{"gene":"FIGNL1","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2013,"finding":"FIGNL1 specifically interacts with RAD51 through a conserved RAD51-binding domain. FIGNL1 is recruited to sites of DNA damage independently of BRCA2, RAD51, and RAD51 paralogs. FIGNL1 depletion causes defective HR repair but does not affect RAD51 loading onto ssDNA. FIGNL1 forms a complex with KIAA0146/SPIDR, which acts together with FIGNL1 in HR repair.","method":"Co-immunoprecipitation, domain mapping, siRNA knockdown, HR reporter assay, immunofluorescence foci analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, siRNA KD with defined HR phenotype, and localization experiments; single lab with multiple orthogonal methods","pmids":["23754376"],"is_preprint":false},{"year":2019,"finding":"Purified FIGNL1 promotes dissociation of RAD51 from ssDNA in vitro (anti-recombinase activity). This RAD51-dismantling activity does not require FIGNL1 ATPase activity but depends on RAD51-binding. The RAD51 paralogue SWSAP1 binds both RAD51 and FIGNL1, and purified SWSAP1 inhibits the RAD51-dismantling activity of FIGNL1, thereby protecting RAD51 filaments. Depletion of FIGNL1 suppresses the defective RAD51 assembly seen in SWSAP1-depleted cells (genetic epistasis).","method":"In vitro RAD51-ssDNA dissociation assay with purified proteins, ATPase-dead mutagenesis, siRNA epistasis, RAD51 foci immunofluorescence","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified proteins, ATPase mutagenesis, epistasis genetics, and multiple orthogonal methods in a single rigorous study","pmids":["30926776"],"is_preprint":false},{"year":2023,"finding":"C1orf112/FLIP forms a stable complex with FIGNL1. Loss of FLIP leads to increased RAD51 amounts and foci on chromatin (with or without DNA damage), defective replication fork progression, and reduced HR competency, consistent with FLIP being required for RAD51 dissociation from nucleofilaments. Both proteins have epistatic roles in ICL repair.","method":"Co-immunoprecipitation, siRNA/CRISPR KO, RAD51 chromatin fractionation, replication fork assay, HR reporter assay","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, KO phenotypes with multiple readouts; preprint with single lab","pmids":["37808755"],"is_preprint":true},{"year":2023,"finding":"C1orf112/FIRRM physically interacts with FIGNL1 and enhances FIGNL1 protein stability. The RAD51 filament disassembly activity of FIGNL1 is directly stimulated by C1orf112 in vitro. BRCA2 directly interacts with the C1orf112-FIGNL1 complex and functions upstream to protect RAD51 filament from premature disassembly. C1orf112- and FIGNL1-deficient cells are primarily sensitive to DNA ICL agents.","method":"RAD51 proximity proteomics, Co-IP, in vitro RAD51 filament disassembly assay with purified proteins, CRISPR KO, DNA damage sensitivity assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified proteins demonstrating direct stimulation, Co-IP for complex, CRISPR KO phenotype; multiple orthogonal methods","pmids":["37515771"],"is_preprint":false},{"year":2023,"finding":"The FLIP-FIGNL1 complex regulates RAD51 and DMC1 dissociation to promote meiotic recombination and replication fork restart. FLIP interacts with FIGNL1; depletion of either protein destabilizes the other and impairs RAD51 dissociation. FLIP-null meiocytes accumulate massive RAD51 and DMC1 foci, arrested at a zygotene-like stage.","method":"Co-immunoprecipitation, germline-specific conditional knockout mice, RAD51/DMC1 immunofluorescence on meiotic spreads, replication fork restart assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in vivo conditional KO mouse model with defined meiotic phenotype, replicated across multiple models","pmids":["37439366"],"is_preprint":false},{"year":2023,"finding":"FIRRM (FIGNL1 Interacting Regulator of Recombination and Mitosis) was identified as a FIGNL1 partner required for RAD51 foci resolution at ICL-induced DSBs. FIGNL1 and FIRRM stability is interdependent. FIRRM binds preferentially to single-stranded DNA in vitro. A FIRRM mutant (ΔWCF) that is stable without FIGNL1 can rescue RAD51 foci resolution and cell survival, indicating FIRRM has FIGNL1-independent function in DNA repair.","method":"CRISPR screen, Co-IP, RAD51 foci immunofluorescence, in vitro ssDNA binding assay, domain mutagenesis, cell survival assay","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen followed by Co-IP, in vitro ssDNA binding, and mutant rescue; single lab with multiple orthogonal methods","pmids":["37556550"],"is_preprint":false},{"year":2023,"finding":"FIGNL1 germline-specific conditional knockout male mice show defective chromosome synapsis, impaired meiotic DSB repair, and accumulation of RAD51/DMC1 on meiotic chromosomes. FIGNL1-cKO spermatocytes also accumulate RAD51/DMC1 in pre-meiotic S-phase independently of SPO11-generated DSBs. Purified FIGNL1 dismantles RAD51 filaments on double-stranded DNA as well as ssDNA, indicating a role in limiting non-productive RAD51/DMC1 assembly on native dsDNA.","method":"Germline-specific conditional knockout mouse, meiotic chromosome spread immunofluorescence, in vitro RAD51 filament disassembly assay with purified protein on dsDNA and ssDNA","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution on dsDNA substrates combined with in vivo conditional KO mouse with detailed meiotic phenotyping; multiple orthogonal methods","pmids":["37891173"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structure of FIGNL1 in complex with RAD51 reveals that FIGNL1 forms a non-planar hexamer that encloses the RAD51 N-terminus within its hexamer pore. Mutations in FIGNL1 pore loop or catalytic (ATPase) residues abolish filament disassembly activity and are