{"gene":"PSMC3IP","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1998,"finding":"Yeast Hop2 (ortholog of PSMC3IP) localizes to meiotic chromosomes prior to and during synapsis, independent of double-strand breaks, and is required to prevent synaptonemal complex formation between nonhomologous chromosomes; hop2 mutants sustain wild-type DSB levels but these breaks remain unrepaired.","method":"Genetic analysis of hop2 mutant, immunofluorescence localization, meiotic chromosome spreads","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with defined cellular phenotype, localization experiments, replicated by subsequent studies in multiple organisms","pmids":["9708739"],"is_preprint":false},{"year":2002,"finding":"Hop2 and Mnd1 co-immunoprecipitate from meiotic cell extracts and form a complex; Mnd1 localization to chromatin requires Hop2; they act together to promote meiotic chromosome pairing and DSB repair.","method":"Co-immunoprecipitation, immunofluorescence, genetic epistasis (null mutant analysis)","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic epistasis, localization, replicated across multiple subsequent studies","pmids":["11940665"],"is_preprint":false},{"year":2003,"finding":"Mouse Hop2 knockout spermatocytes fail to synapse homologous chromosomes (very limited synapsis) and cannot repair meiotic DSBs, despite normal DSB formation and processing, demonstrating a direct role in promoting homologous chromosome synapsis.","method":"Hop2 knockout mouse, immunofluorescence of meiotic chromosome spreads, cytological analysis","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mouse with defined cellular phenotype, orthogonal cytological and molecular analyses","pmids":["14667414"],"is_preprint":false},{"year":2004,"finding":"Purified mouse TBPIP/HOP2 protein stimulates DMC1-mediated homologous pairing in vitro; this stimulation requires HOP2 to first bind double-stranded DNA; the C-terminal basic region is required for DNA binding and pairing stimulation activity; HOP2 did not stimulate RAD51-mediated pairing in this study.","method":"In vitro homologous pairing assay with purified proteins, deletion analysis, DNA-binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro activity, deletion mutagenesis, single lab but multiple orthogonal assays","pmids":["15192114"],"is_preprint":false},{"year":2004,"finding":"Saccharomyces cerevisiae Hop2 and Mnd1 form a stable heterodimer with higher affinity for double-stranded than single-stranded DNA; this heterodimer stimulates the strand assimilation activity of Dmc1 in vitro; genetic double mutant analysis places HOP2, MND1, and DMC1 in the same pathway for homologous chromosome juxtaposition.","method":"Protein purification, biochemical strand assimilation assay, double-mutant genetic epistasis, DNA-binding assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro biochemistry plus genetic epistasis, replicated by multiple subsequent studies","pmids":["15249670"],"is_preprint":false},{"year":2005,"finding":"Mouse Hop2 alone can efficiently form D-loops; upon association with Mnd1, this Hop2 D-loop activity is abrogated; the Hop2-Mnd1 heterodimer physically interacts with both Rad51 and Dmc1 recombinases and stimulates their strand invasion activity up to 35-fold.","method":"In vitro D-loop assay, co-immunoprecipitation, reconstituted strand invasion assay with purified proteins","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro biochemistry with purified components, multiple assays, replicated by independent labs","pmids":["15834424"],"is_preprint":false},{"year":2006,"finding":"Human TBPIP/Hop2-Mnd1 complex significantly stimulates Dmc1- and Rad51-mediated strand exchange and preferentially binds three-stranded DNA branch intermediates.","method":"Purification of human TBPIP/Hop2-Mnd1 complex, in vitro strand exchange assay, DNA-binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified human proteins, multiple assays, single lab","pmids":["16407260"],"is_preprint":false},{"year":2006,"finding":"Interaction with Mnd1 provokes conformational changes in Hop2 that abrogate its own recombinase activity and generate a new molecular interface enabling Hop2-Mnd1 heterodimer to physically interact with and stimulate Dmc1; coiled-coil motifs in Hop2 and Mnd1 are essential for their mutual interaction; a C-terminal region is required for DNA binding and single-strand annealing by the heterodimer; a point mutation in Hop2 dissociates strand invasion from DNA binding/annealing.","method":"Purified protein biochemistry, mutagenesis, in vitro recombination assays, sedimentation analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution, point mutagenesis, multiple functional assays, single lab","pmids":["16675459"],"is_preprint":false},{"year":2006,"finding":"Mnd1/Hop2 is required for Dmc1-mediated interhomolog crossover recombination; in mnd1 rad51 and hop2 rad51 double mutants, crossover recombination can still occur, indicating Mnd1/Hop2 functions specifically in the Dmc1-dependent pathway and is required for stable strand invasion between homologous chromosomes.","method":"Genetic epistasis (double-mutant analysis), recombination assays in S. cerevisiae","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple double-mutant combinations, defined recombination phenotypes","pmids":["16581767"],"is_preprint":false},{"year":2007,"finding":"Hop2-Mnd1 stimulates Dmc1-mediated recombination via two distinct mechanisms: (1) stabilizing the Dmc1-ssDNA nucleoprotein filament, and (2) facilitating duplex DNA capture by the Dmc1-ssDNA filament to promote synaptic complex formation on long duplex DNAs.","method":"In vitro strand invasion and synaptic complex formation assays, nucleoprotein filament stability assays with purified proteins","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro biochemistry with purified components, multiple assays dissecting mechanism, replicated independently","pmids":["17639081"],"is_preprint":false},{"year":2007,"finding":"Hop2 is the major DNA-binding subunit of the Hop2-Mnd1 complex while Mnd1 is the prominent Rad51-interaction entity; Hop2-Mnd1 stabilizes the Rad51-ssDNA nucleoprotein filament and enhances duplex DNA capture by the Rad51-ssDNA filament (bipartite mechanism).","method":"In vitro protein-DNA binding assays, Rad51-interaction mapping, presynaptic filament stability assays, duplex DNA capture assays with purified proteins","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro biochemistry, domain mapping, multiple functional assays","pmids":["17639080"],"is_preprint":false},{"year":2007,"finding":"Fission yeast spHop2-Mnd1 interacts by co-immunoprecipitation; it binds ssDNA ends of 3'-tailed DNA, promotes renaturation of complementary ssDNA, catalyzes strand exchange with short oligonucleotides, and stimulates spDmc1-dependent strand exchange and strand invasion. Mouse Hop2 or Hop2-Mnd1 stimulates both hRad51 and hDmc1, revealing evolutionary divergence in recombinase specificity.","method":"Co-immunoprecipitation, electron microscopy, in vitro strand exchange and strand invasion assays with purified proteins from S. pombe and mouse","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution, EM, Co-IP, multiple assays comparing species","pmids":["17426123"],"is_preprint":false},{"year":2002,"finding":"GT198/PSMC3IP was identified as a tissue-specific nuclear coactivator that interacts with the DNA-binding domains (DBDs) of nuclear receptors (ERα/β, TRβ1, AR, GR, PR); interaction was shown by in vitro binding and yeast two-hybrid; GT198 potently stimulates transcription mediated by these receptors; PKA, PKC, and MAPK can phosphorylate GT198 in vitro, and cotransfection of these kinases regulates GT198 transcriptional activity.","method":"Yeast two-hybrid, in vitro binding assay, transcription reporter assays, in vitro kinase phosphorylation assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro binding, yeast two-hybrid, reporter assays, in vitro kinase assays; single lab with multiple orthogonal methods","pmids":["11739747"],"is_preprint":false},{"year":2009,"finding":"TBP-1 (PSMC3, 19S proteasome ATPase) directly binds TBPIP/PSMC3IP through TBPIP's N-terminal leucine zipper; AR is physically associated with both TBP-1 and TBPIP in vitro and in LNCaP cells; TBP-1 augments AR-mediated transcription additively with TBPIP; TBP-1 is transiently recruited to the PSA gene promoter androgen response element in a ligand-dependent manner.","method":"Yeast two-hybrid, in vitro binding, co-immunoprecipitation in LNCaP cells, transcription reporter assays, chromatin immunoprecipitation","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ChIP, reporter assays, in vitro binding; multiple orthogonal methods","pmids":["19325002"],"is_preprint":false},{"year":2010,"finding":"Hop2-Mnd1 heterodimer efficiently condenses double-stranded DNA via formation of DNA condensates, visualized at single-molecule level; condensation is concentration-dependent, reversible, and specific to the heterodimer (neither Hop2 nor Mnd1 alone can do this); condensation is accelerated by divalent metal ions (Mn2+>Mg2+>Ca2+); Hop2-Mnd1/Dmc1/ssDNA nucleoprotein filaments also condense dsDNA in a heterodimer concentration-dependent manner paralleling strand exchange activity.","method":"Single-molecule optical tweezers, video fluorescence microscopy, DNA condensation assays","journal":"Biophysical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — single-molecule reconstitution with purified proteins, multiple controls, single lab","pmids":["21112301"],"is_preprint":false},{"year":2011,"finding":"A homozygous 3-bp deletion in PSMC3IP (p.Glu201del) in the C-terminal acidic domain causes XX female gonadal dysgenesis; the mutation abolishes PSMC3IP coactivation of estrogen-driven transcription in cell lines, while not affecting the meiotic recombination domain (C-terminus absent in yeast).","method":"Homozygosity mapping, whole-exome sequencing, transcription reporter assay in cell lines","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetics plus functional cell-based reporter assay; single lab, single functional method","pmids":["21963259"],"is_preprint":false},{"year":2013,"finding":"HOP2 alone (without MND1) can promote strand invasion, co-aggregation of ssDNA with duplex DNA, base unstacking on ssDNA, and formation of three-strand synaptic intermediates; this HOP2-only recombinase activity does not require ATP and is more sensitive to mismatches than DMC1; in Mnd1-/- spermatocytes expressing HOP2 without functional HOP2-MND1 complex, a fraction shows chromosome synapsis and DSB repair.","method":"In vitro strand exchange assay, in vitro ssDNA binding, Mnd1 knockout mouse analysis, immunofluorescence of spermatocytes","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemistry with purified protein plus in vivo knockout mouse validation, multiple assays","pmids":["24304900"],"is_preprint":false},{"year":2013,"finding":"Inactivating germline mutations in GT198/PSMC3IP (including nonsense mutation p.Q104X) are found in familial and early-onset breast and ovarian cancer patients; the truncating p.Q104X mutation abolishes DNA damage-induced Rad51 foci formation, demonstrating a functional requirement for PSMC3IP in homologous recombination repair.","method":"Germline mutation screening, Sanger sequencing, Rad51 foci immunofluorescence after DNA damage","journal":"Genes & cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional Rad51 foci assay for one mutation, genetic screening; single lab","pmids":["23946868"],"is_preprint":false},{"year":2013,"finding":"GT198 splice variants lacking the full C-terminal domain act as dominant negatives: they counteract wild-type GT198 transcriptional coactivation activity and abolish Rad51 foci formation during radiation-induced DNA damage; expression of GT198 variant but not wild type induces tumor growth in nude mice.","method":"Transcription reporter assays, Rad51 foci immunofluorescence, in vivo xenograft tumor growth assay","journal":"Genes & cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple functional cell-based assays and in vivo xenograft; single lab","pmids":["23946869"],"is_preprint":false},{"year":2013,"finding":"Small angle X-ray scattering (SAXS) and electron microscopy reveal that the Hop2-Mnd1 heterodimer forms a V-shaped molecule with three distinct DNA binding sites; N-terminal dsDNA-binding functions of Hop2 and Mnd1 cooperate to mediate synaptic complex assembly, while ssDNA binding by the Hop2 C-terminus stabilizes the DMC1-ssDNA filament.","method":"SAXS, electron microscopy, deletion mutagenesis, in vitro DNA-binding assays, strand invasion assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structural (SAXS+EM) plus mutagenesis and functional biochemistry; single lab but multiple orthogonal methods","pmids":["24150939"],"is_preprint":false},{"year":2014,"finding":"HOP2-MND1 induces conformational changes in RAD51 that alter its nucleotide cofactor interactions and DNA-binding specificity: it enables RAD51 DNA strand exchange without divalent metal ions required for ATP binding, offsets the K133A ATP-binding mutation, helps load RAD51 on ssDNA restricting dsDNA-binding during presynaptic filament formation, and promotes dsDNA binding during homology search by removing inhibitory effect of ssDNA.","method":"In vitro strand exchange assays, nucleotide-binding assays, DNA-binding assays with purified proteins and RAD51 mutants","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified proteins, mutagenesis, multiple mechanistic assays; peer-reviewed journal","pmids":["24943459"],"is_preprint":false},{"year":2014,"finding":"The N-terminal domain of mouse HOP2 adopts a winged-helix (WH) DNA-binding fold as determined by NMR solution structure; helix 3 and wing 1 of the WH domain mediate DNA binding; a coiled-coil region mediates HOP2 self-association; mutations in key residues of the WH domain impair DNA binding and strand invasion activity.","method":"NMR solution structure determination, mutagenesis, DNA-binding assays, strand invasion assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with mutagenesis and functional validation; single lab with multiple methods","pmids":["24711446"],"is_preprint":false},{"year":2015,"finding":"Crystal structure of Hop2-Mnd1 reveals a curved rod-like structure with three leucine zippers and two kinked junctions, juxtaposed winged-helix domains at one end, and a helical bundle-like structure at the other; the helical bundle is sufficient for interacting with the Dmc1-ssDNA nucleofilament; molecular modeling suggests the curved rod fits into the helical groove of the nucleofilament.","method":"X-ray crystallography, deletion analysis, molecular modeling","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus functional deletion analysis; single lab with orthogonal structural and biochemical methods","pmids":["25740648"],"is_preprint":false},{"year":2015,"finding":"The HOP2 p.del201Glu mutation (associated with XX ovarian dysgenesis) diminishes association of Hop2-Mnd1 with both RAD51 and DMC1 and reduces functional stimulation of their recombinase activity; both Hop2 and Mnd1 interact with RAD51 via their C-terminal regions; ATP enhances the interaction between Hop2-Mnd1 and RAD51; distinct DNA-binding activities of Hop2-Mnd1 mediate different aspects of RAD51 presynaptic filament stabilization vs. homologous DNA pairing stimulation.","method":"In vitro protein interaction assays, mutagenesis of C-terminal domains, strand invasion assays, presynaptic filament stabilization assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution, structure-function mutagenesis, multiple assays; directly connects disease mutation to molecular mechanism","pmids":["25820426"],"is_preprint":false},{"year":2015,"finding":"PSMC3IP and EPSTI1 modulate the extrinsic apoptotic pathway in estrogen receptor-positive and triple-negative breast cancer cell lines, as demonstrated by modulation of apoptotic markers upon gene knockdown/overexpression.","method":"Gene knockdown/overexpression in cell lines, apoptosis marker analysis","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single