{"gene":"FIRRM","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2023,"finding":"FIRRM interacts with and stabilizes the AAA+ ATPase FIGNL1; inactivation of either FIRRM or FIGNL1 results in ultrafine DNA bridge (UFB) formation, prolonged accumulation of RAD51 at nuclear foci, and impaired replication fork dynamics, indicating that FIRRM-FIGNL1 regulates RAD51 dynamics at replication forks to maintain genome integrity.","method":"Genome-wide loss-of-function screen, co-immunoprecipitation, RAD51 foci analysis, replication fork dynamics assay, UFB imaging","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction established, multiple orthogonal methods (genetic screen, Co-IP, foci analysis, fork dynamics), replicated across multiple papers","pmids":["37347663"],"is_preprint":false},{"year":2021,"finding":"Apolo1 (FIRRM) localizes to kinetochores during early mitosis, sustains PLK1 kinase activity at kinetochores during prometaphase for accurate kinetochore-microtubule attachment, is a cognate substrate of PLK1 (phosphorylated by PLK1), and phosphorylation enables PP1γ to subsequently inactivate PLK1 by dephosphorylation — constituting a feedback loop that governs PLK1 activity.","method":"FRET-based PLK1 activity reporter, live-cell imaging (kinetochore localization), kinase substrate assay, phosphatase (PP1γ) interaction/dephosphorylation assay, siRNA knockdown with chromosome alignment phenotype","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods in one study including FRET reporter, substrate phosphorylation assay, phosphatase recruitment, and localization with functional consequence","pmids":["34260926"],"is_preprint":false},{"year":2023,"finding":"FIRRM is recruited to ICL (interstrand crosslink) sites, controls MUS81 chromatin loading, and thereby mediates resolution of homologous recombination intermediates generated during ICL repair; FIRRM deficiency causes hypersensitivity to ICL agents, DNA damage accumulation in S-G2, chromosomal aberrations, and a unique mutational signature associated with HR deficiency.","method":"Complementary CRISPR genetic screens, ICL sensitivity assays, cell cycle analysis (DNA damage accumulation in S-G2), chromatin fractionation (MUS81 loading), recruitment to ICLs (laser-induced damage foci), chromosomal aberration analysis, mouse knockout (early embryonic lethality)","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including genetic screens, chromatin fractionation, foci recruitment, and in vivo mouse model with epistatic analysis","pmids":["37256941"],"is_preprint":false},{"year":2024,"finding":"FIRRM (FLIP/C1orf112) forms a stable complex with FIGNL1 that is required to limit RAD51 amounts and foci on chromatin both in the presence and absence of exogenous DNA damage, and to promote RAD51 dissociation from nucleofilaments to complete HR; FLIP loss causes defective replication fork progression and reduced HR competency.","method":"Co-immunoprecipitation (stable complex), RAD51 chromatin fractionation/foci quantification, replication fork progression assay (fiber assay), HR reporter assay, ICL sensitivity assay, epistasis analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, chromatin fractionation, fiber assay, HR reporter) in single study, consistent with multiple independent labs","pmids":["38286805"],"is_preprint":false},{"year":2024,"finding":"The FIGNL1-FIRRM complex is essential for meiotic recombination; both proteins are required for completing meiotic prophase in mouse spermatocytes, and the complex limits RAD51 and DMC1 accumulation on intact chromatin independently of SPO11-catalyzed DSBs. Purified human FIGNL1ΔN alters the RAD51/DMC1 nucleoprotein filament structure and inhibits strand invasion in vitro.","method":"Male germline-specific conditional knockout (cKO) mouse models, immunofluorescence (RAD51/DMC1 foci), in vitro strand invasion assay with purified proteins, nucleoprotein filament structure analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified proteins plus in vivo cKO mouse model with defined meiotic phenotype and epistatic relationship to SPO11 DSBs","pmids":["39147779"],"is_preprint":false},{"year":2023,"finding":"FIRRM cooperates with FIGNL1 to promote resolution of RAD51 foci at ICL-induced DSBs; FIRRM stability is interdependent with FIGNL1. A FIRRM mutant lacking the WCF domain (ΔWCF) stabilizes FIRRM independently of FIGNL1 and rescues RAD51 foci resolution and cell survival, suggesting FIGNL1-independent function. FIRRM also