lethal in mouse embryonic stem cells, establishing that ATPase activity and pore loop engagement with RAD51 N-terminus are mechanistically essential for RAD51 removal.","method":"Cryo-EM structure determination, active-site mutagenesis (pore loop and ATPase mutants), in vitro RAD51 filament disassembly assay, mouse embryonic stem cell lethality assay","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with mutagenesis validated by in vitro functional assay and in vivo lethality; multiple orthogonal methods in a single rigorous study","pmids":["39636933"],"is_preprint":false},{"year":2024,"finding":"FIGNL1 knockout human cells accumulate ultra-fine chromosome bridges (UFBs) between sister chromatids at telomeres and centromeres after replication stress. These UFBs depend on RAD51 (not replication fork stalling per se), and are suppressed by FIGNL1, indicating that FIGNL1-mediated post-replicative RAD51 disassembly prevents recombination intermediate-like UFBs and catastrophic genome instability. FIGNL1 is defective in RAD51 dissociation after replication fork restart in its absence.","method":"FIGNL1 CRISPR KO human cells, ultra-fine bridge immunofluorescence (FANCD2/BLM markers), RAD51 foci after fork restart, epistasis with RAD51 inhibitor","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR KO with specific UFB phenotype, mechanistic link to RAD51 via epistasis, replication fork restart assay; multiple orthogonal methods","pmids":["38597669"],"is_preprint":false},{"year":2024,"finding":"The FIGNL1-FIRRM complex is required for completing meiotic prophase in mouse spermatocytes. Both proteins limit RAD51 and DMC1 accumulation on intact chromatin independently of SPO11-catalyzed DSB formation. Purified human FIGNL1ΔN alters the RAD51/DMC1 nucleoprotein filament structure and inhibits strand invasion in vitro, placing FIGNL1-FIRRM activity at a post-assembly step to promote strand invasion and processing of recombination intermediates.","method":"Male germline-specific conditional KO mice, meiotic chromosome spreads, in vitro RAD51/DMC1 filament alteration and strand invasion assay with purified FIGNL1ΔN","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified protein plus in vivo conditional KO mouse with mechanistic phenotyping; multiple orthogonal methods","pmids":["39147779"],"is_preprint":false},{"year":2024,"finding":"FLIP (C1orf112) loss causes increased RAD51 chromatin association, defective replication fork progression, elevated chromosomal instability, and reduced HR competency. FLIP and FIGNL1 form a stable epistatic complex with co-dependent protein stability, and the complex is required for RAD51 dissociation from nucleofilaments upon ICL damage.","method":"CRISPR KO, RAD51 chromatin fractionation, replication fork progression assay (DNA fiber), HR reporter assay, Co-IP, chromosomal instability/micronuclei quantification","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP establishing complex, CRISPR KO with multiple orthogonal phenotypic readouts; published peer-reviewed study","pmids":["38286805"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structure of FIGNL1-RAD51 complex (preprint version): FIGNL1 forms a non-planar hexamer enclosing RAD51 N-terminus in the hexamer pore. Pore loop and ATPase catalytic mutants are defective in RAD51 filament disassembly and lethal in mouse ES cells.","method":"Cryo-EM structure, mutagenesis, in vitro filament disassembly assay, mouse ES cell lethality","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — cryo-EM plus mutagenesis; preprint version of subsequently published peer-reviewed paper (PMID:39636933), included for completeness","pmids":["39071279"],"is_preprint":true},{"year":2025,"finding":"Loss of FIGNL1 (anti-recombinase) restores RAD51 loading at DSBs in BRCA2-deficient cells, leading to genome stability, HR proficiency, and viability of BRCA2-deficient mouse embryonic stem cells. Mechanistically, HR defects upon BRCA2 loss arise primarily from unrestricted FIGNL1-mediated removal of RAD51 from DSBs rather than from defective RAD51 loading. The MMS22L-TONSL complex interacts with FIGNL1 and is critical for HR in BRCA2/FIGNL1 double-deficient cells.","method":"FIGNL1 KO in BRCA2-deficient mouse ES cells, RAD51 foci at DSBs, HR reporter assay, Co-IP (MMS22L-TONSL-FIGNL1 interaction), viability assay","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR double KO genetic epistasis with HR functional assay, Co-IP for new complex partner, mechanistic reinterpretation validated with multiple readouts","pmids":["41166468"],"is_preprint":false},{"year":2023,"finding":"In vitro reconstitution protocol established: purified C1orf112/FIRRM-FIGNL1 complex directly disassembles RAD51 filaments, and BRCA2 antagonizes this disassembly to protect RAD51 filament from premature dismantling.","method":"In vitro reconstitution with purified C1orf112/FIRRM, FIGNL1, mini-BRCA2, and RAD51 from E. coli or S. cerevisiae; RAD51 filament disassembly assay","journal":"STAR protocols","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct in vitro reconstitution with purified components; single lab, protocol paper supporting Zhou et al. 2023","pmids":["38133958"],"is_preprint":false},{"year":2023,"finding":"Compound heterozygous frameshift mutations in FIGNL1 (c.189del and c.1519_1523del) in a human patient cause loss of FIGNL1 nuclear foci formation, fail to increase foci upon DNA damage (phleomycin), and result in increased chromosomal breakage spontaneously and after mitomycin C exposure, establishing FIGNL1 nuclear foci as functionally important for the DDR.","method":"Whole exome sequencing, transfection of DYK-tagged FIGNL1 mutant constructs in HEK293 cells, nuclear foci