{"gene":"FAM111B","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2013,"finding":"Causative missense mutations in FAM111B identified in hereditary fibrosing poikiloderma with tendon contracture, myopathy, and pulmonary fibrosis (POIKTMP); all three mutations cluster within a putative trypsin-like cysteine/serine peptidase domain of the protein.","method":"Whole-exome sequencing, Sanger sequencing validation, segregation analysis in pedigrees","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple independent kindreds, de novo confirmation, replicated across 5 families from different ethnic backgrounds","pmids":["24268661"],"is_preprint":false},{"year":2015,"finding":"All POIKTMP-associated FAM111B mutations localize to the trypsin-like cysteine/serine peptidase domain, suggesting gain-of-function or dominant-negative effects leading to enzymatic activity changes.","method":"Clinical molecular genetics, domain mapping of missense variants across 10 independent families","journal":"Orphanet journal of rare diseases","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — domain clustering of mutations across multiple independent families, but no direct enzymatic assay performed","pmids":["26471370"],"is_preprint":false},{"year":2020,"finding":"FAM111B promotes cell cycle progression in KRAS-driven lung adenocarcinoma by degrading p16, thereby enabling cyclin D1-CDK4-dependent progression; FAM111B-knockout cells showed impaired proliferation and cell cycle progression under serum-starvation conditions.","method":"FAM111B-knockout cell lines, in vitro functional assays (proliferation, cell cycle), western blot for p16/cyclin D1-CDK4","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO cells with defined phenotype and pathway placement, single lab","pmids":["32418298"],"is_preprint":false},{"year":2021,"finding":"FAM111B expression is regulated by adenovirus type 5 (HAdV-C5): levels are upregulated early and downregulated late during infection; downregulation depends on the presence of viral E1B-55K and E4orf6 oncoproteins; FAM111B knockdown increases HAdV-C5 replication, establishing FAM111B as an anti-adenoviral host restriction factor.","method":"shRNA knockdown, adenovirus infection assays, viral replication quantification, immunoblotting","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with defined viral replication phenotype, identification of viral regulatory proteins responsible, single lab","pmids":["34071532"],"is_preprint":false},{"year":2023,"finding":"FAM111B interacts with components of the nuclear pore complex (nucleoporins); loss of FAM111B causes abnormal nuclear shape, reduced telomeric DNA content (independent of telomerase or recombination-driven extension), increased micronuclei, and ultra-fine DNA bridges. HFP-associated mutant FAM111B localizes more frequently to the nuclear envelope compared to wild-type.","method":"Co-immunoprecipitation with nucleoporins, immunofluorescence/live imaging of nuclear localization, telomere length assays (FISH, qPCR), micronuclei counting, U2OS and MCF7 cell lines with FAM111B loss-of-function","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for binding partners, direct localization experiment with functional consequence, multiple orthogonal methods, single lab","pmids":["37342232"],"is_preprint":false},{"year":2023,"finding":"FAM111B binds to GSDMA and promotes its degradation; the trypsin protease domain of FAM111B is essential for this activity. The FAM111B/GSDMA axis promotes esophageal cancer cell progression and regulates sensitivity to cisplatin.","method":"Co-immunoprecipitation, western blot, domain deletion/mutagenesis of trypsin domain, RNA-seq, xenograft assays","journal":"Cellular oncology (Dordrecht, Netherlands)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP binding demonstrated and domain-function linkage via trypsin domain requirement, single lab","pmids":["37672204"],"is_preprint":false},{"year":2024,"finding":"E2F3 transcriptionally activates FAM111B expression; FAM111B (but not its paralog FAM111A) suppresses mouse cytomegalovirus (MCMV) replication in human and rhesus macaque cells; FAM111B localizes predominantly to the nucleus with enrichment in viral replication compartments in infected cells.","method":"shRNA knockdown, CRISPR/Cas9 knockout, transcriptome analysis, immunofluorescence, viral replication assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with viral replication readout, transcriptome + immunofluorescence, single lab with two orthogonal genetic approaches","pmids":["39494906"],"is_preprint":false},{"year":2022,"finding":"DNMT3B methylates the FAM111B promoter (recruited by estrogen signaling), suppressing FAM111B transcription in papillary thyroid cancer; ChIP assay demonstrated DNMT3B binding to the FAM111B promoter.","method":"ChIP assay, DNMT3B overexpression/knockdown, promoter methylation analysis, in vitro and in vivo functional assays","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP directly demonstrates DNMT3B recruitment to FAM111B promoter, functional rescue experiments, single lab","pmids":["35864964"],"is_preprint":false},{"year":2021,"finding":"YY1 transcription factor binds to the promoter of FAM111B and activates its transcription in breast cancer cells, as demonstrated by ChIP-qPCR.","method":"ChIP-qPCR, luciferase reporter assay, siRNA knockdown","journal":"Clinical breast cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/ChIP method, single lab, no direct functional rescue linking YY1-FAM111B axis mechanistically","pmids":["34802969"],"is_preprint":false},{"year":2025,"finding":"FAM111B promotes MFN2 ubiquitination and degradation by recruiting RANBP9, a core subunit of the CTLH E3 ligase complex; FAM111B loss generates hyperfused mitochondria, shifts metabolism from glycolysis to OXPHOS, and antagonizes cytoprotective mitophagy.","method":"Co-immunoprecipitation (FAM111B-RANBP9 interaction), protein stability assays, mitochondrial morphology imaging, metabolic flux assays, xenograft models with siFAM111B lipid nanoparticles","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating binding, protein stability assays, metabolic phenotype with multiple assays, single lab","pmids":["40855067"],"is_preprint":false},{"year":2024,"finding":"PRIM2 upregulates FAM111B at both RNA and protein