binds preferentially to single-stranded DNA in vitro.","method":"CRISPR screen, Co-immunoprecipitation (FIRRM-FIGNL1 complex/stability), RAD51 foci analysis, domain-deletion mutagenesis (ΔWCF), in vitro ssDNA binding assay","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis (ΔWCF), in vitro ssDNA binding, Co-IP for complex stability, foci analysis; single lab but multiple orthogonal methods","pmids":["37556550"],"is_preprint":false},{"year":2023,"finding":"C1orf112 (FIRRM) physically interacts with FIGNL1, enhances FIGNL1 protein stability, and directly stimulates the RAD51 filament disassembly activity of FIGNL1. BRCA2 directly interacts with the C1orf112-FIGNL1 complex and functions upstream to protect RAD51 filaments from premature disassembly by this complex.","method":"RAD51 proximity proteomics, Co-immunoprecipitation, in vitro RAD51 filament disassembly assay with purified proteins, protein stability assay, epistasis analysis (BRCA2 upstream)","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of RAD51 filament disassembly with purified proteins, proximity proteomics, Co-IP, epistasis; single lab but multiple orthogonal methods including biochemical reconstitution","pmids":["37515771"],"is_preprint":false},{"year":2023,"finding":"The in vitro reconstitution of RAD51 filament disassembly by purified C1orf112/FIRRM-FIGNL1 complex was validated, and the antagonistic effect between C1orf112/FIRRM-FIGNL1 and BRCA2 on RAD51 filament stabilization was demonstrated biochemically using purified proteins from E. coli or S. cerevisiae.","method":"Protein purification from E. coli and S. cerevisiae, in vitro RAD51 filament disassembly reconstitution, competition assay with purified miBRCA2","journal":"STAR protocols","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified proteins confirming prior Cell Reports findings; protocol paper supporting biochemical mechanism","pmids":["38133958"],"is_preprint":false},{"year":2026,"finding":"FIRRM knockout in hepatocellular carcinoma cells reduces PLK1 phosphorylation and inhibits mitotic progression and the G2-to-M transition of the cell cycle, establishing that FIRRM promotes mitotic entry via PLK1-mediated signaling.","method":"CRISPR knockout of FIRRM in HCC cell lines, PLK1 phosphorylation assay (western blot), cell cycle analysis (flow cytometry), in vivo tumor proliferation assay","journal":"Journal of gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KO with defined cell cycle phenotype and PLK1 phosphorylation readout, but single lab, no mechanistic dissection of the pathway beyond PLK1 phosphorylation level","pmids":["42007975"],"is_preprint":false},{"year":2024,"finding":"Methionine restriction reduces C1orf112 expression in osteosarcoma cells, and reduced C1orf112 expression underlies methionine deprivation-initiated suppression of mitochondrial functions (dysregulated respiratory chain gene expression, increased mitochondrial ROS, reduced ATP production, decreased respiration, damaged mitochondrial membrane potential).","method":"Transcriptomic analysis, C1orf112 expression knockdown in cultured cells, mitochondrial function assays (ROS, ATP, oxygen consumption, membrane potential), xenograft models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — functional assays in cultured cells and in vivo, but mechanistic link between C1orf112 and mitochondrial function is correlative/knockdown-based without direct biochemical mechanism","pmids":["38769167"],"is_preprint":false}],"current_model":"FIRRM (C1orf112/Apolo1) forms a stable complex with the AAA+ ATPase FIGNL1 that is required to limit RAD51 (and DMC1) accumulation on chromatin, promote RAD51 disassembly from nucleofilaments after strand invasion, and ensure efficient resolution of homologous recombination intermediates at interstrand crosslinks and replication forks; independently, FIRRM localizes to kinetochores during prometaphase, acts as a PLK1 substrate that bridges PLK1 and PP1γ to create a feedback loop controlling PLK1 activity and accurate chromosome segregation."