quantification, chromosomal breakage assay","journal":"European journal of endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human loss-of-function variants with defined foci/chromosomal breakage phenotype; single case with cell-based validation","pmids":["37740949"],"is_preprint":false}],"current_model":"FIGNL1 is an AAA+ ATPase anti-recombinase that forms a non-planar hexamer (resolved by cryo-EM) which engages the RAD51 N-terminus through its pore loop and, using ATPase activity, actively dismantles RAD51 (and DMC1) filaments on both ssDNA and dsDNA; it operates as a stable complex with FIRRM/C1orf112/FLIP, whose binding enhances FIGNL1 stability and filament-disassembly activity, while upstream regulators BRCA2 and SWSAP1 antagonize FIGNL1 to protect productive RAD51 filaments—thereby balancing RAD51 assembly and disassembly during homologous recombination, meiosis, and replication fork restart to maintain genome stability."},"narrative":{"mechanistic_narrative":"FIGNL1 is an AAA+ ATPase that functions as an anti-recombinase, actively dismantling RAD51 (and the meiotic recombinase DMC1) nucleoprotein filaments to balance recombinase assembly and disassembly during homologous recombination, meiosis, and replication fork restart [PMID:30926776, PMID:37891173, PMID:39147779]. It engages RAD51 through a conserved RAD51-binding domain and is recruited to DNA damage sites independently of BRCA2, RAD51, and RAD51 paralogs [PMID:23754376]. Cryo-EM shows FIGNL1 assembles into a non-planar hexamer that encloses the RAD51 N-terminus within its central pore; both pore-loop engagement and ATPase catalysis are essential for filament removal and for viability in mouse embryonic stem cells [PMID:39636933]. FIGNL1 disassembles RAD51 from both ssDNA and dsDNA, limiting non-productive recombinase assembly on native chromatin [PMID:37891173], and acts at a post-assembly step to alter filament structure and promote processing of recombination intermediates [PMID:39147779]. FIGNL1 operates as a stable, mutually stabilizing complex with FIRRM/C1orf112/FLIP, which directly stimulates its filament-disassembly activity and is required for RAD51 dissociation following ICL damage and fork restart [PMID:37515771, PMID:37439366, PMID:38286805]. Its activity is antagonized by upstream regulators: BRCA2 directly binds the FIGNL1-FIRRM complex to protect productive RAD51 filaments from premature dismantling [PMID:37515771, PMID:38133958], and the RAD51 paralog SWSAP1 inhibits FIGNL1-mediated RAD51 dissociation [PMID:30926776]; loss of FIGNL1 restores RAD51 loading and viability in BRCA2-deficient cells, showing that unrestricted FIGNL1 activity, not defective loading, underlies the BRCA2 HR defect [PMID:41166468]. By promoting post-replicative RAD51 disassembly, FIGNL1 prevents RAD51-dependent ultra-fine chromosome bridges and catastrophic genome instability [PMID:38597669]. Compound heterozygous frameshift mutations in FIGNL1 abolish its nuclear foci and cause spontaneous and induced chromosomal breakage in a human patient [PMID:37740949].","teleology":[{"year":2013,"claim":"Established FIGNL1 as a direct RAD51 interactor required for homologous recombination, distinguishing it from RAD51 loading factors by showing it acts without affecting RAD51 loading onto ssDNA.","evidence":"Co-IP, domain mapping, siRNA knockdown with HR reporter and foci analysis","pmids":["23754376"],"confidence":"Medium","gaps":["Biochemical activity on RAD51 filaments not yet demonstrated","Functional role of the SPIDR/KIAA0146 complex partner unresolved","No structural basis for RAD51 engagement"]},{"year":2019,"claim":"Defined FIGNL1 biochemically as an anti-recombinase that dissociates RAD51 from ssDNA and identified SWSAP1 as a regulator that protects filaments by inhibiting this activity.","evidence":"In vitro RAD51-ssDNA dissociation with purified proteins, ATPase-dead mutagenesis, siRNA epistasis","pmids":["30926776"],"confidence":"High","gaps":["Reported ATPase-independence of dismantling later refined by structural work","Mechanism of pore engagement not established","Activity on dsDNA-bound RAD51 not tested"]},{"year":2023,"claim":"Identified FIRRM/C1orf112/FLIP as the stable, mutually stabilizing partner that directly stimulates FIGNL1 filament-disassembly activity, and placed BRCA2 upstream as an antagonist protecting RAD51 filaments.","evidence":"Proximity proteomics, Co-IP, in vitro filament disassembly with purified FIGNL1/C1orf112/BRCA2/RAD51, CRISPR KO, ICL sensitivity","pmids":["37515771","37439366","37556550","38133958","37808755"],"confidence":"High","gaps":["Stoichiometry of the FIGNL1-FIRRM-BRCA2 assembly not defined","FIGNL1-independent FIRRM functions only partially mapped","Regulation of complex assembly at damage sites unclear"]},{"year":2023,"claim":"Extended FIGNL1-FIRRM function to meiosis and replication, showing it dismantles both RAD51 and DMC1 and acts on dsDNA to limit non-productive recombinase assembly on intact chromatin.","evidence":"Germline-specific conditional KO mice, meiotic chromosome spreads, in vitro filament disassembly on dsDNA and ssDNA","pmids":["37439366","37891173"],"confidence":"High","gaps":["How DMC1 versus RAD51 selectivity is controlled is unknown","Coupling to meiotic crossover designation not resolved","Substrate discrimination between productive and non-productive filaments unclear"]},{"year":2024,"claim":"Resolved the mechanism: FIGNL1 forms a non-planar hexamer that captures the RAD51 N-terminus in its pore, with pore-loop and ATPase residues essential for disassembly and for ES cell viability.","evidence":"Cryo-EM structure with pore-loop/ATPase mutagenesis, in vitro disassembly assay, mouse ES cell lethality","pmids":["39636933","39071279"],"confidence":"High","gaps":["How