stability levels; the PRIM2/FAM111B axis promotes proliferation and migration via PI3K/AKT pathway and EMT markers in pancreatic ductal adenocarcinoma.","method":"Co-immunoprecipitation, protein stability assays, western blot, xenograft models","journal":"Medical oncology (Northwood, London, England)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and protein stability, single lab, pathway placement inferred from downstream markers without direct mechanistic dissection","pmids":["39556158"],"is_preprint":false},{"year":2025,"finding":"FAM111B protein binds and hydrolyzes the CDK inhibitor P27, which activates the Cyclin-CDKs/RB/E2F1 signaling pathway to increase LDHA transcription, thereby enhancing glycolysis and promoting prostate cancer metastasis.","method":"Transcriptomic and proteomic analysis, western blot, in vitro hydrolysis assay (functional coding region including hydrolytic triad), gene enrichment analysis, in vivo metastasis assays","journal":"Neoplasia (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct proteolytic activity on P27 demonstrated via hydrolytic triad of FAM111B, pathway activation validated by multiple downstream markers, single lab","pmids":["40975977"],"is_preprint":false},{"year":2025,"finding":"Loss of FAM111B expression perturbs ubiquitin-proteasome system (UPS) function in patient-derived cells carrying FAM111B missense variants, leading to increased ubiquitin-protein conjugates and a sterile type I interferon signature; variants clustering in the D-box domain associate with more severe phenotypes.","method":"Omics analysis of patient-derived cells (proteomics/transcriptomics), ubiquitin conjugate accumulation assays, interferon signature analysis; 41 POIKTMP patients compiled","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived cell omics with multiple orthogonal technologies, large patient cohort, single lab","pmids":["40840166"],"is_preprint":false},{"year":2025,"finding":"FAM111B downregulates ATF3 expression in prostate cancer cells; reduced ATF3 occupancy at the KRAS promoter leads to upregulated KRAS and enhanced RAF1-MEK-ERK pathway activation, inhibiting apoptosis; rescue experiments with ATF3 overexpression reversed FAM111B-driven phenotypes.","method":"qPCR, western blot, immunofluorescence, rescue experiments (ATF3 overexpression), in vitro and in vivo models","journal":"Cancer cell international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway inferred from rescue experiments without direct FAM111B-ATF3 binding demonstrated, no direct chromatin or protease assay","pmids":["41454362"],"is_preprint":false},{"year":2025,"finding":"IGF2BP2 stabilizes FAM111B mRNA; ELF1 transcriptionally upregulates IGF2BP2; this ELF1/IGF2BP2/FAM111B cascade promotes colorectal cancer cell proliferation, migration, and ferroptosis resistance; demonstrated by luciferase reporter and ChIP assays.","method":"Luciferase reporter assay, ChIP assay, mRNA stability assay, knockdown/rescue experiments, xenograft","journal":"Clinical and experimental pharmacology & physiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ChIP and reporter assays for ELF1-IGF2BP2 axis, mRNA stability for IGF2BP2-FAM111B, single lab","pmids":["41211642"],"is_preprint":false},{"year":2025,"finding":"FAM111B regulates intracellular pH homeostasis in pancreatic cancer cells under acidic conditions; FAM111B knockdown altered pHi and sensitized cells to gemcitabine in vitro and in xenograft models.","method":"RNA sequencing (acidic condition screen), intracellular pH measurement assays, siRNA knockdown, xenograft models","journal":"Cancer science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pHi measurement after knockdown, single lab, mechanism of pH regulation not established at molecular level","pmids":["41027839"],"is_preprint":false},{"year":2021,"finding":"Nuclear localization of FAM111B was confirmed in fibrosarcoma (HT1080) cells; FAM111B promotes cell migration, decreases apoptosis, and has modulatory effects on proliferation; POIKTMP-associated Y621D mutation shows similar effects on migration but minimal impact on apoptosis compared to wild-type.","method":"Western blot, cell-based functional assays (migration, apoptosis, proliferation), nuclear fractionation/immunofluorescence in HT1080 cells and POIKTMP patient-derived fibroblasts","journal":"Cancer treatment and research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, localization by imaging plus functional assays but no molecular partner identified","pmids":["36610347"],"is_preprint":false}],"current_model":"FAM111B encodes a nuclear trypsin-like serine protease whose catalytic (peptidase) domain directly degrades substrates including p16, P27, and GSDMA to drive cell cycle progression and tumor cell survival; it interacts with nucleoporins at the nuclear pore complex and recruits RANBP9/CTLH E3 ligase to promote MFN2 ubiquitination; loss of FAM111B perturbs the ubiquitin-proteasome system and telomere maintenance, while disease-associated gain-of-function or dominant-negative mutations in the peptidase domain cause POIKTMP by altering protease activity and promoting accumulation of the mutant protein at the nuclear envelope."},"narrative":{"mechanistic_narrative":"FAM111B is a nuclear trypsin-like serine protease that controls cell cycle progression and cell survival by directly degrading cell-cycle inhibitors and other substrates [PMID:32418298, PMID:40975977]. Its catalytic activity drives proliferation: it degrades p16 to permit cyclin D1-CDK4-dependent progression in KRAS-driven lung adenocarcinoma [PMID:32418298], and hydrolyzes the CDK inhibitor P27 via its catalytic triad to activate Cyclin-CDK/RB/E2F1 signaling, raise LDHA transcription, and promote glycolytic metastasis [PMID:40975977]. The trypsin protease domain is also required for binding and degradation of GSDMA, an axis that drives esophageal cancer progression and modulates cisplatin sensitivity [PMID:37672204]. Beyond direct proteolysis, FAM111B interacts with nucleoporins of the nuclear pore complex and maintains nuclear shape and telomeric DNA content, with its loss producing micronuclei and ultra-fine DNA bridges [PMID:37342232], and it recruits the CTLH E3 ligase subunit RANBP9 to promote MFN2 ubiquitination, thereby controlling mitochondrial fusion, metabolic balance, and mitophagy [PMID:40855067]. FAM111B additionally acts as a host restriction factor against DNA viruses, suppressing adenovirus and cytomegalovirus replication from nuclear viral replication compartments [PMID:34071532, PMID:39494906]. Dominant missense mutations clustering in the peptidase domain cause hereditary fibrosing poikiloderma with tendon contracture, myopathy and pulmonary fibrosis (POIKTMP) [PMID:24268661], and these variants perturb ubiquitin-proteasome function and drive a sterile type I interferon signature in patient cells [PMID:40840166].","teleology":[{"year":2013,"claim":"Established FAM111B as a disease gene by linking it to a defined Mendelian multisystem fibrosing syndrome, and pinpointed its likely catalytic identity through mutation clustering.","evidence":"Whole-exome sequencing and segregation analysis across POIKTMP pedigrees","pmids":["24268661"],"confidence":"High","gaps":["No enzymatic assay confirming protease activity","Mechanism by which mutations cause multisystem fibrosis unknown","No substrate identified"]},{"year":2015,"claim":"Reinforced that pathogenic variants concentrate in the trypsin-like peptidase domain, framing disease as a gain-of-function or dominant-negative alteration of enzymatic activity.","evidence":"Domain mapping of missense variants across 10 independent families","pmids":["26471370"],"confidence":"Medium","gaps":["No direct enzymatic measurement","Gain-of-function vs dominant-negative not distinguished biochemically"]},{"year":2020,"claim":"Provided the first mechanistic function by showing FAM111B drives cell cycle progression through degradation of the CDK4 inhibitor p16, placing it in proliferative signaling.","evidence":"FAM111B-knockout cell lines with proliferation/cell-cycle assays and p16/cyclin D1-CDK4 immunoblotting","pmids":["32418298"],"confidence":"Medium","gaps":["Direct proteolysis of p16 not biochemically reconstituted","Single tumor context (KRAS lung adenocarcinoma)"]},{"year":2021,"claim":"Identified FAM111B as an antiviral host restriction factor whose levels are actively counteracted by viral oncoproteins, expanding its role beyond proliferation.","evidence":"shRNA knockdown and adenovirus replication assays implicating E1B-55K/E4orf6","pmids":["34071532"],"confidence":"Medium","gaps":["Molecular mechanism of restriction unknown","Whether protease activity is required not tested"]},{"year":2022,"claim":"Showed FAM111B expression is epigenetically silenced, defining upstream transcriptional control via promoter methylation.","evidence":"ChIP for DNMT3B promoter binding plus methylation and functional assays in thyroid cancer","pmids":["35864964"],"confidence":"Medium","gaps":["Downstream FAM111B effector in this context not defined","Single cancer type"]},{"year":2023,"claim":"Connected FAM111B to nuclear architecture and genome stability, demonstrating physical association with the nuclear pore complex and a role in telomere maintenance.","evidence":"Co-IP with nucleoporins, nuclear imaging, telomere FISH/qPCR and micronuclei assays in U2OS/MCF7 cells","pmids":["37342232"],"confidence":"Medium","gaps":["Specific nucleoporin partners not resolved","Mechanism linking protease activity to telomere maintenance unknown","Single lab"]},{"year":2023,"claim":"Demonstrated that the trypsin protease domain is required for degrading a specific substrate (GSDMA), directly tying catalytic function to tumor phenotypes and drug response.","evidence":"Co-IP, trypsin-domain mutagenesis, RNA-seq and xenografts in esophageal cancer","pmids":["37672204"],"confidence":"Medium","gaps":["Cleavage site on GSDMA not mapped","In vitro proteolysis not reconstituted"]},{"year":2024,"claim":"Extended antiviral function to herpesviruses and identified an activating transcription factor, distinguishing FAM111B from its paralog FAM111A.","evidence":"CRISPR knockout and shRNA with MCMV replication readouts, transcriptome analysis, and immunofluorescence of viral replication compartments","pmids":["39494906"],"confidence":"Medium","gaps":["Restriction mechanism within replication compartments undefined","Role of protease activity not tested"]},{"year":2025,"claim":"Defined a non-proteolytic adaptor function in which FAM111B recruits an E3 ligase to control mitochondrial dynamics and metabolism.","evidence":"Co-IP of FAM111B-RANBP9, MFN2 stability assays, mitochondrial imaging and metabolic flux assays with xenografts","pmids":["40855067"],"confidence":"Medium","gaps":["Whether MFN2 ubiquitination requires FAM111B catalytic activity unclear","Direct vs scaffold role in ligase recruitment not separated"]},{"year":2025,"claim":"Provided direct biochemical evidence of FAM111B protease activity by showing catalytic-triad-dependent hydrolysis of P27 driving a glycolytic, pro-metastatic program.","evidence":"In vitro hydrolysis assay with hydrolytic triad, transcriptomic/proteomic analysis and in vivo metastasis assays in prostate cancer","pmids":["40975977"],"confidence":"Medium","gaps":["Cleavage site on P27 not mapped","Full substrate repertoire unknown"]},{"year":2025,"claim":"Linked disease-causing variants to a molecular pathology in patients, showing UPS dysfunction and a sterile interferon signature that scales with mutation location.","evidence":"Multi-omics of patient-derived cells, ubiquitin conjugate assays and interferon signature analysis in a 41-patient POIKTMP cohort","pmids":["40840166"],"confidence":"Medium","gaps":["Causal chain from variant protease change to UPS perturbation undefined","Trigger of interferon signature unknown"]},{"year":null,"claim":"How FAM111B catalytic activity, substrate selection, nuclear pore association, and E3-ligase scaffolding are coordinated — and how disease mutations mechanistically alter these functions to produce multisystem fibrosis — remains unresolved.","evidence":"No single study integrates the protease, adaptor, genome-maintenance, and antiviral roles","pmids":[],"confidence":"Medium","gaps":["No structure of FAM111B or substrate-bound complex","Full physiological substrate repertoire unknown","Mechanistic basis of tissue-specific POIKTMP pathology