},"narrative":{"mechanistic_narrative":"FIRRM (C1orf112/FLIP/Apolo1) is a genome-stability factor that, through a stable complex with the AAA+ ATPase FIGNL1, controls the dynamics of RAD51 (and the meiotic recombinase DMC1) on chromatin to ensure faithful homologous recombination [PMID:37347663, PMID:38286805, PMID:37515771]. FIRRM and FIGNL1 are mutually stabilizing partners, and FIRRM directly stimulates the RAD51 filament-disassembly activity of FIGNL1, limiting RAD51 accumulation both with and without exogenous damage and promoting RAD51 dissociation from nucleofilaments after strand invasion to complete recombination [PMID:38286805, PMID:37515771]; this disassembly activity has been reconstituted in vitro with purified proteins, where BRCA2 acts upstream to protect filaments from premature disassembly by the complex [PMID:37515771, PMID:38133958]. Loss of FIRRM produces ultrafine DNA bridges, persistent RAD51 foci, defective replication fork progression, hypersensitivity to interstrand crosslinking agents with S-G2 damage accumulation and chromosomal aberrations, the complex acting at ICLs in part by controlling MUS81 chromatin loading [PMID:37347663, PMID:37256941, PMID:38286805]. The FIGNL1-FIRRM complex is likewise essential for meiotic recombination, limiting RAD51/DMC1 loading on intact chromatin independently of SPO11-generated breaks and altering recombinase filament structure to inhibit strand invasion in vitro, with mouse knockouts causing meiotic prophase arrest and early embryonic lethality [PMID:37256941, PMID:39147779]. Independently of its recombination role, FIRRM localizes to kinetochores in prometaphase where it serves as a PLK1 substrate, bridging PLK1 and PP1γ in a feedback loop that tunes PLK1 activity for accurate kinetochore-microtubule attachment and chromosome segregation [PMID:34260926].","teleology":[{"year":2021,"claim":"Established a mitotic role for FIRRM distinct from any recombination function by placing it at kinetochores as a regulator of PLK1 activity.","evidence":"FRET-based PLK1 activity reporter, live-cell kinetochore imaging, kinase substrate and PP1γ dephosphorylation assays, siRNA with chromosome alignment phenotype","pmids":["34260926"],"confidence":"High","gaps":["Relationship between the kinetochore/PLK1 role and the FIGNL1/RAD51 role is unresolved","Structural basis of PLK1-FIRRM-PP1γ bridging not defined"]},{"year":2023,"claim":"Identified FIRRM as a stabilizing partner of the AAA+ ATPase FIGNL1 that regulates RAD51 dynamics at replication forks, explaining UFB formation and fork defects on its loss.","evidence":"Genome-wide loss-of-function screen, Co-IP, RAD51 foci analysis, replication fork dynamics and UFB imaging","pmids":["37347663"],"confidence":"High","gaps":["Direct enzymatic mechanism not yet reconstituted at this stage","Did not define FIRRM action at ICLs versus other lesions"]},{"year":2023,"claim":"Defined FIRRM's role in interstrand crosslink repair, linking it to MUS81 chromatin loading, HR-intermediate resolution, and a HR-deficiency mutational signature, with in vivo essentiality.","evidence":"CRISPR screens, ICL sensitivity and cell-cycle assays, chromatin fractionation for MUS81, laser-induced ICL recruitment, chromosomal aberration analysis, mouse knockout","pmids":["37256941"],"confidence":"High","gaps":["How FIRRM controls MUS81 loading mechanistically is not defined","Whether ICL role is fully FIGNL1-dependent not resolved here"]},{"year":2023,"claim":"Dissected the FIRRM-FIGNL1 interdependence and revealed a potential FIGNL1-independent FIRRM activity, plus direct ssDNA binding.","evidence":"CRISPR screen, Co-IP for complex stability, ΔWCF domain-deletion mutagenesis, RAD51 foci analysis, in vitro ssDNA binding assay","pmids":["37556550"],"confidence":"High","gaps":["Functional significance of ssDNA binding not established","Nature of the FIGNL1-independent function not defined"]},{"year":2023,"claim":"Provided the biochemical mechanism: FIRRM directly stimulates FIGNL1-mediated RAD51 filament disassembly, with BRCA2 acting upstream to protect filaments.","evidence":"RAD51 proximity proteomics, Co-IP, in vitro RAD51 filament disassembly reconstitution with purified proteins, epistasis analysis","pmids":["37515771","38133958"],"confidence":"High","gaps":["Stoichiometry and structure of the complex on filaments unknown","How BRCA2 antagonism is regulated in cells not defined"]},{"year":2024,"claim":"Consolidated the stable FIRRM-FIGNL1 complex as the unit limiting chromatin RAD51 and promoting filament dissociation to complete HR and maintain fork progression.","evidence":"Co-IP, RAD51 chromatin fractionation/foci quantification, DNA fiber assay, HR reporter, ICL sensitivity, epistasis","pmids":["38286805"],"confidence":"High","gaps":["Temporal coordination of disassembly during HR steps not mapped","Regulation of the complex by post-translational signals unknown"]},{"year":2024,"claim":"Extended