FIRRM modulates the hexamer is not visualized","Conformational cycle during ATP hydrolysis not captured","Structure of the FIGNL1-FIRRM-BRCA2 assembly absent"]},{"year":2024,"claim":"Linked FIGNL1 anti-recombinase activity to genome stability by showing it prevents RAD51-dependent ultra-fine chromosome bridges after replication stress and processes recombination intermediates to promote strand invasion.","evidence":"FIGNL1 CRISPR KO human cells, UFB immunofluorescence, RAD51 foci after fork restart, in vitro strand invasion assay with FIGNL1ΔN, conditional KO mice","pmids":["38597669","39147779","38286805"],"confidence":"High","gaps":["Temporal coordination of disassembly with fork restart not fully defined","Why some RAD51 filaments are productive and spared is unclear"]},{"year":2025,"claim":"Reinterpreted the BRCA2 HR defect by showing FIGNL1 loss restores RAD51 loading and viability in BRCA2-deficient cells, establishing unrestricted FIGNL1 activity as the primary cause of failed RAD51 retention.","evidence":"FIGNL1 KO in BRCA2-deficient mouse ES cells, RAD51 foci, HR reporter, Co-IP of MMS22L-TONSL-FIGNL1, viability assay","pmids":["41166468"],"confidence":"High","gaps":["Role of MMS22L-TONSL in regulating FIGNL1 not mechanistically defined","Therapeutic implications for BRCA2-mutant tumors not tested","How BRCA2 spatially restricts FIGNL1 in normal cells unresolved"]},{"year":null,"claim":"How FIGNL1 distinguishes productive RAD51/DMC1 filaments to be spared from non-productive ones to be dismantled, and how its activity is spatiotemporally licensed by BRCA2, SWSAP1, FIRRM, and MMS22L-TONSL, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No integrated structural model of the regulated complex","Substrate selectivity logic unknown","In vivo regulation across cell cycle not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[1,6,7]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,6,7,9]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,9]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,14]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[6,9]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0,3,8]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[4,6,9]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[8,10]}],"complexes":["FIGNL1-FIRRM/C1orf112/FLIP complex"],"partners":["RAD51","FIRRM","C1ORF112","BRCA2","SWSAP1","DMC1","SPIDR","MMS22L"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6PIW4","full_name":"Fidgetin-like protein 1","aliases":[],"length_aa":674,"mass_kda":74.1,"function":"Involved in DNA double-strand break (DBS) repair via homologous recombination (HR). Recruited at DSB sites independently of BRCA2, RAD51 and RAD51 paralogs in a H2AX-dependent manner. May regulate osteoblast proliferation and differentiation (PubMed:23754376). May play a role in the control of male meiosis dynamic (By similarity)","subcellular_location":"Nucleus; Cytoplasm; Cytoplasm, perinuclear region","url":"https://www.uniprot.org/uniprotkb/Q6PIW4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FIGNL1","classification":"Not Classified","n_dependent_lines":30,"n_total_lines":1208,"dependency_fraction":0.024834437086092714},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"MIF","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/FIGNL1","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":"615384","title":"SCAFFOLDING PROTEIN INVOLVED IN DNA REPAIR; SPIDR","url":"https://www.omim.org/entry/615384"},{"mim_id":"615383","title":"FIDGETIN-LIKE PROTEIN 1; FIGNL1","url":"https://www.omim.org/entry/615383"},{"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":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FIGNL1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q6PIW4","domains":[{"cath_id":"-","chopping":"9-92","consensus_level":"high","plddt":73.3626,"start":9,"end":92},{"cath_id":"3.40.50.300","chopping":"375-565","consensus_level":"high","plddt":91.3759,"start":375,"end":565},{"cath_id":"1.10.8.60","chopping":"571-655","consensus_level":"high","plddt":94.4367,"start":571,"end":655}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6PIW4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6PIW4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6PIW4-F1-predicted_aligned_error_v6.png","plddt_mean":67.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FIGNL1","jax_strain_url":"https://www.jax.org/strain/search?query=FIGNL1"},"sequence":{"accession":"Q6PIW4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6PIW4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6PIW4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6PIW4"}},"corpus_meta":[{"pmid":"23754376","id":"PMC_23754376","title":"FIGNL1-containing 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and meiotic recombination.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37891173","citation_count":23,"is_preprint":false},{"pmid":"35898226","id":"PMC_35898226","title":"FIGNL1 Inhibits Non-homologous Chromosome Association and Crossover Formation.","date":"2022","source":"Frontiers in plant science","url":"https://pubmed.ncbi.nlm.nih.gov/35898226","citation_count":17,"is_preprint":false},{"pmid":"28260065","id":"PMC_28260065","title":"FIGNL1 is overexpressed in small cell lung cancer patients and enhances NCI-H446 cell resistance to cisplatin and etoposide.","date":"2017","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/28260065","citation_count":15,"is_preprint":false},{"pmid":"38286805","id":"PMC_38286805","title":"FLIP(C1orf112)-FIGNL1 complex regulates RAD51 chromatin association to promote viability after replication stress.","date":"2024","source":"Nature 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RAD51-mediated