation is required for cell migration; it associates with PLEKHM1/NDEL1 to link lysosomes to microtubules for peripheral lysosome positioning and bone resorption in osteoclasts; it localizes to stress granules via its C-terminal low-complexity region where it scaffolds DDX1, ATXN2, ATXN2L, and NUFIP2; and it defines a cytoplasmic, Ashwin-lacking form of the RTCB-containing tRNA ligase complex, with its paralog FAM98B defining the nuclear (Ashwin-containing) form responsible for pre-tRNA splicing.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FAM98A is a multifunctional scaffolding protein that operates within the RTCB-containing tRNA ligase complex and partitions that machinery to the cytoplasm [#8]. Through compositional control, FAM98A defines a form of the tRNA ligase complex that lacks the nuclear import factor Ashwin, retaining the assembly in the cytoplasm rather than directing it to the nucleus for pre-tRNA splicing; this is rationalized structurally by its paralog FAM98B forming a co-folded heterodimer with CGI-99 that clamps Ashwin, an architecture FAM98A-containing complexes do not adopt [#7, #8]. FAM98A is a direct PRMT1 substrate, and arginine dimethylation at defined sites is required for its role in promoting cell migration, since dimethylation-deficient mutants phenocopy FAM98A loss [#1, #6]. FAM98A also forms a complex with DDX1 and C14orf166 together with FAM98B and is required to sustain PRMT1 expression and proliferation in cancer cells [#2]. Upon cellular stress, FAM98A localizes to stress granules via its C-terminal low-complexity region, where it scaffolds DDX1, ATXN2, ATXN2L, and NUFIP2 and supports stress granule assembly [#3]. In osteoclasts, FAM98A associates with PLEKHM1 and NDEL1 to couple lysosomes to microtubules for peripheral lysosome positioning and bone resorption [#0], though conditional Fam98a knockout in mice does not impair bone resorption owing to compensatory upregulation of Fam98b [#9].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established FAM98A as a post-translationally regulated effector of cell motility by identifying it as a PRMT1 methylation substrate with a migration/invasion phenotype.\",\n      \"evidence\": \"In vitro PRMT1 methylation assay and siRNA knockdown with migration, invasion, and colony formation readouts in ovarian cancer cells\",\n      \"pmids\": [\"26503212\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific methylated residues not yet mapped\", \"Mechanistic link between methylation and migration not defined\", \"Single cell-type context\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed FAM98A in a stable cytoplasmic complex (DDX1-C14orf166-FAM98A/B) and linked it to maintenance of PRMT1 expression and proliferation, connecting the scaffold to its own upstream modifier.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA knockdown with proliferation/colony assays, and TCGA correlation in colorectal cancer cells\",\n      \"pmids\": [\"28040436\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How the complex regulates PRMT1 levels mechanistically unclear\", \"Direct vs indirect effect on PRMT1 not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined a membrane-trafficking role for FAM98A by showing it bridges lysosomes to microtubules within a PLEKHM1/DEF8/RAB7/NDEL1 complex governing lysosome positioning and bone resorption.\",\n      \"evidence\": \"Co-IP/interaction mapping and siRNA knockdown with lysosome distribution and bone resorption readouts in osteoclasts\",\n      \"pmids\": [\"27777970\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding interface within the complex not mapped\", \"Whether this role is osteoclast-specific unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified FAM98A as a stress granule component and assembly factor, mapping the responsible domain and its RNA-granule partners.\",\n      \"evidence\": \"Fluorescence microscopy, C-terminal low-complexity deletion mutants, siRNA knockdown of granule number, and co-IP of DDX1/ATXN2/ATXN2L/NUFIP2\",\n      \"pmids\": [\"29992460\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RNA targets within granules not identified\", \"Role of phase separation vs protein-protein scaffolding unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Proposed a P38-ATF2 signaling axis downstream of FAM98A in lung cancer proliferation.\",\n      \"evidence\": \"Overexpression/knockdown in NSCLC lines with Western blotting and pharmacological P38 inhibition\",\n      \"pmids\": [\"30100758\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct FAM98A-P38 interaction demonstrated\", \"Pathway placement inferred from OE and inhibitor only\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked FAM98A stress-granule function to chemoresistance via xCT translational control and ferroptosis inhibition.\",\n      \"evidence\": \"Overexpression/knockdown, immunoblotting, immunoprecipitation, and in vitro/in vivo proliferation assays in colorectal cancer cells\",\n      \"pmids\": [\"35421356\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"xCT translation regulation not reconstituted\", \"Direct vs indirect role in ferroptosis unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved how PRMT1 modification controls FAM98A by mapping five arginine dimethylation sites and demonstrating their functional requirement for migration.\",\n      \"evidence\": \"mNeuCode metabolic labeling, targeted MS/MS, site-directed mutagenesis, and migration assays in FAM98A-KO HeLa cells\",\n      \"pmids\": [\"36757215\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effectors of dimethylated FAM98A unknown\", \"Whether methylation affects complex assembly or localization untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established FAM98A as a compositional determinant of tRNA ligase complex identity and cytoplasmic localization by showing FAM98A-containing complexes lack Ashwin and are retained in the cytoplasm, with cryo-EM providing the structural rationale.\",\n      \"evidence\": \"Cryo-EM structure of the tRNA-LC, structure-based mutagenesis, biochemical fractionation, and NLS disruption/rescue with pre-tRNA splicing assays (two preprints from different labs)\",\n      \"pmids\": [\"bio_10.1101_2025.08.01.668197\", \"bio_10.1101_2025.08.01.668163\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cytoplasmic substrate/function of the FAM98A-tRNA-LC not fully defined\", \"Peer review pending (preprints)\", \"Functional distinction from FAM98C-containing complex unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Tested the in vivo requirement for FAM98A in bone, revealing functional redundancy with FAM98B.\",\n      \"evidence\": \"Myeloid-specific conditional Fam98a knockout mice, shRNA knockdown, osteoclastogenesis and bone resorption assays, and micro-CT\",\n      \"pmids\": [\"39857276\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Extent of FAM98A/FAM98B functional overlap in other tissues unknown\", \"Whether compensation occurs outside osteoclasts untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The specific cytoplasmic RNA-processing function unique to the FAM98A-defined tRNA ligase complex, and how its PRMT1 dimethylation and stress-granule recruitment integrate with this role, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No defined catalytic or substrate-specific output unique to FAM98A complexes\", \"Connection between methylation, stress granules, and tRNA-LC roles not integrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 7, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"complexes\": [\n      \"RTCB-containing tRNA ligase complex\",\n      \"DDX1-C14orf166-FAM98A/B complex\",\n      \"PLEKHM1/DEF8/RAB7/FAM98A/NDEL1 lysosome-microtubule complex\",\n      \"stress granule\"\n    ],\n    \"partners\": [\n      \"RTCB\",\n      \"FAM98B\",\n      \"DDX1\",\n      \"C14orf166\",\n      \"PLEKHM1\",\n      \"NDEL1\",\n      \"ATXN2\",\n      \"NUFIP2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}