unestablished"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[5,11]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[2,5,11]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[9]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,6,16]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2,11]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[9,12]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,6,12]}],"complexes":["nuclear pore complex"],"partners":["GSDMA","RANBP9","MFN2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6SJ93","full_name":"Serine protease FAM111B","aliases":["Cancer-associated nucleoprotein"],"length_aa":734,"mass_kda":84.7,"function":"Serine protease","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q6SJ93/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FAM111B","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FAM111B","total_profiled":1310},"omim":[{"mim_id":"615704","title":"POIKILODERMA, HEREDITARY FIBROSING, WITH TENDON CONTRACTURES, MYOPATHY, AND PULMONARY FIBROSIS; POIKTMP","url":"https://www.omim.org/entry/615704"},{"mim_id":"615584","title":"FAMILY WITH SEQUENCE SIMILARITY 111, MEMBER B; FAM111B","url":"https://www.omim.org/entry/615584"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":16.7}],"url":"https://www.proteinatlas.org/search/FAM111B"},"hgnc":{"alias_symbol":["CANP"],"prev_symbol":[]},"alphafold":{"accession":"Q6SJ93","domains":[{"cath_id":"-","chopping":"80-271","consensus_level":"medium","plddt":81.1278,"start":80,"end":271},{"cath_id":"-","chopping":"384-440","consensus_level":"high","plddt":76.5339,"start":384,"end":440},{"cath_id":"2.40.10.120","chopping":"449-605_623-718","consensus_level":"medium","plddt":87.4283,"start":449,"end":718}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6SJ93","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6SJ93-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6SJ93-F1-predicted_aligned_error_v6.png","plddt_mean":69.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FAM111B","jax_strain_url":"https://www.jax.org/strain/search?query=FAM111B"},"sequence":{"accession":"Q6SJ93","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6SJ93.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6SJ93/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6SJ93"}},"corpus_meta":[{"pmid":"24268661","id":"PMC_24268661","title":"Mutations in FAM111B cause hereditary fibrosing poikiloderma with tendon contracture, myopathy, and pulmonary fibrosis.","date":"2013","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24268661","citation_count":73,"is_preprint":false},{"pmid":"35864964","id":"PMC_35864964","title":"DNMT3B-mediated FAM111B methylation promotes papillary thyroid tumor glycolysis, growth and metastasis.","date":"2022","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35864964","citation_count":50,"is_preprint":false},{"pmid":"31114230","id":"PMC_31114230","title":"FAM111B, a direct target of p53, promotes the malignant process of lung adenocarcinoma.","date":"2019","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/31114230","citation_count":50,"is_preprint":false},{"pmid":"32418298","id":"PMC_32418298","title":"FAM111B enhances proliferation of KRAS-driven lung adenocarcinoma by degrading p16.","date":"2020","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/32418298","citation_count":48,"is_preprint":false},{"pmid":"26471370","id":"PMC_26471370","title":"Expanding the clinical spectrum of hereditary fibrosing poikiloderma with tendon contractures, myopathy and pulmonary fibrosis due to FAM111B mutations.","date":"2015","source":"Orphanet journal of rare diseases","url":"https://pubmed.ncbi.nlm.nih.gov/26471370","citation_count":37,"is_preprint":false},{"pmid":"26495788","id":"PMC_26495788","title":"FAM111B Mutation Is Associated With Inherited Exocrine Pancreatic Dysfunction.","date":"2016","source":"Pancreas","url":"https://pubmed.ncbi.nlm.nih.gov/26495788","citation_count":31,"is_preprint":false},{"pmid":"34802969","id":"PMC_34802969","title":"YY1-Induced Transcriptional Activation of FAM111B Contributes to the Malignancy of Breast Cancer.","date":"2021","source":"Clinical breast 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Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/37672204","citation_count":13,"is_preprint":false},{"pmid":"37270349","id":"PMC_37270349","title":"Silencing of FAM111B inhibited proliferation, migration and invasion of hepatoma cells through activating p53 pathway.","date":"2023","source":"Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver","url":"https://pubmed.ncbi.nlm.nih.gov/37270349","citation_count":11,"is_preprint":false},{"pmid":"31392773","id":"PMC_31392773","title":"Family of hereditary fibrosing poikiloderma with tendon contractures, myopathy and pulmonary fibrosis caused by a novel FAM111B mutation.","date":"2019","source":"The Journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/31392773","citation_count":11,"is_preprint":false},{"pmid":"37095701","id":"PMC_37095701","title":"Silencing of FAM111B inhibits tumor growth and promotes apoptosis by decreasing AKT activity in ovarian cancer.","date":"2023","source":"Experimental biology and medicine (Maywood, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/37095701","citation_count":8,"is_preprint":false},{"pmid":"37487252","id":"PMC_37487252","title":"A Boolean model of the oncogene role of FAM111B in lung adenocarcinoma.","date":"2023","source":"Computational biology and chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37487252","citation_count":8,"is_preprint":false},{"pmid":"34071532","id":"PMC_34071532","title":"Differential Regulation of Cellular FAM111B by Human Adenovirus C Type 5 E1 Oncogenes.","date":"2021","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/34071532","citation_count":7,"is_preprint":false},{"pmid":"39337462","id":"PMC_39337462","title":"Identification of Tumor Suppressive miR-144-5p Targets: FAM111B Expression Accelerates the Malignant Phenotypes of Lung Adenocarcinoma.","date":"2024","source":"International journal of molecular 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promotes proliferation and metastasis of pancreatic ductal adenocarcinoma through interactions with FAM111B.","date":"2024","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/39556158","citation_count":6,"is_preprint":false},{"pmid":"36610347","id":"PMC_36610347","title":"FAM111B dysregulation promotes malignancy in fibrosarcoma and POIKTMP and a low-cost method for its mutation screening.","date":"2023","source":"Cancer treatment and research communications","url":"https://pubmed.ncbi.nlm.nih.gov/36610347","citation_count":4,"is_preprint":false},{"pmid":"36092869","id":"PMC_36092869","title":"Case Report: Diverse phenotypes of congenital poikiloderma associated with FAM111B mutations in codon 628: A case report and literature review.