ultra-fine bridge formation.","date":"2024","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/38597669","citation_count":9,"is_preprint":false},{"pmid":"38494375","id":"PMC_38494375","title":"FIRRM and FIGNL1: partners in the regulation of homologous recombination.","date":"2024","source":"Trends in genetics : TIG","url":"https://pubmed.ncbi.nlm.nih.gov/38494375","citation_count":7,"is_preprint":false},{"pmid":"35791674","id":"PMC_35791674","title":"FIGNL1 is a potential biomarker of cisplatin resistance in non-small cell lung cancer.","date":"2022","source":"The International journal of biological markers","url":"https://pubmed.ncbi.nlm.nih.gov/35791674","citation_count":7,"is_preprint":false},{"pmid":"41166468","id":"PMC_41166468","title":"FIGNL1 inhibits homologous recombination in BRCA2 deficient cells by dissociating RAD51 filaments.","date":"2025","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/41166468","citation_count":3,"is_preprint":false},{"pmid":"37740949","id":"PMC_37740949","title":"Loss of function of FIGNL1, a DNA damage response gene, causes human ovarian dysgenesis.","date":"2023","source":"European journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/37740949","citation_count":3,"is_preprint":false},{"pmid":"39071279","id":"PMC_39071279","title":"Molecular basis of FIGNL1 in dissociating RAD51 from DNA and chromatin.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39071279","citation_count":1,"is_preprint":false},{"pmid":"39893069","id":"PMC_39893069","title":"FIGNL1 hexamer dissociates RAD51-filament: a new mechanism.","date":"2025","source":"Trends in biochemical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39893069","citation_count":1,"is_preprint":false},{"pmid":"38133958","id":"PMC_38133958","title":"Reconstitution of the antagonistic effect between C1orf112/FIRRM-FIGNL1 and BRCA2 on RAD51 filament stabilization.","date":"2023","source":"STAR protocols","url":"https://pubmed.ncbi.nlm.nih.gov/38133958","citation_count":0,"is_preprint":false},{"pmid":"37808755","id":"PMC_37808755","title":"RADIF(C1orf112)-FIGNL1 Complex Regulates RAD51 Chromatin Association to Promote Viability After Replication Stress.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37808755","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11402,"output_tokens":4494,"usd":0.050808,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12348,"output_tokens":3545,"usd":0.075182,"stage2_stop_reason":"end_turn"},"total_usd":0.12599,"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\": \"FIGNL1 specifically interacts with RAD51 through a conserved RAD51-binding domain. FIGNL1 is recruited to sites of DNA damage independently of BRCA2, RAD51, and RAD51 paralogs. FIGNL1 depletion causes defective HR repair but does not affect RAD51 loading onto ssDNA. FIGNL1 forms a complex with KIAA0146/SPIDR, which acts together with FIGNL1 in HR repair.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, siRNA knockdown, HR reporter assay, immunofluorescence foci analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, siRNA KD with defined HR phenotype, and localization experiments; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23754376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Purified FIGNL1 promotes dissociation of RAD51 from ssDNA in vitro (anti-recombinase activity). This RAD51-dismantling activity does not require FIGNL1 ATPase activity but depends on RAD51-binding. The RAD51 paralogue SWSAP1 binds both RAD51 and FIGNL1, and purified SWSAP1 inhibits the RAD51-dismantling activity of FIGNL1, thereby protecting RAD51 filaments. Depletion of FIGNL1 suppresses the defective RAD51 assembly seen in SWSAP1-depleted cells (genetic epistasis).\",\n      \"method\": \"In vitro RAD51-ssDNA dissociation assay with purified proteins, ATPase-dead mutagenesis, siRNA epistasis, RAD51 foci immunofluorescence\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified proteins, ATPase mutagenesis, epistasis genetics, and multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"30926776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"C1orf112/FLIP forms a stable complex with FIGNL1. Loss of FLIP leads to increased RAD51 amounts and foci on chromatin (with or without DNA damage), defective replication fork progression, and reduced HR competency, consistent with FLIP being required for RAD51 dissociation from nucleofilaments. Both proteins have epistatic roles in ICL repair.\",\n      \"method\": \"Co-immunoprecipitation, siRNA/CRISPR KO, RAD51 chromatin fractionation, replication fork assay, HR reporter assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, KO phenotypes with multiple readouts; preprint with single lab\",\n      \"pmids\": [\"37808755\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"C1orf112/FIRRM physically interacts with FIGNL1 and enhances FIGNL1 protein stability. The RAD51 filament disassembly activity of FIGNL1 is directly stimulated by C1orf112 in vitro. BRCA2 directly interacts with the C1orf112-FIGNL1 complex and functions upstream to protect RAD51 filament from premature disassembly. C1orf112- and FIGNL1-deficient cells are primarily sensitive to DNA ICL agents.\",\n      \"method\": \"RAD51 proximity proteomics, Co-IP, in vitro RAD51 filament disassembly assay with purified proteins, CRISPR KO, DNA damage sensitivity assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified proteins demonstrating direct stimulation, Co-IP for complex, CRISPR KO phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"37515771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The FLIP-FIGNL1 complex regulates RAD51 and DMC1 dissociation to promote meiotic recombination and replication fork restart. FLIP interacts with FIGNL1; depletion of either protein destabilizes the other and impairs RAD51 dissociation. FLIP-null meiocytes accumulate massive RAD51 and DMC1 foci, arrested at a zygotene-like stage.