the complex's function to meiosis, showing it limits RAD51/DMC1 loading independently of SPO11 breaks and directly alters recombinase filament structure to inhibit strand invasion.","evidence":"Germline-specific conditional knockout mice, RAD51/DMC1 immunofluorescence, in vitro strand invasion assay with purified FIGNL1ΔN, filament structure analysis","pmids":["39147779"],"confidence":"High","gaps":["Specific FIRRM contribution within the meiotic complex not separately reconstituted","How DMC1 versus RAD51 selectivity is achieved unknown"]},{"year":2024,"claim":"Linked FIRRM expression to mitochondrial function under methionine restriction in cancer cells, a context distinct from its recombination role.","evidence":"Transcriptomics, knockdown in osteosarcoma cells, mitochondrial function assays, xenografts","pmids":["38769167"],"confidence":"Medium","gaps":["Link to mitochondrial function is correlative/knockdown-based without direct biochemical mechanism","Connection to RAD51 or PLK1 roles unclear"]},{"year":2026,"claim":"Connected FIRRM to mitotic entry in hepatocellular carcinoma via PLK1 phosphorylation, reinforcing the PLK1 axis in a tumor context.","evidence":"CRISPR knockout in HCC cell lines, PLK1 phosphorylation western blot, flow-cytometry cell-cycle analysis, in vivo tumor proliferation","pmids":["42007975"],"confidence":"Medium","gaps":["No mechanistic dissection beyond PLK1 phosphorylation level","Single-lab observation; relationship to kinetochore feedback loop not addressed"]},{"year":null,"claim":"How FIRRM's two roles — FIGNL1-dependent RAD51 disassembly and PLK1/PP1γ mitotic regulation — are integrated or temporally separated within the cell remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of FIRRM or its complexes","Whether the FIGNL1-independent and PLK1 roles share a domain is unknown","Regulatory cues switching between functions undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,6]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[5]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,3]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[2]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[2,3,6]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,8]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[4]}],"complexes":["FIGNL1-FIRRM complex"],"partners":["FIGNL1","RAD51","BRCA2","PLK1","PP1Γ","MUS81","DMC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NSG2","full_name":"FIGNL1-interacting regulator of recombination and mitosis","aliases":["FIDGETIN-like-1 interacting protein","FLIP","POLO1-associating protein"],"length_aa":853,"mass_kda":96.6,"function":"Regulates PLK1 kinase activity at kinetochores and promotes faithful chromosome segregation in prometaphase by bridging kinase and phosphatase activities (PubMed:34260926). Phosphorylation of FIRRM by PLK1 negatively regulates its interaction with the phosphatase, PPP1CC, thus creating a negative feedback loop for maintaining proper PLK1 kinase activity during mitosis (PubMed:34260926). In complex with FIGL1 may regulate homologous recombination (PubMed:29608566)","subcellular_location":"Chromosome, centromere, kinetochore; Nucleus; Chromosome, centromere; Midbody; Cytoplasm, cytoskeleton, spindle","url":"https://www.uniprot.org/uniprotkb/Q9NSG2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FIRRM","classification":"Not Classified","n_dependent_lines":27,"n_total_lines":1208,"dependency_fraction":0.022350993377483443},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FIRRM","total_profiled":1310},"omim":[{"mim_id":"621430","title":"FIGNL1-INTERACTING REGULATOR OF RECOMBINATION AND MITOSIS; FIRRM","url":"https://www.omim.org/entry/621430"},{"mim_id":"615383","title":"FIDGETIN-LIKE PROTEIN 1; FIGNL1","url":"https://www.omim.org/entry/615383"},{"mim_id":"602098","title":"POLO-LIKE KINASE 1; PLK1","url":"https://www.omim.org/entry/602098"},{"mim_id":"300687","title":"ERCC EXCISION REPAIR 6-LIKE, SPINDLE ASSEMBLY CHECKPOINT HELICASE; ERCC6L","url":"https://www.omim.org/entry/300687"}],"hpa":{"profiled":true,"resolved_as":"C1ORF112","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"parathyroid gland","ntpm":12.7}],"url":"https://www.proteinatlas.org/search/C1ORF112"},"hgnc":{"alias_symbol":["FLJ10706","Apolo1","FLIP","MEICA1"],"prev_symbol":["C1orf112"]},"alphafold":{"accession":"Q9NSG2","domains":[{"cath_id":"-","chopping":"638-748","consensus_level":"medium","plddt":87.3955,"start":638,"end":748},{"cath_id":"1.20.190","chopping":"1-200","consensus_level":"medium","plddt":88.8362,"start":1,"end":200}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NSG2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NSG2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NSG2-F1-predicted_aligned_error_v6.png","plddt_mean":86.