cell-line phenotypic assays without defined molecular mechanism; single lab","pmids":["25590583"],"is_preprint":false},{"year":2017,"finding":"GT198/PSMC3IP-expressing pericytes give rise to tumor cells; activation of GT198 induces VEGF expression; GT198 promotes tube formation in cultured U251 cells, supporting a role in angiogenesis.","method":"Cell culture overexpression/activation, VEGF reporter assay, tube formation assay, in vivo xenograft and vaccination models","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — cell-based functional assays with in vivo validation; single lab","pmids":["28881671"],"is_preprint":false},{"year":2018,"finding":"Yeast Hop2-Mnd1 binds rapidly to Dmc1-ssDNA filaments with high affinity (residence time ~1.3 min) in a highly specific manner; no association of Hop2-Mnd1 with Rad51-ssDNA or RPA-ssDNA was detected, demonstrating Dmc1-specific binding in S. cerevisiae.","method":"Single-molecule imaging using DNA curtains, real-time binding measurements","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — single-molecule reconstitution with quantitative kinetic measurements; rigorous controls for specificity","pmids":["30420424"],"is_preprint":false},{"year":2019,"finding":"Hop2 physically interacts with ATF4 transcription factor via its Zip domain (identified by yeast two-hybrid and confirmed by interaction assays); Hop2 enhances ATF4-dependent transcription; Hop2-/- mice exhibit an osteopenic phenotype similar to Atf4-/- mice with decreased Osteocalcin mRNA and reduced type I collagen synthesis; compound heterozygous Atf4+/-:Hop2+/- mice display the same skeletal defects as Hop2-/- mice.","method":"Yeast two-hybrid, deletional mapping, transcription reporter assay, Hop2 knockout mouse skeletal phenotype, genetic epistasis (compound heterozygotes)","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid with domain mapping plus in vivo genetic epistasis and KO mouse phenotype; multiple orthogonal methods","pmids":["31433867"],"is_preprint":false},{"year":2021,"finding":"Hop2 physically interacts with CEBPα (confirmed by pull-down with recombinant proteins and co-immunoprecipitation of endogenous proteins from preadipocytes and adipocytes); Hop2 suppresses CEBPα-mediated transactivation; Hop2 stable overexpression inhibits adipocyte differentiation; Hop2-/- mice exhibit increased adiposity and adipogenic marker gene expression; ChIP shows higher CEBPα binding to PPARγ promoter in Hop2-/- adipose-derived MSCs.","method":"Pull-down, co-immunoprecipitation, transcription reporter assay, stable overexpression, Hop2 knockout mouse, ChIP","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal endogenous Co-IP, KO mouse, ChIP, multiple functional assays; single lab with multiple orthogonal methods","pmids":["34600885"],"is_preprint":false},{"year":2021,"finding":"Oct4 A transcriptionally regulates PSMC3IP expression; knockdown of PSMC3IP reduces HNSCC self-renewal capacity and clonogenic cell survival after irradiation, indicating PSMC3IP contributes to homologous recombination-mediated radioresistance and cancer stem cell phenotype.","method":"Knockdown of PSMC3IP, clonogenic survival assay, self-renewal assay, PARP inhibitor combination studies","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — KD with defined cellular phenotypes in multiple assays; transcriptional regulation shown but upstream mechanism less rigorously defined","pmids":["34079088"],"is_preprint":false},{"year":2023,"finding":"Depletion of PSMC3IP or MND1 in mitotic cells causes sensitivity to PARP inhibitors and ionizing radiation, independently of alternative lengthening of telomeres; depleted cells accumulate toxic RAD51 foci and show impaired homology-directed DNA repair; PARPi sensitivity occurs even in BRCA1/TP53BP1-deficient cells; wild-type PSMC3IP reverses PARPi sensitivity but the p.Glu201del ovarian dysgenesis mutant does not, linking the D-loop formation function to PARPi sensitivity.","method":"Genome-scale CRISPR screens, PSMC3IP/MND1 depletion, RAD51 foci immunofluorescence, HR reporter assay, PARP inhibitor sensitivity assays, rescue with wild-type vs mutant PSMC3IP","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — CRISPR screens plus targeted depletion, multiple functional assays including structure-function rescue; single lab with multiple orthogonal methods","pmids":["37163373"],"is_preprint":false},{"year":2023,"finding":"Fission yeast Hop2-Mnd1 and Swi5-Sfr1 stimulate Dmc1 filament assembly by distinct mechanisms: Hop2-Mnd1 enhances the binding rate (nucleation) of Dmc1 at ssDNA/dsDNA junctions by binding DNA first to recruit Dmc1, while Swi5-Sfr1 specifically reduces the Dmc1 dissociation rate during nucleation; both proteins together allow further stimulation.","method":"Single-molecule FRET (smFRET), tethered particle motion (TPM), order-of-addition experiments with purified proteins","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — single-molecule reconstitution (smFRET + TPM) with purified proteins, kinetic dissection of mechanism; single lab","pmids":["37395447"],"is_preprint":false},{"year":2024,"finding":"Hop2-Mnd1 acts as a DNA sequence fidelity switch for Dmc1: it upregulates Dmc1 activity with fully homologous or mismatch-containing substrates, but suppresses illegitimate recombination between substrates with only microhomology; suppression of illegitimate recombination requires the Dmc1 filament interaction attributable to Hop2-Mnd1 but not its DNA binding activity, as demonstrated by separation-of-function variants.","method":"In vitro strand exchange assays with Hop2-Mnd1 separation-of-function variants, DNA substrates with defined mismatches/microhomology","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with structure-function variants, multiple substrate types; rigorous mechanistic dissection","pmids":["39463417"],"is_preprint":false},{"year":2025,"finding":"GDF15 overexpression upregulates Hop2/PSMC3IP expression in pre-adipocytes; Hop2 mediates GDF15-induced suppression of C/EBPα expression and inhibition of adipogenesis, as Hop2 knockdown during GDF15 overexpression abolishes the suppression of C/EBPα.","method":"GDF15 overexpression, Hop2 knockdown, adipogenesis assay, gene expression analysis","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — epistasis by genetic KD, functional adipogenesis assay, consistent with prior Hop2-CEBPα mechanism","pmids":["39814165"],"is_preprint":false},{"year":2026,"finding":"Human DMC1-ssDNA presynaptic complex employs diffusion-based homology search generating a migrating DNA bubble; HOP2-MND1 codiffuses with the DMC1-ssDNA presynaptic complex, clamps the ssDNA-dsDNA junctions, and maintains an expanded DNA bubble to enable homology recognition that cannot occur without HOP2-MND1 or free DMC1.","method":"Single-molecule imaging of human proteins, reconstituted in vitro system","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — single-molecule reconstitution with human proteins, rigorous mechanistic dissection; most recent mechanistic study","pmids":["41746729"],"is_preprint":false},{"year":1997,"finding":"Mouse TBPIP (ortholog of PSMC3IP) was cloned as a TBP-1-interacting protein; it co-localizes with TBP-1 in vivo and enhances TBP-1's inhibitory action on Tat-mediated transactivation of HIV replication in vitro.","method":"Protein-protein interaction cloning, co-localization, transactivation reporter assay","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single interaction and reporter assay, mouse protein, single lab","pmids":["9345291"],"is_preprint":false}],"current_model":"PSMC3IP (also known as HOP2, GT198, TBPIP) is a multifunctional nuclear protein that, as part of the HOP2-MND1 heterodimer, acts as an essential cofactor for the DMC1 and RAD51 recombinases in meiotic (and mitotic) homologous recombination: it stabilizes the recombinase-ssDNA presynaptic filament, captures duplex DNA to promote synaptic complex formation, suppresses illegitimate recombination, and codiffuses with the DMC1-ssDNA complex to enable homology recognition; structurally, HOP2-MND1 forms a V-shaped/curved rod with a winged-helix DNA-binding domain and leucine zipper coiled-coil, with distinct regions mediating dsDNA capture, ssDNA filament stabilization, and recombinase interaction via the C-terminal helical bundle; outside of recombination, PSMC3IP functions as a tissue-specific nuclear receptor coactivator (interacting with DBDs of ER, AR, GR, PR, TRβ) and interacts with ATF4 to promote osteoblast differentiation and with CEBPα to suppress adipogenesis, while disease-associated mutations (p.Glu201del causing XX gonadal dysgenesis; truncating mutations in breast/ovarian cancer) disrupt its coactivation of estrogen-driven transcription and its stimulation of RAD51/DMC1-mediated D-loop formation."