\",\n      \"method\": \"Co-immunoprecipitation, germline-specific conditional knockout mice, RAD51/DMC1 immunofluorescence on meiotic spreads, replication fork restart assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in vivo conditional KO mouse model with defined meiotic phenotype, replicated across multiple models\",\n      \"pmids\": [\"37439366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FIRRM (FIGNL1 Interacting Regulator of Recombination and Mitosis) was identified as a FIGNL1 partner required for RAD51 foci resolution at ICL-induced DSBs. FIGNL1 and FIRRM stability is interdependent. FIRRM binds preferentially to single-stranded DNA in vitro. A FIRRM mutant (ΔWCF) that is stable without FIGNL1 can rescue RAD51 foci resolution and cell survival, indicating FIRRM has FIGNL1-independent function in DNA repair.\",\n      \"method\": \"CRISPR screen, Co-IP, RAD51 foci immunofluorescence, in vitro ssDNA binding assay, domain mutagenesis, cell survival assay\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen followed by Co-IP, in vitro ssDNA binding, and mutant rescue; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37556550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FIGNL1 germline-specific conditional knockout male mice show defective chromosome synapsis, impaired meiotic DSB repair, and accumulation of RAD51/DMC1 on meiotic chromosomes. FIGNL1-cKO spermatocytes also accumulate RAD51/DMC1 in pre-meiotic S-phase independently of SPO11-generated DSBs. Purified FIGNL1 dismantles RAD51 filaments on double-stranded DNA as well as ssDNA, indicating a role in limiting non-productive RAD51/DMC1 assembly on native dsDNA.\",\n      \"method\": \"Germline-specific conditional knockout mouse, meiotic chromosome spread immunofluorescence, in vitro RAD51 filament disassembly assay with purified protein on dsDNA and ssDNA\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution on dsDNA substrates combined with in vivo conditional KO mouse with detailed meiotic phenotyping; multiple orthogonal methods\",\n      \"pmids\": [\"37891173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structure of FIGNL1 in complex with RAD51 reveals that FIGNL1 forms a non-planar hexamer that encloses the RAD51 N-terminus within its hexamer pore. Mutations in FIGNL1 pore loop or catalytic (ATPase) residues abolish filament disassembly activity and are lethal in mouse embryonic stem cells, establishing that ATPase activity and pore loop engagement with RAD51 N-terminus are mechanistically essential for RAD51 removal.\",\n      \"method\": \"Cryo-EM structure determination, active-site mutagenesis (pore loop and ATPase mutants), in vitro RAD51 filament disassembly assay, mouse embryonic stem cell lethality assay\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with mutagenesis validated by in vitro functional assay and in vivo lethality; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"39636933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FIGNL1 knockout human cells accumulate ultra-fine chromosome bridges (UFBs) between sister chromatids at telomeres and centromeres after replication stress. These UFBs depend on RAD51 (not replication fork stalling per se), and are suppressed by FIGNL1, indicating that FIGNL1-mediated post-replicative RAD51 disassembly prevents recombination intermediate-like UFBs and catastrophic genome instability. FIGNL1 is defective in RAD51 dissociation after replication fork restart in its absence.\",\n      \"method\": \"FIGNL1 CRISPR KO human cells, ultra-fine bridge immunofluorescence (FANCD2/BLM markers), RAD51 foci after fork restart, epistasis with RAD51 inhibitor\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR KO with specific UFB phenotype, mechanistic link to RAD51 via epistasis, replication fork restart assay; multiple orthogonal methods\",\n      \"pmids\": [\"38597669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The FIGNL1-FIRRM complex is required for completing meiotic prophase in mouse spermatocytes. Both proteins limit RAD51 and DMC1 accumulation on intact chromatin independently of SPO11-catalyzed DSB formation. Purified human FIGNL1ΔN alters the RAD51/DMC1 nucleoprotein filament structure and inhibits strand invasion in vitro, placing FIGNL1-FIRRM activity at a post-assembly step to promote strand invasion and processing of recombination intermediates.\",\n      \"method\": \"Male germline-specific conditional KO mice, meiotic chromosome spreads, in vitro RAD51/DMC1 filament alteration and strand invasion assay with purified FIGNL1ΔN\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified protein plus in vivo conditional KO mouse with mechanistic phenotyping; multiple orthogonal methods\",\n      \"pmids\": [\"39147779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FLIP (C1orf112) loss causes increased RAD51 chromatin association, defective replication fork progression, elevated chromosomal instability, and reduced HR competency. FLIP and FIGNL1 form a stable epistatic complex with co-dependent protein stability, and the complex is required for RAD51 dissociation from nucleofilaments upon ICL damage.