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FIRRM","jax_strain_url":"https://www.jax.org/strain/search?query=FIRRM"},"sequence":{"accession":"Q9NSG2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NSG2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NSG2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NSG2"}},"corpus_meta":[{"pmid":"37347663","id":"PMC_37347663","title":"FIRRM/C1orf112 is synthetic lethal with PICH and mediates RAD51 dynamics.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/37347663","citation_count":24,"is_preprint":false},{"pmid":"34260926","id":"PMC_34260926","title":"Feedback control of PLK1 by Apolo1 ensures accurate chromosome segregation.","date":"2021","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/34260926","citation_count":24,"is_preprint":false},{"pmid":"38769167","id":"PMC_38769167","title":"Deprivation of methionine inhibits osteosarcoma growth and metastasis via C1orf112-mediated regulation of mitochondrial functions.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/38769167","citation_count":21,"is_preprint":false},{"pmid":"34490347","id":"PMC_34490347","title":"Pan-Cancer Analysis Identified C1ORF112 as a Potential Biomarker for Multiple Tumor Types.","date":"2021","source":"Frontiers in molecular 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or FIGNL1 results in ultrafine DNA bridge (UFB) formation, prolonged accumulation of RAD51 at nuclear foci, and impaired replication fork dynamics, indicating that FIRRM-FIGNL1 regulates RAD51 dynamics at replication forks to maintain genome integrity.\",\n      \"method\": \"Genome-wide loss-of-function screen, co-immunoprecipitation, RAD51 foci analysis, replication fork dynamics assay, UFB imaging\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction established, multiple orthogonal methods (genetic screen, Co-IP, foci analysis, fork dynamics), replicated across multiple papers\",\n      \"pmids\": [\"37347663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Apolo1 (FIRRM) localizes to kinetochores during early mitosis, sustains PLK1 kinase activity at kinetochores during prometaphase for accurate kinetochore-microtubule attachment, is a cognate substrate of PLK1 (phosphorylated by PLK1), and phosphorylation enables PP1γ to subsequently inactivate PLK1 by dephosphorylation — constituting a feedback loop that governs PLK1 activity.\",\n      \"method\": \"FRET-based PLK1 activity reporter, live-cell imaging (kinetochore localization), kinase substrate assay, phosphatase (PP1γ) interaction/dephosphorylation assay, siRNA knockdown with chromosome alignment phenotype\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods in one study including FRET reporter, substrate phosphorylation assay, phosphatase recruitment, and localization with functional consequence\",\n      \"pmids\": [\"34260926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FIRRM is recruited to ICL (interstrand crosslink) sites, controls MUS81 chromatin loading, and thereby mediates resolution of homologous recombination intermediates generated during ICL repair; FIRRM deficiency causes hypersensitivity to ICL agents, DNA damage accumulation in S-G2, chromosomal aberrations, and a unique mutational signature associated with HR deficiency.\",\n      \"method\": \"Complementary CRISPR genetic screens, ICL sensitivity assays, cell cycle analysis (DNA damage accumulation in S-G2), chromatin fractionation (MUS81 loading), recruitment to ICLs (laser-induced damage foci), chromosomal aberration analysis, mouse knockout (early embryonic lethality)\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including genetic screens, chromatin fractionation, foci recruitment, and in vivo mouse model with epistatic analysis\",\n      \"pmids\": [\"37256941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FIRRM (FLIP/C1orf112) forms a stable complex with FIGNL1 that is required to limit RAD51 amounts and foci on chromatin both in the presence and absence of exogenous DNA damage, and to promote RAD51 dissociation from nucleofilaments to complete HR; FLIP loss causes defective replication fork progression and reduced HR competency.