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36092869","citation_count":4,"is_preprint":false},{"pmid":"40855067","id":"PMC_40855067","title":"Targeting FAM111B attenuates mitophagy and increases the sensitivity to lenvatinib treatment by increasing MFN2 stability in hepatocellular carcinoma.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/40855067","citation_count":3,"is_preprint":false},{"pmid":"39494906","id":"PMC_39494906","title":"E2F3-dependent activation of FAM111B restricts mouse cytomegalovirus replication in primate cells.","date":"2024","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/39494906","citation_count":3,"is_preprint":false},{"pmid":"40975977","id":"PMC_40975977","title":"FAM111B enhances glycolysis and promotes metastasis of prostate cancer by upregulating LDHA.","date":"2025","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/40975977","citation_count":2,"is_preprint":false},{"pmid":"30375432","id":"PMC_30375432","title":"Mutations of FAM111B gene are not associated with Systemic Sclerosis.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30375432","citation_count":2,"is_preprint":false},{"pmid":"40781291","id":"PMC_40781291","title":"FAM111B knockdown attenuates tumorigenesis of ovarian cancer via the downregulation of MYC.","date":"2025","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/40781291","citation_count":2,"is_preprint":false},{"pmid":"36575358","id":"PMC_36575358","title":"A Novel De Novo Frameshift Pathogenic Variant in the FAM111B Resulting in Progressive Osseous Heteroplasia Phenotype.","date":"2022","source":"Calcified tissue international","url":"https://pubmed.ncbi.nlm.nih.gov/36575358","citation_count":2,"is_preprint":false},{"pmid":"41027839","id":"PMC_41027839","title":"FAM111B Suppression Enhances Sensitivity to Gemcitabine in Pancreatic Cancer Through Intracellular pH Regulation.","date":"2025","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/41027839","citation_count":1,"is_preprint":false},{"pmid":"40564014","id":"PMC_40564014","title":"FAM111B Overexpression and Immune Cell Infiltration: Implications for Ovarian Cancer Immunotherapy.","date":"2025","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/40564014","citation_count":0,"is_preprint":false},{"pmid":"40405284","id":"PMC_40405284","title":"FAM111B and FANCD2, a dual expression signature, defines a distinct phenotype of pancreatic cancer.","date":"2025","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/40405284","citation_count":0,"is_preprint":false},{"pmid":"41454362","id":"PMC_41454362","title":"FAM111B promotes prostate cancer progression by inhibiting apoptosis via ATF3 suppression and MAPK pathway activation: a novel biomarker and therapeutic target.","date":"2025","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/41454362","citation_count":0,"is_preprint":false},{"pmid":"41211642","id":"PMC_41211642","title":"The ELF1/IGF2BP2/FAM111B Cascade Drives Colorectal Cancer Progression and Ferroptosis Resistance.","date":"2025","source":"Clinical and experimental pharmacology & physiology","url":"https://pubmed.ncbi.nlm.nih.gov/41211642","citation_count":0,"is_preprint":false},{"pmid":"40840166","id":"PMC_40840166","title":"Ubiquitin-proteasome system dysregulation in FAM111B-related poikiloderma and phenotypic spectrum expansion: new case reports and long-term follow-up.","date":"2025","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/40840166","citation_count":0,"is_preprint":false},{"pmid":"40390043","id":"PMC_40390043","title":"The role of FAM111B in the malignant progression and molecular regulation of human glioma through the PI3K/Akt pathway.","date":"2025","source":"Chinese neurosurgical journal","url":"https://pubmed.ncbi.nlm.nih.gov/40390043","citation_count":0,"is_preprint":false},{"pmid":"41815140","id":"PMC_41815140","title":"Pan-cancer analysis identifies FAM111B as a biomarker for immune suppression microenvironment in low-grade gliomas.","date":"2026","source":"Translational cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/41815140","citation_count":0,"is_preprint":false},{"pmid":"42230862","id":"PMC_42230862","title":"FAM111B may promote the progression of lung squamous cell carcinoma through PI3K signaling pathway.","date":"2026","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/42230862","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":20391,"output_tokens":3861,"usd":0.059544,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11733,"output_tokens":3511,"usd":0.07322,"stage2_stop_reason":"end_turn"},"total_usd":0.132764,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"Causative missense mutations in FAM111B identified in hereditary fibrosing poikiloderma with tendon contracture, myopathy, and pulmonary fibrosis (POIKTMP); all three mutations cluster within a putative trypsin-like cysteine/serine peptidase domain of the protein.\",\n      \"method\": \"Whole-exome sequencing, Sanger sequencing validation, segregation analysis in pedigrees\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple independent kindreds, de novo confirmation, replicated across 5 families from different ethnic backgrounds\",\n      \"pmids\": [\"24268661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"All POIKTMP-associated FAM111B mutations localize to the trypsin-like cysteine/serine peptidase domain, suggesting gain-of-function or dominant-negative effects leading to enzymatic activity changes.\",\n      \"method\": \"Clinical molecular genetics, domain mapping of missense variants across 10 independent families\",\n      \"journal\": \"Orphanet journal of rare diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — domain clustering of mutations across multiple independent families, but no direct enzymatic assay performed\",\n      \"pmids\": [\"26471370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FAM111B promotes cell cycle progression in KRAS-driven lung adenocarcinoma by degrading p16, thereby enabling cyclin D1-CDK4-dependent progression; FAM111B-knockout cells showed impaired proliferation and cell cycle progression under serum-starvation conditions.