\",\n      \"method\": \"CRISPR KO, RAD51 chromatin fractionation, replication fork progression assay (DNA fiber), HR reporter assay, Co-IP, chromosomal instability/micronuclei quantification\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP establishing complex, CRISPR KO with multiple orthogonal phenotypic readouts; published peer-reviewed study\",\n      \"pmids\": [\"38286805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structure of FIGNL1-RAD51 complex (preprint version): FIGNL1 forms a non-planar hexamer enclosing RAD51 N-terminus in the hexamer pore. Pore loop and ATPase catalytic mutants are defective in RAD51 filament disassembly and lethal in mouse ES cells.\",\n      \"method\": \"Cryo-EM structure, mutagenesis, in vitro filament disassembly assay, mouse ES cell lethality\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM plus mutagenesis; preprint version of subsequently published peer-reviewed paper (PMID:39636933), included for completeness\",\n      \"pmids\": [\"39071279\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of FIGNL1 (anti-recombinase) restores RAD51 loading at DSBs in BRCA2-deficient cells, leading to genome stability, HR proficiency, and viability of BRCA2-deficient mouse embryonic stem cells. Mechanistically, HR defects upon BRCA2 loss arise primarily from unrestricted FIGNL1-mediated removal of RAD51 from DSBs rather than from defective RAD51 loading. The MMS22L-TONSL complex interacts with FIGNL1 and is critical for HR in BRCA2/FIGNL1 double-deficient cells.\",\n      \"method\": \"FIGNL1 KO in BRCA2-deficient mouse ES cells, RAD51 foci at DSBs, HR reporter assay, Co-IP (MMS22L-TONSL-FIGNL1 interaction), viability assay\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR double KO genetic epistasis with HR functional assay, Co-IP for new complex partner, mechanistic reinterpretation validated with multiple readouts\",\n      \"pmids\": [\"41166468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In vitro reconstitution protocol established: purified C1orf112/FIRRM-FIGNL1 complex directly disassembles RAD51 filaments, and BRCA2 antagonizes this disassembly to protect RAD51 filament from premature dismantling.\",\n      \"method\": \"In vitro reconstitution with purified C1orf112/FIRRM, FIGNL1, mini-BRCA2, and RAD51 from E. coli or S. cerevisiae; RAD51 filament disassembly assay\",\n      \"journal\": \"STAR protocols\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro reconstitution with purified components; single lab, protocol paper supporting Zhou et al. 2023\",\n      \"pmids\": [\"38133958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Compound heterozygous frameshift mutations in FIGNL1 (c.189del and c.1519_1523del) in a human patient cause loss of FIGNL1 nuclear foci formation, fail to increase foci upon DNA damage (phleomycin), and result in increased chromosomal breakage spontaneously and after mitomycin C exposure, establishing FIGNL1 nuclear foci as functionally important for the DDR.\",\n      \"method\": \"Whole exome sequencing, transfection of DYK-tagged FIGNL1 mutant constructs in HEK293 cells, nuclear foci quantification, chromosomal breakage assay\",\n      \"journal\": \"European journal of endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human loss-of-function variants with defined foci/chromosomal breakage phenotype; single case with cell-based validation\",\n      \"pmids\": [\"37740949\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FIGNL1 is an AAA+ ATPase anti-recombinase that forms a non-planar hexamer (resolved by cryo-EM) which engages the RAD51 N-terminus through its pore loop and, using ATPase activity, actively dismantles RAD51 (and DMC1) filaments on both ssDNA and dsDNA; it operates as a stable complex with FIRRM/C1orf112/FLIP, whose binding enhances FIGNL1 stability and filament-disassembly activity, while upstream regulators BRCA2 and SWSAP1 antagonize FIGNL1 to protect productive RAD51 filaments—thereby balancing RAD51 assembly and disassembly during homologous recombination, meiosis, and replication fork restart to maintain genome stability.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FIGNL1 is an AAA+ ATPase that functions as an anti-recombinase, actively dismantling RAD51 (and the meiotic recombinase DMC1) nucleoprotein filaments to balance recombinase assembly and disassembly during homologous recombination, meiosis, and replication fork restart [#1, #6, #9]. It engages RAD51 through a conserved RAD51-binding domain and is recruited to DNA damage sites independently of BRCA2, RAD51, and RAD51 paralogs [#0]. Cryo-EM shows FIGNL1 assembles into a non-planar hexamer that encloses the RAD51 N-terminus within its central pore; both pore-loop engagement and ATPase catalysis are essential for filament removal and for viability in mouse embryonic stem cells [#7]. FIGNL1 disassembles RAD51 from both ssDNA and dsDNA, limiting non-productive recombinase assembly on native chromatin [#6], and acts at a post-assembly step to alter filament structure and promote processing of recombination intermediates [#9]. FIGNL1 operates as a stable, mutually stabilizing complex with FIRRM/C1orf112/FLIP, which directly stimulates its filament-disassembly activity and is required for RAD51 dissociation following ICL damage and fork restart [#3, #4, #10]. Its activity is antagonized by upstream regulators: BRCA2 directly binds the FIGNL1-FIRRM complex to protect productive RAD51 filaments from premature dismantling [#3, #13], and the RAD51 paralog SWSAP1 inhibits FIGNL1-mediated RAD51 dissociation [#1]; loss of FIGNL1 restores RAD51 loading and viability in BRCA2-deficient cells, showing that unrestricted FIGNL1 activity, not defective loading, underlies the BRCA2 HR defect [#12]. By promoting post-replicative RAD51 disassembly, FIGNL1 prevents RAD51-dependent ultra-fine chromosome bridges and catastrophic genome instability [#8]. Compound heterozygous frameshift mutations in FIGNL1 abolish its nuclear foci and cause spontaneous and induced chromosomal breakage in a human patient [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established FIGNL1 as a direct RAD51 interactor required for homologous recombination, distinguishing it from RAD51 loading factors by showing it acts without affecting RAD51 loading onto ssDNA.