\",\n      \"method\": \"Co-immunoprecipitation (stable complex), RAD51 chromatin fractionation/foci quantification, replication fork progression assay (fiber assay), HR reporter assay, ICL sensitivity assay, epistasis analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, chromatin fractionation, fiber assay, HR reporter) in single study, consistent with multiple independent labs\",\n      \"pmids\": [\"38286805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The FIGNL1-FIRRM complex is essential for meiotic recombination; both proteins are required for completing meiotic prophase in mouse spermatocytes, and the complex limits RAD51 and DMC1 accumulation on intact chromatin independently of SPO11-catalyzed DSBs. Purified human FIGNL1ΔN alters the RAD51/DMC1 nucleoprotein filament structure and inhibits strand invasion in vitro.\",\n      \"method\": \"Male germline-specific conditional knockout (cKO) mouse models, immunofluorescence (RAD51/DMC1 foci), in vitro strand invasion assay with purified proteins, nucleoprotein filament structure analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified proteins plus in vivo cKO mouse model with defined meiotic phenotype and epistatic relationship to SPO11 DSBs\",\n      \"pmids\": [\"39147779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FIRRM cooperates with FIGNL1 to promote resolution of RAD51 foci at ICL-induced DSBs; FIRRM stability is interdependent with FIGNL1. A FIRRM mutant lacking the WCF domain (ΔWCF) stabilizes FIRRM independently of FIGNL1 and rescues RAD51 foci resolution and cell survival, suggesting FIGNL1-independent function. FIRRM also binds preferentially to single-stranded DNA in vitro.\",\n      \"method\": \"CRISPR screen, Co-immunoprecipitation (FIRRM-FIGNL1 complex/stability), RAD51 foci analysis, domain-deletion mutagenesis (ΔWCF), in vitro ssDNA binding assay\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis (ΔWCF), in vitro ssDNA binding, Co-IP for complex stability, foci analysis; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"37556550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"C1orf112 (FIRRM) physically interacts with FIGNL1, enhances FIGNL1 protein stability, and directly stimulates the RAD51 filament disassembly activity of FIGNL1. BRCA2 directly interacts with the C1orf112-FIGNL1 complex and functions upstream to protect RAD51 filaments from premature disassembly by this complex.\",\n      \"method\": \"RAD51 proximity proteomics, Co-immunoprecipitation, in vitro RAD51 filament disassembly assay with purified proteins, protein stability assay, epistasis analysis (BRCA2 upstream)\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of RAD51 filament disassembly with purified proteins, proximity proteomics, Co-IP, epistasis; single lab but multiple orthogonal methods including biochemical reconstitution\",\n      \"pmids\": [\"37515771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The in vitro reconstitution of RAD51 filament disassembly by purified C1orf112/FIRRM-FIGNL1 complex was validated, and the antagonistic effect between C1orf112/FIRRM-FIGNL1 and BRCA2 on RAD51 filament stabilization was demonstrated biochemically using purified proteins from E. coli or S. cerevisiae.\",\n      \"method\": \"Protein purification from E. coli and S. cerevisiae, in vitro RAD51 filament disassembly reconstitution, competition assay with purified miBRCA2\",\n      \"journal\": \"STAR protocols\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified proteins confirming prior Cell Reports findings; protocol paper supporting biochemical mechanism\",\n      \"pmids\": [\"38133958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FIRRM knockout in hepatocellular carcinoma cells reduces PLK1 phosphorylation and inhibits mitotic progression and the G2-to-M transition of the cell cycle, establishing that FIRRM promotes mitotic entry via PLK1-mediated signaling.\",\n      \"method\": \"CRISPR knockout of FIRRM in HCC cell lines, PLK1 phosphorylation assay (western blot), cell cycle analysis (flow cytometry), in vivo tumor proliferation assay\",\n      \"journal\": \"Journal of gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KO with defined cell cycle phenotype and PLK1 phosphorylation readout, but single lab, no mechanistic dissection of the pathway beyond PLK1 phosphorylation level\",\n      \"pmids\": [\"42007975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Methionine restriction reduces C1orf112 expression in osteosarcoma cells, and reduced C1orf112 expression underlies methionine deprivation-initiated suppression of mitochondrial functions (dysregulated respiratory chain gene expression, increased mitochondrial ROS, reduced ATP production, decreased respiration, damaged mitochondrial membrane potential).