\",\n      \"method\": \"FAM111B-knockout cell lines, in vitro functional assays (proliferation, cell cycle), western blot for p16/cyclin D1-CDK4\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO cells with defined phenotype and pathway placement, single lab\",\n      \"pmids\": [\"32418298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FAM111B expression is regulated by adenovirus type 5 (HAdV-C5): levels are upregulated early and downregulated late during infection; downregulation depends on the presence of viral E1B-55K and E4orf6 oncoproteins; FAM111B knockdown increases HAdV-C5 replication, establishing FAM111B as an anti-adenoviral host restriction factor.\",\n      \"method\": \"shRNA knockdown, adenovirus infection assays, viral replication quantification, immunoblotting\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with defined viral replication phenotype, identification of viral regulatory proteins responsible, single lab\",\n      \"pmids\": [\"34071532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FAM111B interacts with components of the nuclear pore complex (nucleoporins); loss of FAM111B causes abnormal nuclear shape, reduced telomeric DNA content (independent of telomerase or recombination-driven extension), increased micronuclei, and ultra-fine DNA bridges. HFP-associated mutant FAM111B localizes more frequently to the nuclear envelope compared to wild-type.\",\n      \"method\": \"Co-immunoprecipitation with nucleoporins, immunofluorescence/live imaging of nuclear localization, telomere length assays (FISH, qPCR), micronuclei counting, U2OS and MCF7 cell lines with FAM111B loss-of-function\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for binding partners, direct localization experiment with functional consequence, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"37342232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FAM111B binds to GSDMA and promotes its degradation; the trypsin protease domain of FAM111B is essential for this activity. The FAM111B/GSDMA axis promotes esophageal cancer cell progression and regulates sensitivity to cisplatin.\",\n      \"method\": \"Co-immunoprecipitation, western blot, domain deletion/mutagenesis of trypsin domain, RNA-seq, xenograft assays\",\n      \"journal\": \"Cellular oncology (Dordrecht, Netherlands)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP binding demonstrated and domain-function linkage via trypsin domain requirement, single lab\",\n      \"pmids\": [\"37672204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"E2F3 transcriptionally activates FAM111B expression; FAM111B (but not its paralog FAM111A) suppresses mouse cytomegalovirus (MCMV) replication in human and rhesus macaque cells; FAM111B localizes predominantly to the nucleus with enrichment in viral replication compartments in infected cells.\",\n      \"method\": \"shRNA knockdown, CRISPR/Cas9 knockout, transcriptome analysis, immunofluorescence, viral replication assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with viral replication readout, transcriptome + immunofluorescence, single lab with two orthogonal genetic approaches\",\n      \"pmids\": [\"39494906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DNMT3B methylates the FAM111B promoter (recruited by estrogen signaling), suppressing FAM111B transcription in papillary thyroid cancer; ChIP assay demonstrated DNMT3B binding to the FAM111B promoter.\",\n      \"method\": \"ChIP assay, DNMT3B overexpression/knockdown, promoter methylation analysis, in vitro and in vivo functional assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP directly demonstrates DNMT3B recruitment to FAM111B promoter, functional rescue experiments, single lab\",\n      \"pmids\": [\"35864964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YY1 transcription factor binds to the promoter of FAM111B and activates its transcription in breast cancer cells, as demonstrated by ChIP-qPCR.\",\n      \"method\": \"ChIP-qPCR, luciferase reporter assay, siRNA knockdown\",\n      \"journal\": \"Clinical breast cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/ChIP method, single lab, no direct functional rescue linking YY1-FAM111B axis mechanistically\",\n      \"pmids\": [\"34802969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FAM111B promotes MFN2 ubiquitination and degradation by recruiting RANBP9, a core subunit of the CTLH E3 ligase complex; FAM111B loss generates hyperfused mitochondria, shifts metabolism from glycolysis to OXPHOS, and antagonizes cytoprotective mitophagy.\",\n      \"method\": \"Co-immunoprecipitation (FAM111B-RANBP9 interaction), protein stability assays, mitochondrial morphology imaging, metabolic flux assays, xenograft models with siFAM111B lipid nanoparticles\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating binding, protein stability assays, metabolic phenotype with multiple assays, single lab\",\n      \"pmids\": [\"40855067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRIM2 upregulates FAM111B at both RNA and protein stability levels; the PRIM2/FAM111B axis promotes proliferation and migration via PI3K/AKT pathway and EMT markers in pancreatic ductal adenocarcinoma.\",\n      \"method\": \"Co-immunoprecipitation, protein stability assays, western blot, xenograft models\",\n      \"journal\": \"Medical oncology (Northwood, London, England)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and protein stability, single lab, pathway placement inferred from downstream markers without direct mechanistic dissection\",\n      \"pmids\": [\"39556158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FAM111B protein binds and hydrolyzes the CDK inhibitor P27, which activates the Cyclin-CDKs/RB/E2F1 signaling pathway to increase LDHA transcription, thereby enhancing glycolysis and promoting prostate cancer metastasis.