},"narrative":{"mechanistic_narrative":"PSMC3IP (HOP2/GT198/TBPIP) is a nuclear protein that functions principally as an essential cofactor for the DMC1 and RAD51 recombinases during homologous recombination, while also serving as a tissue-specific transcriptional regulator. In meiosis it localizes to chromosomes before and during synapsis and is required to repair programmed double-strand breaks and to prevent synaptonemal complex formation between nonhomologous chromosomes [PMID:9708739, PMID:14667414]. It acts as a stable heterodimer with MND1, whose chromatin localization depends on HOP2 [PMID:11940665]; this heterodimer binds DNA—preferring duplex and three-stranded branch intermediates—and stimulates DMC1- and RAD51-mediated strand invasion and exchange up to 35-fold [PMID:15249670, PMID:15834424, PMID:16407260]. Mechanistically, HOP2-MND1 acts through a bipartite scheme: it stabilizes the recombinase-ssDNA presynaptic filament and facilitates capture of duplex DNA to nucleate the synaptic complex [PMID:17639081, PMID:17639080], and it codiffuses with the DMC1-ssDNA complex, clamping ssDNA-dsDNA junctions and maintaining an expanded DNA bubble to enable homology recognition [PMID:41746729]. The heterodimer additionally serves as a sequence-fidelity switch that suppresses illegitimate recombination between microhomologous substrates via its recombinase-interaction surface [PMID:39463417]. Structurally HOP2-MND1 forms a curved/V-shaped rod with juxtaposed winged-helix DNA-binding domains, leucine-zipper coiled coils, and a C-terminal helical bundle that engages the recombinase nucleofilament [PMID:24150939, PMID:24711446, PMID:25740648]. Independent of recombination, PSMC3IP acts as a nuclear-receptor coactivator that binds the DNA-binding domains of ERα/β, AR, GR, PR, and TRβ1 and potentiates their transcription [PMID:11739747], interacts with the proteasomal ATPase PSMC3/TBP-1 to augment AR-driven transcription [PMID:19325002], and modulates osteoblast and adipocyte differentiation through interactions with ATF4 and CEBPα [PMID:31433867, PMID:34600885]. A homozygous in-frame deletion (p.Glu201del) in the C-terminal acidic domain causes XX gonadal dysgenesis by abolishing estrogen-driven coactivation and impairing recombinase stimulation [PMID:21963259, PMID:25820426], and the recombination function underlies PARP-inhibitor and irradiation sensitivity in mitotic and cancer cells [PMID:37163373].","teleology":[{"year":1998,"claim":"Established that HOP2 is a meiotic chromosome factor required for repair of double-strand breaks and for fidelity of synapsis, distinguishing it from break-formation machinery.","evidence":"Genetic analysis and immunofluorescence of hop2 mutant yeast meiotic chromosome spreads","pmids":["9708739"],"confidence":"High","gaps":["No biochemical activity defined","Partner proteins unknown","Molecular basis of synapsis defect not resolved"]},{"year":2002,"claim":"Identified MND1 as HOP2's obligate partner, defining the functional unit as a heterodimer and showing HOP2 directs MND1 to chromatin.","evidence":"Co-immunoprecipitation, immunofluorescence and genetic epistasis in meiotic cells","pmids":["11940665"],"confidence":"High","gaps":["Biochemical mechanism of the complex unknown","Direct DNA/recombinase activities not yet shown"]},{"year":2002,"claim":"Revealed a recombination-independent role: PSMC3IP/GT198 is a tissue-specific coactivator binding nuclear-receptor DNA-binding domains and is regulated by phosphorylation.","evidence":"Yeast two-hybrid, in vitro binding, reporter and in vitro kinase assays","pmids":["11739747"],"confidence":"High","gaps":["In vivo relevance of each receptor interaction not established","Coactivation mechanism (chromatin/cofactor recruitment) undefined"]},{"year":2003,"claim":"Confirmed in mammals that HOP2 is required for homologous chromosome synapsis and meiotic DSB repair without affecting break formation.","evidence":"Hop2 knockout mouse cytological analysis of spermatocytes","pmids":["14667414"],"confidence":"High","gaps":["Direct molecular substrate not defined in vivo","Relationship to recombinase activity not yet biochemically shown"]},{"year":2004,"claim":"Demonstrated direct biochemical activity: purified HOP2 binds dsDNA and stimulates DMC1-mediated pairing, and the HOP2-MND1 heterodimer stimulates DMC1 strand assimilation, placing HOP2/MND1/DMC1 in one pathway.","evidence":"Reconstituted in vitro pairing/strand assimilation assays, deletion analysis, genetic epistasis","pmids":["15192114","15249670"],"confidence":"High","gaps":["RAD51 specificity unresolved across species","Structural basis of recombinase stimulation unknown"]},{"year":2005,"claim":"Showed that MND1 binding switches off HOP2's intrinsic D-loop activity and creates the interface enabling the heterodimer to physically engage and strongly stimulate both RAD51 and DMC1.","evidence":"In vitro D-loop and strand invasion assays, co-immunoprecipitation","pmids":["15834424"],"confidence":"High","gaps":["Conformational change not structurally defined","Division of labor between subunits unclear"]},{"year":2006,"claim":"Defined the bipartite/conformational logic of the complex—coiled-coil-mediated dimerization, MND1-induced HOP2 conformational change, C-terminal DNA binding, and recombinase stimulation—and extended activity to human proteins.","evidence":"Purified protein biochemistry, mutagenesis, strand exchange assays, sedimentation analysis (human and yeast)","pmids":["16407260","16675459","16581767"],"confidence":"High","gaps":["Atomic structure still lacking","Quantitative kinetics of stimulation unresolved"]},{"year":2007,"claim":"Dissected the dual mechanism: HOP2-MND1 both stabilizes the recombinase-ssDNA presynaptic filament and promotes duplex DNA capture for synaptic complex assembly, with HOP2 as the DNA-binding and MND1 as the RAD51-interacting subunit.","evidence":"Reconstituted filament-stability and duplex-capture assays, interaction mapping, EM (yeast and mouse)","pmids":["17639081","17639080","17426123"],"confidence":"High","gaps":["Structural arrangement on the filament not resolved","Cross-species recombinase specificity differences unexplained"]},{"year":2009,"claim":"Connected the coactivator role to the proteasomal ATPase PSMC3/TBP-1, which binds the HOP2 N-terminal leucine zipper and augments androgen-receptor transcription at target promoters.","evidence":"Yeast two-hybrid, Co-IP in LNCaP cells, reporter assays and ChIP","pmids":["19325002"],"confidence":"High","gaps":["Mechanism linking proteasome ATPase to transcription unclear","Generality beyond AR/PSA promoter untested"]},{"year":2011,"claim":"Provided a human disease link, showing that a C-terminal acidic-domain deletion (p.Glu201del) causes XX gonadal dysgenesis by abolishing estrogen-driven coactivation.","evidence":"Homozygosity mapping, exome sequencing, cell-based reporter assay","pmids":["21963259"],"confidence":"Medium","gaps":["Single functional readout (reporter only)","Effect on recombinase function not tested in this study","How a coactivation defect produces dysgenesis unresolved"]},{"year":2013,"claim":"Refined subunit autonomy and disease association: HOP2 alone has ATP-independent recombinase activity partly active in vivo, while truncating GT198 mutations and dominant-negative splice variants disrupt RAD51 foci, coactivation, and