\",\n      \"method\": \"Transcriptomic analysis, C1orf112 expression knockdown in cultured cells, mitochondrial function assays (ROS, ATP, oxygen consumption, membrane potential), xenograft models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — functional assays in cultured cells and in vivo, but mechanistic link between C1orf112 and mitochondrial function is correlative/knockdown-based without direct biochemical mechanism\",\n      \"pmids\": [\"38769167\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FIRRM (C1orf112/Apolo1) forms a stable complex with the AAA+ ATPase FIGNL1 that is required to limit RAD51 (and DMC1) accumulation on chromatin, promote RAD51 disassembly from nucleofilaments after strand invasion, and ensure efficient resolution of homologous recombination intermediates at interstrand crosslinks and replication forks; independently, FIRRM localizes to kinetochores during prometaphase, acts as a PLK1 substrate that bridges PLK1 and PP1γ to create a feedback loop controlling PLK1 activity and accurate chromosome segregation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FIRRM (C1orf112/FLIP/Apolo1) is a genome-stability factor that, through a stable complex with the AAA+ ATPase FIGNL1, controls the dynamics of RAD51 (and the meiotic recombinase DMC1) on chromatin to ensure faithful homologous recombination [#0, #3, #6]. FIRRM and FIGNL1 are mutually stabilizing partners, and FIRRM directly stimulates the RAD51 filament-disassembly activity of FIGNL1, limiting RAD51 accumulation both with and without exogenous damage and promoting RAD51 dissociation from nucleofilaments after strand invasion to complete recombination [#3, #6]; this disassembly activity has been reconstituted in vitro with purified proteins, where BRCA2 acts upstream to protect filaments from premature disassembly by the complex [#6, #7]. Loss of FIRRM produces ultrafine DNA bridges, persistent RAD51 foci, defective replication fork progression, hypersensitivity to interstrand crosslinking agents with S-G2 damage accumulation and chromosomal aberrations, the complex acting at ICLs in part by controlling MUS81 chromatin loading [#0, #2, #3]. The FIGNL1-FIRRM complex is likewise essential for meiotic recombination, limiting RAD51/DMC1 loading on intact chromatin independently of SPO11-generated breaks and altering recombinase filament structure to inhibit strand invasion in vitro, with mouse knockouts causing meiotic prophase arrest and early embryonic lethality [#2, #4]. Independently of its recombination role, FIRRM localizes to kinetochores in prometaphase where it serves as a PLK1 substrate, bridging PLK1 and PP1\\u03b3 in a feedback loop that tunes PLK1 activity for accurate kinetochore-microtubule attachment and chromosome segregation [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 2021,\n      \"claim\": \"Established a mitotic role for FIRRM distinct from any recombination function by placing it at kinetochores as a regulator of PLK1 activity.\",\n      \"evidence\": \"FRET-based PLK1 activity reporter, live-cell kinetochore imaging, kinase substrate and PP1\\u03b3 dephosphorylation assays, siRNA with chromosome alignment phenotype\",\n      \"pmids\": [\"34260926\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between the kinetochore/PLK1 role and the FIGNL1/RAD51 role is unresolved\", \"Structural basis of PLK1-FIRRM-PP1\\u03b3 bridging not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified FIRRM as a stabilizing partner of the AAA+ ATPase FIGNL1 that regulates RAD51 dynamics at replication forks, explaining UFB formation and fork defects on its loss.\",\n      \"evidence\": \"Genome-wide loss-of-function screen, Co-IP, RAD51 foci analysis, replication fork dynamics and UFB imaging\",\n      \"pmids\": [\"37347663\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzymatic mechanism not yet reconstituted at this stage\", \"Did not define FIRRM action at ICLs versus other lesions\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined FIRRM's role in interstrand crosslink repair, linking it to MUS81 chromatin loading, HR-intermediate resolution, and a HR-deficiency mutational signature, with in vivo essentiality.