\",\n      \"method\": \"Transcriptomic and proteomic analysis, western blot, in vitro hydrolysis assay (functional coding region including hydrolytic triad), gene enrichment analysis, in vivo metastasis assays\",\n      \"journal\": \"Neoplasia (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct proteolytic activity on P27 demonstrated via hydrolytic triad of FAM111B, pathway activation validated by multiple downstream markers, single lab\",\n      \"pmids\": [\"40975977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of FAM111B expression perturbs ubiquitin-proteasome system (UPS) function in patient-derived cells carrying FAM111B missense variants, leading to increased ubiquitin-protein conjugates and a sterile type I interferon signature; variants clustering in the D-box domain associate with more severe phenotypes.\",\n      \"method\": \"Omics analysis of patient-derived cells (proteomics/transcriptomics), ubiquitin conjugate accumulation assays, interferon signature analysis; 41 POIKTMP patients compiled\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived cell omics with multiple orthogonal technologies, large patient cohort, single lab\",\n      \"pmids\": [\"40840166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FAM111B downregulates ATF3 expression in prostate cancer cells; reduced ATF3 occupancy at the KRAS promoter leads to upregulated KRAS and enhanced RAF1-MEK-ERK pathway activation, inhibiting apoptosis; rescue experiments with ATF3 overexpression reversed FAM111B-driven phenotypes.\",\n      \"method\": \"qPCR, western blot, immunofluorescence, rescue experiments (ATF3 overexpression), in vitro and in vivo models\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway inferred from rescue experiments without direct FAM111B-ATF3 binding demonstrated, no direct chromatin or protease assay\",\n      \"pmids\": [\"41454362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IGF2BP2 stabilizes FAM111B mRNA; ELF1 transcriptionally upregulates IGF2BP2; this ELF1/IGF2BP2/FAM111B cascade promotes colorectal cancer cell proliferation, migration, and ferroptosis resistance; demonstrated by luciferase reporter and ChIP assays.\",\n      \"method\": \"Luciferase reporter assay, ChIP assay, mRNA stability assay, knockdown/rescue experiments, xenograft\",\n      \"journal\": \"Clinical and experimental pharmacology & physiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ChIP and reporter assays for ELF1-IGF2BP2 axis, mRNA stability for IGF2BP2-FAM111B, single lab\",\n      \"pmids\": [\"41211642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FAM111B regulates intracellular pH homeostasis in pancreatic cancer cells under acidic conditions; FAM111B knockdown altered pHi and sensitized cells to gemcitabine in vitro and in xenograft models.\",\n      \"method\": \"RNA sequencing (acidic condition screen), intracellular pH measurement assays, siRNA knockdown, xenograft models\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pHi measurement after knockdown, single lab, mechanism of pH regulation not established at molecular level\",\n      \"pmids\": [\"41027839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Nuclear localization of FAM111B was confirmed in fibrosarcoma (HT1080) cells; FAM111B promotes cell migration, decreases apoptosis, and has modulatory effects on proliferation; POIKTMP-associated Y621D mutation shows similar effects on migration but minimal impact on apoptosis compared to wild-type.\",\n      \"method\": \"Western blot, cell-based functional assays (migration, apoptosis, proliferation), nuclear fractionation/immunofluorescence in HT1080 cells and POIKTMP patient-derived fibroblasts\",\n      \"journal\": \"Cancer treatment and research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, localization by imaging plus functional assays but no molecular partner identified\",\n      \"pmids\": [\"36610347\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FAM111B encodes a nuclear trypsin-like serine protease whose catalytic (peptidase) domain directly degrades substrates including p16, P27, and GSDMA to drive cell cycle progression and tumor cell survival; it interacts with nucleoporins at the nuclear pore complex and recruits RANBP9/CTLH E3 ligase to promote MFN2 ubiquitination; loss of FAM111B perturbs the ubiquitin-proteasome system and telomere maintenance, while disease-associated gain-of-function or dominant-negative mutations in the peptidase domain cause POIKTMP by altering protease activity and promoting accumulation of the mutant protein at the nuclear envelope.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FAM111B is a nuclear trypsin-like serine protease that controls cell cycle progression and cell survival by directly degrading cell-cycle inhibitors and other substrates [#2, #11]. Its catalytic activity drives proliferation: it degrades p16 to permit cyclin D1-CDK4-dependent progression in KRAS-driven lung adenocarcinoma [#2], and hydrolyzes the CDK inhibitor P27 via its catalytic triad to activate Cyclin-CDK/RB/E2F1 signaling, raise LDHA transcription, and promote glycolytic metastasis [#11]. The trypsin protease domain is also required for binding and degradation of GSDMA, an axis that drives esophageal cancer progression and modulates cisplatin sensitivity [#5]. Beyond direct proteolysis, FAM111B interacts with nucleoporins of the nuclear pore complex and maintains nuclear shape and telomeric DNA content, with its loss producing micronuclei and ultra-fine DNA bridges [#4], and it recruits the CTLH E3 ligase subunit RANBP9 to promote MFN2 ubiquitination, thereby controlling mitochondrial fusion, metabolic balance, and mitophagy [#9]. FAM111B additionally acts as a host restriction factor against DNA viruses, suppressing adenovirus and cytomegalovirus replication from nuclear viral replication compartments [#3, #6]. Dominant missense mutations clustering in the peptidase domain cause hereditary fibrosing poikiloderma with tendon contracture, myopathy and pulmonary fibrosis (POIKTMP) [#0], and these variants perturb ubiquitin-proteasome function and drive a sterile type I interferon signature in patient cells [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established FAM111B as a disease gene by linking it to a defined Mendelian multisystem fibrosing syndrome, and pinpointed its likely catalytic identity through mutation clustering.