promote tumor growth.","evidence":"In vitro strand exchange, Mnd1 knockout mouse, germline mutation screening, RAD51 foci assays, xenografts","pmids":["24304900","23946868","23946869"],"confidence":"High","gaps":["Cancer-association statistics limited to single-lab cohorts","Dominant-negative mechanism not structurally defined"]},{"year":2014,"claim":"Established structural and mechanistic detail: HOP2's N-terminal winged-helix DNA-binding fold, and HOP2-MND1-induced conformational changes that reprogram RAD51 nucleotide/DNA-binding behavior during filament formation and homology search.","evidence":"NMR solution structure with mutagenesis; in vitro strand exchange and nucleotide/DNA-binding assays with RAD51 mutants","pmids":["24711446","24943459"],"confidence":"High","gaps":["Full heterodimer structure not yet solved","Conformational change in RAD51 not visualized directly"]},{"year":2015,"claim":"Delivered the architecture and disease mechanism: a curved rod with juxtaposed winged-helix domains and a recombinase-engaging helical bundle, and direct evidence that p.Glu201del weakens RAD51/DMC1 association and stimulation.","evidence":"Crystal structure and SAXS/EM, deletion analysis, modeling onto the nucleofilament; mutant protein interaction and strand-invasion assays","pmids":["24150939","25740648","25820426"],"confidence":"High","gaps":["Cryo-EM of the complex on a filament not available","How disease mutant affects both transcription and recombination jointly unresolved"]},{"year":2017,"claim":"Extended GT198 to angiogenesis and tumor-cell-of-origin biology by linking its activation to VEGF expression and tube formation.","evidence":"Cell culture activation/overexpression, VEGF reporter and tube-formation assays, xenograft models","pmids":["28881671"],"confidence":"Medium","gaps":["Molecular pathway to VEGF undefined","Single-lab evidence"]},{"year":2018,"claim":"Quantified the specificity of recombinase engagement in budding yeast, showing rapid high-affinity binding to DMC1-ssDNA filaments but not RAD51- or RPA-ssDNA.","evidence":"Single-molecule DNA-curtain real-time binding measurements","pmids":["30420424"],"confidence":"High","gaps":["Species divergence in RAD51 vs DMC1 specificity unresolved","Structural basis of selective binding unknown"]},{"year":2019,"claim":"Defined a coactivator role in bone: HOP2 binds ATF4 via its Zip domain and enhances ATF4-dependent transcription, with KO and compound-heterozygote mice phenocopying osteopenia.","evidence":"Yeast two-hybrid, deletion mapping, reporter assays, knockout mouse skeletal phenotype, genetic epistasis","pmids":["31433867"],"confidence":"High","gaps":["Direct chromatin co-occupancy of HOP2-ATF4 not shown","Relationship to recombination function in osteoblasts unclear"]},{"year":2021,"claim":"Defined an opposing differentiation role in fat: HOP2 binds CEBPα and suppresses its transactivation to inhibit adipogenesis, with KO mice showing increased adiposity.","evidence":"Pull-down, endogenous Co-IP, reporter assays, stable overexpression, knockout mouse, ChIP","pmids":["34600885"],"confidence":"High","gaps":["How HOP2 suppresses rather than coactivates here is unexplained","Tissue-specific switch between coactivation and repression undefined"]},{"year":2021,"claim":"Linked PSMC3IP-dependent HR to cancer radioresistance and stemness, with Oct4A upstream regulation.","evidence":"Knockdown, clonogenic and self-renewal assays, PARP inhibitor combinations in HNSCC","pmids":["34079088"],"confidence":"Medium","gaps":["Upstream Oct4A regulation mechanism not rigorously defined","Direct HR contribution vs indirect effects not separated"]},{"year":2023,"claim":"Established PSMC3IP/MND1 as targetable HR factors in mitotic cells: their loss causes toxic RAD51 foci, HR defects and PARPi/IR sensitivity even in BRCA1/53BP1-deficient cells, with rescue dependent on the intact D-loop function lost in p.Glu201del.","evidence":"Genome-scale CRISPR screens, depletion, RAD51 foci, HR reporter, PARPi assays, WT vs mutant rescue","pmids":["37163373"],"confidence":"High","gaps":["Therapeutic window in patient tumors untested","Source of toxic RAD51 foci not fully mechanistically defined"]},{"year":2023,"claim":"Resolved the kinetic mechanism of DMC1 filament stimulation: HOP2-MND1 binds DNA first to recruit DMC1 and enhance nucleation rate, distinct from Swi5-Sfr1 which slows dissociation.","evidence":"Single-molecule FRET and TPM with order-of-addition experiments (fission yeast)","pmids":["37395447"],"confidence":"High","gaps":["Conservation of nucleation mechanism in human proteins not shown here","Coordination with other mediators in vivo unclear"]},{"year":2024,"claim":"Defined a fidelity-switch function: HOP2-MND1 promotes recombination on homologous/mismatched substrates but suppresses illegitimate recombination on microhomology via its recombinase-interaction surface, not DNA binding.","evidence":"In vitro strand exchange with separation-of-function variants and defined mismatch/microhomology substrates","pmids":["39463417"],"confidence":"High","gaps":["In vivo relevance of fidelity switch untested","Structural basis of microhomology discrimination unknown"]},{"year":2025,"claim":"Placed HOP2 downstream of GDF15 in adipogenic control, where it mediates GDF15-induced CEBPα suppression.","evidence":"GDF15 overexpression with HOP2 knockdown and adipogenesis assays","pmids":["39814165"],"confidence":"Medium","gaps":["Direct GDF15-HOP2 signaling link not defined","Single functional epistasis readout"]},{"year":2026,"claim":"Captured the homology-search mechanism in human proteins: HOP2-MND1 codiffuses with the DMC1-ssDNA complex, clamps ssDNA-dsDNA junctions and maintains an expanded migrating DNA bubble enabling homology recognition.","evidence":"Single-molecule imaging of reconstituted human DMC1/HOP2-MND1 system","pmids":["41746729"],"confidence":"High","gaps":["Coupling of bubble maintenance to downstream strand exchange not resolved","Structure of the migrating complex not solved"]},{"year":null,"claim":"How PSMC3IP is partitioned between its recombination and transcriptional-coactivator/repressor roles in different tissues, and what regulatory signals (e.g. phosphorylation) toggle these functions, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Tissue-specific control of dual function undefined","No structural model unifying coactivation and recombination domains","Direct chromatin-targeting mechanism of the coactivator role unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[3,4,10,19,21]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[5,9,10,20]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,9,23,32]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[12,13,27,28]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[5,6,16]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[12,13,35]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA 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Stimulates DMC1-mediated strand exchange required for pairing homologous chromosomes during meiosis. The complex PSMC3IP/MND1 binds DNA, stimulates the recombinase activity of DMC1 as well as DMC1 D-loop formation from double-strand DNA. This complex stabilizes presynaptic RAD51 and DMC1 filaments formed on single strand DNA to capture double-strand DNA. This complex stimulates both synaptic and presynaptic critical steps in RAD51 and DMC1-promoted homologous pairing. May inhibit HIV-1 viral protein TAT activity and modulate the activity of proteasomes through association with PSMC3. Acts as a tissue specific coactivator of hormone-dependent transcription mediated by nuclear receptors","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9P2W1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PSMC3IP","classification":"Not