\",\n      \"evidence\": \"Co-IP, domain mapping, siRNA knockdown with HR reporter and foci analysis\",\n      \"pmids\": [\"23754376\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Biochemical activity on RAD51 filaments not yet demonstrated\", \"Functional role of the SPIDR/KIAA0146 complex partner unresolved\", \"No structural basis for RAD51 engagement\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined FIGNL1 biochemically as an anti-recombinase that dissociates RAD51 from ssDNA and identified SWSAP1 as a regulator that protects filaments by inhibiting this activity.\",\n      \"evidence\": \"In vitro RAD51-ssDNA dissociation with purified proteins, ATPase-dead mutagenesis, siRNA epistasis\",\n      \"pmids\": [\"30926776\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Reported ATPase-independence of dismantling later refined by structural work\", \"Mechanism of pore engagement not established\", \"Activity on dsDNA-bound RAD51 not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified FIRRM/C1orf112/FLIP as the stable, mutually stabilizing partner that directly stimulates FIGNL1 filament-disassembly activity, and placed BRCA2 upstream as an antagonist protecting RAD51 filaments.\",\n      \"evidence\": \"Proximity proteomics, Co-IP, in vitro filament disassembly with purified FIGNL1/C1orf112/BRCA2/RAD51, CRISPR KO, ICL sensitivity\",\n      \"pmids\": [\"37515771\", \"37439366\", \"37556550\", \"38133958\", \"37808755\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Stoichiometry of the FIGNL1-FIRRM-BRCA2 assembly not defined\", \"FIGNL1-independent FIRRM functions only partially mapped\", \"Regulation of complex assembly at damage sites unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended FIGNL1-FIRRM function to meiosis and replication, showing it dismantles both RAD51 and DMC1 and acts on dsDNA to limit non-productive recombinase assembly on intact chromatin.\",\n      \"evidence\": \"Germline-specific conditional KO mice, meiotic chromosome spreads, in vitro filament disassembly on dsDNA and ssDNA\",\n      \"pmids\": [\"37439366\", \"37891173\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"How DMC1 versus RAD51 selectivity is controlled is unknown\", \"Coupling to meiotic crossover designation not resolved\", \"Substrate discrimination between productive and non-productive filaments unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved the mechanism: FIGNL1 forms a non-planar hexamer that captures the RAD51 N-terminus in its pore, with pore-loop and ATPase residues essential for disassembly and for ES cell viability.\",\n      \"evidence\": \"Cryo-EM structure with pore-loop/ATPase mutagenesis, in vitro disassembly assay, mouse ES cell lethality\",\n      \"pmids\": [\"39636933\", \"39071279\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"How FIRRM modulates the hexamer is not visualized\", \"Conformational cycle during ATP hydrolysis not captured\", \"Structure of the FIGNL1-FIRRM-BRCA2 assembly absent\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked FIGNL1 anti-recombinase activity to genome stability by showing it prevents RAD51-dependent ultra-fine chromosome bridges after replication stress and processes recombination intermediates to promote strand invasion.\",\n      \"evidence\": \"FIGNL1 CRISPR KO human cells, UFB immunofluorescence, RAD51 foci after fork restart, in vitro strand invasion assay with FIGNL1\\u0394N, conditional KO mice\",\n      \"pmids\": [\"38597669\", \"39147779\", \"38286805\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Temporal coordination of disassembly with fork restart not fully defined\", \"Why some RAD51 filaments are productive and spared is unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Reinterpreted the BRCA2 HR defect by showing FIGNL1 loss restores RAD51 loading and viability in BRCA2-deficient cells, establishing unrestricted FIGNL1 activity as the primary cause of failed RAD51 retention.\",\n      \"evidence\": \"FIGNL1 KO in BRCA2-deficient mouse ES cells, RAD51 foci, HR reporter, Co-IP of MMS22L-TONSL-FIGNL1, viability assay\",\n      \"pmids\": [\"41166468\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Role of MMS22L-TONSL in regulating FIGNL1 not mechanistically defined\", \"Therapeutic implications for BRCA2-mutant tumors not tested\", \"How BRCA2 spatially restricts FIGNL1 in normal cells unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FIGNL1 distinguishes productive RAD51/DMC1 filaments to be spared from non-productive ones to be dismantled, and how its activity is spatiotemporally licensed by BRCA2, SWSAP1, FIRRM, and MMS22L-TONSL, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No integrated structural model of the regulated complex\", \"Substrate selectivity logic unknown\", \"In vivo regulation across cell cycle not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [1, 6, 7]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 6, 7, 9]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 14]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [6, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0, 3, 8]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [4, 6, 9]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [8, 10]}\n    ],\n    \"complexes\": [\"FIGNL1-FIRRM/C1orf112/FLIP complex\"],\n    \"partners\": [\"RAD51\", \"FIRRM\", \"C1orf112\", \"BRCA2\", \"SWSAP1\", \"DMC1\", \"SPIDR\", \"MMS22L\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}