\",\n      \"evidence\": \"Whole-exome sequencing and segregation analysis across POIKTMP pedigrees\",\n      \"pmids\": [\"24268661\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No enzymatic assay confirming protease activity\", \"Mechanism by which mutations cause multisystem fibrosis unknown\", \"No substrate identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Reinforced that pathogenic variants concentrate in the trypsin-like peptidase domain, framing disease as a gain-of-function or dominant-negative alteration of enzymatic activity.\",\n      \"evidence\": \"Domain mapping of missense variants across 10 independent families\",\n      \"pmids\": [\"26471370\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct enzymatic measurement\", \"Gain-of-function vs dominant-negative not distinguished biochemically\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided the first mechanistic function by showing FAM111B drives cell cycle progression through degradation of the CDK4 inhibitor p16, placing it in proliferative signaling.\",\n      \"evidence\": \"FAM111B-knockout cell lines with proliferation/cell-cycle assays and p16/cyclin D1-CDK4 immunoblotting\",\n      \"pmids\": [\"32418298\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct proteolysis of p16 not biochemically reconstituted\", \"Single tumor context (KRAS lung adenocarcinoma)\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified FAM111B as an antiviral host restriction factor whose levels are actively counteracted by viral oncoproteins, expanding its role beyond proliferation.\",\n      \"evidence\": \"shRNA knockdown and adenovirus replication assays implicating E1B-55K/E4orf6\",\n      \"pmids\": [\"34071532\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of restriction unknown\", \"Whether protease activity is required not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed FAM111B expression is epigenetically silenced, defining upstream transcriptional control via promoter methylation.\",\n      \"evidence\": \"ChIP for DNMT3B promoter binding plus methylation and functional assays in thyroid cancer\",\n      \"pmids\": [\"35864964\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream FAM111B effector in this context not defined\", \"Single cancer type\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected FAM111B to nuclear architecture and genome stability, demonstrating physical association with the nuclear pore complex and a role in telomere maintenance.\",\n      \"evidence\": \"Co-IP with nucleoporins, nuclear imaging, telomere FISH/qPCR and micronuclei assays in U2OS/MCF7 cells\",\n      \"pmids\": [\"37342232\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific nucleoporin partners not resolved\", \"Mechanism linking protease activity to telomere maintenance unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated that the trypsin protease domain is required for degrading a specific substrate (GSDMA), directly tying catalytic function to tumor phenotypes and drug response.\",\n      \"evidence\": \"Co-IP, trypsin-domain mutagenesis, RNA-seq and xenografts in esophageal cancer\",\n      \"pmids\": [\"37672204\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cleavage site on GSDMA not mapped\", \"In vitro proteolysis not reconstituted\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended antiviral function to herpesviruses and identified an activating transcription factor, distinguishing FAM111B from its paralog FAM111A.\",\n      \"evidence\": \"CRISPR knockout and shRNA with MCMV replication readouts, transcriptome analysis, and immunofluorescence of viral replication compartments\",\n      \"pmids\": [\"39494906\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Restriction mechanism within replication compartments undefined\", \"Role of protease activity not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a non-proteolytic adaptor function in which FAM111B recruits an E3 ligase to control mitochondrial dynamics and metabolism.\",\n      \"evidence\": \"Co-IP of FAM111B-RANBP9, MFN2 stability assays, mitochondrial imaging and metabolic flux assays with xenografts\",\n      \"pmids\": [\"40855067\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MFN2 ubiquitination requires FAM111B catalytic activity unclear\", \"Direct vs scaffold role in ligase recruitment not separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided direct biochemical evidence of FAM111B protease activity by showing catalytic-triad-dependent hydrolysis of P27 driving a glycolytic, pro-metastatic program.\",\n      \"evidence\": \"In vitro hydrolysis assay with hydrolytic triad, transcriptomic/proteomic analysis and in vivo metastasis assays in prostate cancer\",\n      \"pmids\": [\"40975977\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cleavage site on P27 not mapped\", \"Full substrate repertoire unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked disease-causing variants to a molecular pathology in patients, showing UPS dysfunction and a sterile interferon signature that scales with mutation location.\",\n      \"evidence\": \"Multi-omics of patient-derived cells, ubiquitin conjugate assays and interferon signature analysis in a 41-patient POIKTMP cohort\",\n      \"pmids\": [\"40840166\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain from variant protease change to UPS perturbation undefined\", \"Trigger of interferon signature unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FAM111B catalytic activity, substrate selection, nuclear pore association, and E3-ligase scaffolding are coordinated — and how disease mutations mechanistically alter these functions to produce multisystem fibrosis — remains unresolved.\",\n      \"evidence\": \"No single study integrates the protease, adaptor, genome-maintenance, and antiviral roles\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of FAM111B or substrate-bound complex\", \"Full physiological substrate repertoire unknown\", \"Mechanistic basis of tissue-specific POIKTMP pathology unestablished\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [5, 11]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [2, 5, 11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 6, 16]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2, 11]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [9, 12]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 6, 12]}\n    ],\n    \"complexes\": [\"nuclear pore complex\"],\n    \"partners\": [\"GSDMA\", \"RANBP9\", \"MFN2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}