Classified","n_dependent_lines":17,"n_total_lines":1208,"dependency_fraction":0.014072847682119206},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000131470","cell_line_id":"CID000134","localizations":[{"compartment":"big_aggregates","grade":3},{"compartment":"nuclear_punctae","grade":2},{"compartment":"nucleoplasm","grade":2}],"interactors":[{"gene":"MND1","stoichiometry":10.0},{"gene":"CCNB1","stoichiometry":0.2},{"gene":"MED25","stoichiometry":0.2},{"gene":"PSME1","stoichiometry":0.2},{"gene":"MED23","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000134","total_profiled":1310},"omim":[{"mim_id":"614324","title":"OVARIAN DYSGENESIS 3; ODG3","url":"https://www.omim.org/entry/614324"},{"mim_id":"608665","title":"PSMC3-INTERACTING PROTEIN; PSMC3IP","url":"https://www.omim.org/entry/608665"},{"mim_id":"602020","title":"MAF bZIP TRANSCRIPTION FACTOR G; MAFG","url":"https://www.omim.org/entry/602020"},{"mim_id":"258150","title":"SPERMATOGENIC FAILURE 1; SPGF1","url":"https://www.omim.org/entry/258150"},{"mim_id":"233300","title":"OVARIAN DYSGENESIS 1; ODG1","url":"https://www.omim.org/entry/233300"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"testis","ntpm":24.3}],"url":"https://www.proteinatlas.org/search/PSMC3IP"},"hgnc":{"alias_symbol":["TBPIP","GT198","HUMGT198A","Hop2"],"prev_symbol":[]},"alphafold":{"accession":"Q9P2W1","domains":[{"cath_id":"1.10.10.10","chopping":"8-72","consensus_level":"high","plddt":93.6748,"start":8,"end":72},{"cath_id":"1.20.5","chopping":"82-120","consensus_level":"medium","plddt":96.4287,"start":82,"end":120},{"cath_id":"1.10.287","chopping":"170-209","consensus_level":"high","plddt":93.3883,"start":170,"end":209}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P2W1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P2W1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P2W1-F1-predicted_aligned_error_v6.png","plddt_mean":92.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSMC3IP","jax_strain_url":"https://www.jax.org/strain/search?query=PSMC3IP"},"sequence":{"accession":"Q9P2W1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9P2W1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9P2W1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P2W1"}},"corpus_meta":[{"pmid":"9708739","id":"PMC_9708739","title":"The 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of sex determination and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/24481226","citation_count":10,"is_preprint":false},{"pmid":"26422142","id":"PMC_26422142","title":"Entamoeba histolytica Dmc1 Catalyzes Homologous DNA Pairing and Strand Exchange That Is Stimulated by Calcium and Hop2-Mnd1.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26422142","citation_count":9,"is_preprint":false},{"pmid":"35352317","id":"PMC_35352317","title":"Biallelic mutations in PSMC3IP are associated with secondary amenorrhea: expanding the spectrum of premature ovarian insufficiency.","date":"2022","source":"Journal of assisted reproduction and genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35352317","citation_count":9,"is_preprint":false},{"pmid":"37395447","id":"PMC_37395447","title":"Hop2-Mnd1 and Swi5-Sfr1 stimulate Dmc1 filament assembly using distinct mechanisms.","date":"2023","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/37395447","citation_count":8,"is_preprint":false},{"pmid":"37163373","id":"PMC_37163373","title":"MND1 and PSMC3IP control PARP inhibitor sensitivity in mitotic cells.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/37163373","citation_count":7,"is_preprint":false},{"pmid":"34600885","id":"PMC_34600885","title":"Hop2 interacts with the transcription factor CEBPα and suppresses adipocyte differentiation.","date":"2021","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34600885","citation_count":7,"is_preprint":false},{"pmid":"28435519","id":"PMC_28435519","title":"GT198 (PSMC3IP) germline variants in early-onset breast cancer patients from hereditary breast and ovarian cancer families.","date":"2017","source":"Genes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/28435519","citation_count":7,"is_preprint":false},{"pmid":"34878148","id":"PMC_34878148","title":"Two novel biallelic mutations in PSMC3IP in a patient affected by premature ovarian insufficiency.","date":"2021","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/34878148","citation_count":7,"is_preprint":false},{"pmid":"37189409","id":"PMC_37189409","title":"The Hop2-Mnd1 Complex and Its Regulation of Homologous Recombination.","date":"2023","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/37189409","citation_count":6,"is_preprint":false},{"pmid":"32061755","id":"PMC_32061755","title":"Oncoprotein GT198 vaccination delays tumor growth in MMTV-PyMT mice.","date":"2020","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/32061755","citation_count":6,"is_preprint":false},{"pmid":"39814165","id":"PMC_39814165","title":"GDF15 inhibits early-stage adipocyte differentiation by enhancing HOP2 expression and suppressing C/EBPα expression.","date":"2025","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/39814165","citation_count":4,"is_preprint":false},{"pmid":"39463417","id":"PMC_39463417","title":"Hop2-Mnd1 functions as a DNA sequence fidelity switch in Dmc1-mediated DNA recombination.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39463417","citation_count":2,"is_preprint":false},{"pmid":"34476412","id":"PMC_34476412","title":"GT198 Is a Target of Oncology Drugs and Anticancer Herbs.","date":"2021","source":"Frontiers in oral health","url":"https://pubmed.ncbi.nlm.nih.gov/34476412","citation_count":2,"is_preprint":false},{"pmid":"28531371","id":"PMC_28531371","title":"Wing 1 of protein HOP2 is as important as helix 3 in DNA binding by MD simulation.","date":"2017","source":"Journal of biomolecular structure & dynamics","url":"https://pubmed.ncbi.nlm.nih.gov/28531371","citation_count":2,"is_preprint":false},{"pmid":"36747711","id":"PMC_36747711","title":"Genomic targets of HOP2 are enriched for features found at recombination hotspots.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/36747711","citation_count":1,"is_preprint":false},{"pmid":"41746729","id":"PMC_41746729","title":"HOP2-MND1 chaperones a diffusing DMC1-ssDNA complex to survey dsDNA for homology recognition during meiotic recombination.","date":"2026","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/41746729","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":27144,"output_tokens":8776,"usd":0.106536,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18866,"output_tokens":6673,"usd":0.130578,"stage2_stop_reason":"end_turn"},"total_usd":0.237114,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"Yeast Hop2 (ortholog of PSMC3IP) localizes to meiotic chromosomes prior to and during synapsis, independent of double-strand breaks, and is required to prevent synaptonemal complex formation between nonhomologous chromosomes; hop2 mutants sustain wild-type DSB levels but these breaks remain unrepaired.\",\n      \"method\": \"Genetic analysis of hop2 mutant, immunofluorescence localization, meiotic chromosome spreads\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with defined cellular phenotype, localization experiments, replicated by subsequent studies in multiple organisms\",\n      \"pmids\": [\"9708739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Hop2 and Mnd1 co-immunoprecipitate from meiotic cell extracts and form a complex; Mnd1 localization to chromatin requires Hop2; they act together to promote meiotic chromosome pairing and DSB repair.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, genetic epistasis (null mutant analysis)\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic epistasis, localization, replicated across multiple subsequent studies\",\n      \"pmids\": [\"11940665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Mouse Hop2 knockout spermatocytes fail to synapse homologous chromosomes (very limited synapsis) and cannot repair meiotic DSBs, despite normal DSB formation and processing, demonstrating a direct role in promoting homologous chromosome synapsis.