\",\n      \"evidence\": \"CRISPR screens, ICL sensitivity and cell-cycle assays, chromatin fractionation for MUS81, laser-induced ICL recruitment, chromosomal aberration analysis, mouse knockout\",\n      \"pmids\": [\"37256941\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How FIRRM controls MUS81 loading mechanistically is not defined\", \"Whether ICL role is fully FIGNL1-dependent not resolved here\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Dissected the FIRRM-FIGNL1 interdependence and revealed a potential FIGNL1-independent FIRRM activity, plus direct ssDNA binding.\",\n      \"evidence\": \"CRISPR screen, Co-IP for complex stability, \\u0394WCF domain-deletion mutagenesis, RAD51 foci analysis, in vitro ssDNA binding assay\",\n      \"pmids\": [\"37556550\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional significance of ssDNA binding not established\", \"Nature of the FIGNL1-independent function not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided the biochemical mechanism: FIRRM directly stimulates FIGNL1-mediated RAD51 filament disassembly, with BRCA2 acting upstream to protect filaments.\",\n      \"evidence\": \"RAD51 proximity proteomics, Co-IP, in vitro RAD51 filament disassembly reconstitution with purified proteins, epistasis analysis\",\n      \"pmids\": [\"37515771\", \"38133958\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structure of the complex on filaments unknown\", \"How BRCA2 antagonism is regulated in cells not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Consolidated the stable FIRRM-FIGNL1 complex as the unit limiting chromatin RAD51 and promoting filament dissociation to complete HR and maintain fork progression.\",\n      \"evidence\": \"Co-IP, RAD51 chromatin fractionation/foci quantification, DNA fiber assay, HR reporter, ICL sensitivity, epistasis\",\n      \"pmids\": [\"38286805\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Temporal coordination of disassembly during HR steps not mapped\", \"Regulation of the complex by post-translational signals unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the complex's function to meiosis, showing it limits RAD51/DMC1 loading independently of SPO11 breaks and directly alters recombinase filament structure to inhibit strand invasion.\",\n      \"evidence\": \"Germline-specific conditional knockout mice, RAD51/DMC1 immunofluorescence, in vitro strand invasion assay with purified FIGNL1\\u0394N, filament structure analysis\",\n      \"pmids\": [\"39147779\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific FIRRM contribution within the meiotic complex not separately reconstituted\", \"How DMC1 versus RAD51 selectivity is achieved unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked FIRRM expression to mitochondrial function under methionine restriction in cancer cells, a context distinct from its recombination role.\",\n      \"evidence\": \"Transcriptomics, knockdown in osteosarcoma cells, mitochondrial function assays, xenografts\",\n      \"pmids\": [\"38769167\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link to mitochondrial function is correlative/knockdown-based without direct biochemical mechanism\", \"Connection to RAD51 or PLK1 roles unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected FIRRM to mitotic entry in hepatocellular carcinoma via PLK1 phosphorylation, reinforcing the PLK1 axis in a tumor context.\",\n      \"evidence\": \"CRISPR knockout in HCC cell lines, PLK1 phosphorylation western blot, flow-cytometry cell-cycle analysis, in vivo tumor proliferation\",\n      \"pmids\": [\"42007975\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mechanistic dissection beyond PLK1 phosphorylation level\", \"Single-lab observation; relationship to kinetochore feedback loop not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FIRRM's two roles \\u2014 FIGNL1-dependent RAD51 disassembly and PLK1/PP1\\u03b3 mitotic regulation \\u2014 are integrated or temporally separated within the cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of FIRRM or its complexes\", \"Whether the FIGNL1-independent and PLK1 roles share a domain is unknown\", \"Regulatory cues switching between functions undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [2, 3, 6]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\"FIGNL1-FIRRM complex\"],\n    \"partners\": [\"FIGNL1\", \"RAD51\", \"BRCA2\", \"PLK1\", \"PP1\\u03b3\", \"MUS81\", \"DMC1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}