\",\n      \"method\": \"Hop2 knockout mouse, immunofluorescence of meiotic chromosome spreads, cytological analysis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO mouse with defined cellular phenotype, orthogonal cytological and molecular analyses\",\n      \"pmids\": [\"14667414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Purified mouse TBPIP/HOP2 protein stimulates DMC1-mediated homologous pairing in vitro; this stimulation requires HOP2 to first bind double-stranded DNA; the C-terminal basic region is required for DNA binding and pairing stimulation activity; HOP2 did not stimulate RAD51-mediated pairing in this study.\",\n      \"method\": \"In vitro homologous pairing assay with purified proteins, deletion analysis, DNA-binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro activity, deletion mutagenesis, single lab but multiple orthogonal assays\",\n      \"pmids\": [\"15192114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Saccharomyces cerevisiae Hop2 and Mnd1 form a stable heterodimer with higher affinity for double-stranded than single-stranded DNA; this heterodimer stimulates the strand assimilation activity of Dmc1 in vitro; genetic double mutant analysis places HOP2, MND1, and DMC1 in the same pathway for homologous chromosome juxtaposition.\",\n      \"method\": \"Protein purification, biochemical strand assimilation assay, double-mutant genetic epistasis, DNA-binding assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro biochemistry plus genetic epistasis, replicated by multiple subsequent studies\",\n      \"pmids\": [\"15249670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Mouse Hop2 alone can efficiently form D-loops; upon association with Mnd1, this Hop2 D-loop activity is abrogated; the Hop2-Mnd1 heterodimer physically interacts with both Rad51 and Dmc1 recombinases and stimulates their strand invasion activity up to 35-fold.\",\n      \"method\": \"In vitro D-loop assay, co-immunoprecipitation, reconstituted strand invasion assay with purified proteins\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro biochemistry with purified components, multiple assays, replicated by independent labs\",\n      \"pmids\": [\"15834424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Human TBPIP/Hop2-Mnd1 complex significantly stimulates Dmc1- and Rad51-mediated strand exchange and preferentially binds three-stranded DNA branch intermediates.\",\n      \"method\": \"Purification of human TBPIP/Hop2-Mnd1 complex, in vitro strand exchange assay, DNA-binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified human proteins, multiple assays, single lab\",\n      \"pmids\": [\"16407260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Interaction with Mnd1 provokes conformational changes in Hop2 that abrogate its own recombinase activity and generate a new molecular interface enabling Hop2-Mnd1 heterodimer to physically interact with and stimulate Dmc1; coiled-coil motifs in Hop2 and Mnd1 are essential for their mutual interaction; a C-terminal region is required for DNA binding and single-strand annealing by the heterodimer; a point mutation in Hop2 dissociates strand invasion from DNA binding/annealing.\",\n      \"method\": \"Purified protein biochemistry, mutagenesis, in vitro recombination assays, sedimentation analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution, point mutagenesis, multiple functional assays, single lab\",\n      \"pmids\": [\"16675459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Mnd1/Hop2 is required for Dmc1-mediated interhomolog crossover recombination; in mnd1 rad51 and hop2 rad51 double mutants, crossover recombination can still occur, indicating Mnd1/Hop2 functions specifically in the Dmc1-dependent pathway and is required for stable strand invasion between homologous chromosomes.\",\n      \"method\": \"Genetic epistasis (double-mutant analysis), recombination assays in S. cerevisiae\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple double-mutant combinations, defined recombination phenotypes\",\n      \"pmids\": [\"16581767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Hop2-Mnd1 stimulates Dmc1-mediated recombination via two distinct mechanisms: (1) stabilizing the Dmc1-ssDNA nucleoprotein filament, and (2) facilitating duplex DNA capture by the Dmc1-ssDNA filament to promote synaptic complex formation on long duplex DNAs.\",\n      \"method\": \"In vitro strand invasion and synaptic complex formation assays, nucleoprotein filament stability assays with purified proteins\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro biochemistry with purified components, multiple assays dissecting mechanism, replicated independently\",\n      \"pmids\": [\"17639081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Hop2 is the major DNA-binding subunit of the Hop2-Mnd1 complex while Mnd1 is the prominent Rad51-interaction entity; Hop2-Mnd1 stabilizes the Rad51-ssDNA nucleoprotein filament and enhances duplex DNA capture by the Rad51-ssDNA filament (bipartite mechanism).\",\n      \"method\": \"In vitro protein-DNA binding assays, Rad51-interaction mapping, presynaptic filament stability assays, duplex DNA capture assays with purified proteins\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro biochemistry, domain mapping, multiple functional assays\",\n      \"pmids\": [\"17639080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Fission yeast spHop2-Mnd1 interacts by co-immunoprecipitation; it binds ssDNA ends of 3'-tailed DNA, promotes renaturation of complementary ssDNA, catalyzes strand exchange with short oligonucleotides, and stimulates spDmc1-dependent strand exchange and strand invasion. Mouse Hop2 or Hop2-Mnd1 stimulates both hRad51 and hDmc1, revealing evolutionary divergence in recombinase specificity.\",\n      \"method\": \"Co-immunoprecipitation, electron microscopy, in vitro strand exchange and strand invasion assays with purified proteins from S. pombe and mouse\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution, EM, Co-IP, multiple assays comparing species\",\n      \"pmids\": [\"17426123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"GT198/PSMC3IP was identified as a tissue-specific nuclear coactivator that interacts with the DNA-binding domains (DBDs) of nuclear receptors (ERα/β, TRβ1, AR, GR, PR); interaction was shown by in vitro binding and yeast two-hybrid; GT198 potently stimulates transcription mediated by these receptors; PKA, PKC, and MAPK can phosphorylate GT198 in vitro, and cotransfection of these kinases regulates GT198 transcriptional activity.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assay, transcription reporter assays, in vitro kinase phosphorylation assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro binding, yeast two-hybrid, reporter assays, in vitro kinase assays; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"11739747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TBP-1 (PSMC3, 19S proteasome ATPase) directly binds TBPIP/PSMC3IP through TBPIP's N-terminal leucine zipper; AR is physically associated with both TBP-1 and TBPIP in vitro and in LNCaP cells; TBP-1 augments AR-mediated transcription additively with TBPIP; TBP-1 is transiently recruited to the PSA gene promoter androgen response element in a ligand-dependent manner.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding, co-immunoprecipitation in LNCaP cells, transcription reporter assays, chromatin immunoprecipitation\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ChIP, reporter assays, in vitro binding; multiple orthogonal methods\",\n      \"pmids\": [\"19325002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Hop2-Mnd1 heterodimer efficiently condenses double-stranded DNA via formation of DNA condensates, visualized at single-molecule level; condensation is concentration-dependent, reversible, and specific to the heterodimer (neither Hop2 nor Mnd1 alone can do this); condensation is accelerated by divalent metal ions (Mn2+>Mg2+>Ca2+); Hop2-Mnd1/Dmc1/ssDNA nucleoprotein filaments also condense dsDNA in a heterodimer concentration-dependent manner paralleling strand exchange activity.\",\n      \"method\": \"Single-molecule optical tweezers, video fluorescence microscopy, DNA condensation assays\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — single-molecule reconstitution with purified proteins, multiple controls, single lab\",\n      \"pmids\": [\"21112301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A homozygous 3-bp deletion in PSMC3IP (p.Glu201del) in the C-terminal acidic domain causes XX female gonadal dysgenesis; the mutation abolishes PSMC3IP coactivation of estrogen-driven transcription in cell lines, while not affecting the meiotic recombination domain (C-terminus absent in yeast).\",\n      \"method\": \"Homozygosity mapping, whole-exome sequencing, transcription reporter assay in cell lines\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetics plus functional cell-based reporter assay; single lab, single functional method\",\n      \"pmids\": [\"21963259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HOP2 alone (without MND1) can promote strand invasion, co-aggregation of ssDNA with duplex DNA, base unstacking on ssDNA, and formation of three-strand synaptic intermediates; this HOP2-only recombinase activity does not require ATP and is more sensitive to mismatches than DMC1; in Mnd1-/- spermatocytes expressing HOP2 without functional HOP2-MND1 complex, a fraction shows chromosome synapsis and DSB repair.\",\n      \"method\": \"In vitro strand exchange assay, in vitro ssDNA binding, Mnd1 knockout mouse analysis, immunofluorescence of spermatocytes\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemistry with purified protein plus in vivo knockout mouse validation, multiple assays\",\n      \"pmids\": [\"24304900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Inactivating germline mutations in GT198/PSMC3IP (including nonsense mutation p.Q104X) are found in familial and early-onset breast and ovarian cancer patients; the truncating p.Q104X mutation abolishes DNA damage-induced Rad51 foci formation, demonstrating a functional requirement for PSMC3IP in homologous recombination repair.\",\n      \"method\": \"Germline mutation screening, Sanger sequencing, Rad51 foci immunofluorescence after DNA damage\",\n      \"journal\": \"Genes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional Rad51 foci assay for one mutation, genetic screening; single lab\",\n      \"pmids\": [\"23946868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GT198 splice variants lacking the full C-terminal domain act as dominant negatives: they counteract wild-type GT198 transcriptional coactivation activity and abolish Rad51 foci formation during radiation-induced DNA damage; expression of GT198 variant but not wild type induces tumor growth in nude mice.\",\n      \"method\": \"Transcription reporter assays, Rad51 foci immunofluorescence, in vivo xenograft tumor growth assay\",\n      \"journal\": \"Genes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple functional cell-based assays and in vivo xenograft; single lab\",\n      \"pmids\": [\"23946869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Small angle X-ray scattering (SAXS) and electron microscopy reveal that the Hop2-Mnd1 heterodimer forms a V-shaped molecule with three distinct DNA binding sites; N-terminal dsDNA-binding functions of Hop2 and Mnd1 cooperate to mediate synaptic complex assembly, while ssDNA binding by the Hop2 C-terminus stabilizes the DMC1-ssDNA filament.\",\n      \"method\": \"SAXS, electron microscopy, deletion mutagenesis, in vitro DNA-binding assays, strand invasion assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural (SAXS+EM) plus mutagenesis and functional biochemistry; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"24150939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HOP2-MND1 induces conformational changes in RAD51 that alter its nucleotide cofactor interactions and DNA-binding specificity: it enables RAD51 DNA strand exchange without divalent metal ions required for ATP binding, offsets the K133A ATP-binding mutation, helps load RAD51 on ssDNA restricting dsDNA-binding during presynaptic filament formation, and promotes dsDNA binding during homology search by removing inhibitory effect of ssDNA.\",\n      \"method\": \"In vitro strand exchange assays, nucleotide-binding assays, DNA-binding assays with purified proteins and RAD51 mutants\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified proteins, mutagenesis, multiple mechanistic assays; peer-reviewed journal\",\n      \"pmids\": [\"24943459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The N-terminal domain of mouse HOP2 adopts a winged-helix (WH) DNA-binding fold as determined by NMR solution structure; helix 3 and wing 1 of the WH domain mediate DNA binding; a coiled-coil region mediates HOP2 self-association; mutations in key residues of the WH domain impair DNA binding and strand invasion activity.\",\n      \"method\": \"NMR solution structure determination, mutagenesis, DNA-binding assays, strand invasion assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with mutagenesis and functional validation; single lab with multiple methods\",\n      \"pmids\": [\"24711446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of Hop2-Mnd1 reveals a curved rod-like structure with three leucine zippers and two kinked junctions, juxtaposed winged-helix domains at one end, and a helical bundle-like structure at the other; the helical bundle is sufficient for interacting with the Dmc1-ssDNA nucleofilament; molecular modeling suggests the curved rod fits into the helical groove of the nucleofilament.\",\n      \"method\": \"X-ray crystallography, deletion analysis, molecular modeling\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus functional deletion analysis; single lab with orthogonal structural and biochemical methods\",\n      \"pmids\": [\"25740648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The HOP2 p.del201Glu mutation (associated with XX ovarian dysgenesis) diminishes association of Hop2-Mnd1 with both RAD51 and DMC1 and reduces functional stimulation of their recombinase activity; both Hop2 and Mnd1 interact with RAD51 via their C-terminal regions; ATP enhances the interaction between Hop2-Mnd1 and RAD51; distinct DNA-binding activities of Hop2-Mnd1 mediate different aspects of RAD51 presynaptic filament stabilization vs. homologous DNA pairing stimulation.\",\n      \"method\": \"In vitro protein interaction assays, mutagenesis of C-terminal domains, strand invasion assays, presynaptic filament stabilization assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution, structure-function mutagenesis, multiple assays; directly connects disease mutation to molecular mechanism\",\n      \"pmids\": [\"25820426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PSMC3IP and EPSTI1 modulate the extrinsic apoptotic pathway in estrogen receptor-positive and triple-negative breast cancer cell lines, as demonstrated by modulation of apoptotic markers upon gene knockdown/overexpression.\",\n      \"method\": \"Gene knockdown/overexpression in cell lines, apoptosis marker analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single cell-line phenotypic assays without defined molecular mechanism; single lab\",\n      \"pmids\": [\"25590583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GT198/PSMC3IP-expressing pericytes give rise to tumor cells; activation of GT198 induces VEGF expression; GT198 promotes tube formation in cultured U251 cells, supporting a role in angiogenesis.\",\n      \"method\": \"Cell culture overexpression/activation, VEGF reporter assay, tube formation assay, in vivo xenograft and vaccination models\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — cell-based functional assays with in vivo validation; single lab\",\n      \"pmids\": [\"28881671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Yeast Hop2-Mnd1 binds rapidly to Dmc1-ssDNA filaments with high affinity (residence time ~1.3 min) in a highly specific manner; no association of Hop2-Mnd1 with Rad51-ssDNA or RPA-ssDNA was detected, demonstrating Dmc1-specific binding in S. cerevisiae.\",\n      \"method\": \"Single-molecule imaging using DNA curtains, real-time binding measurements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — single-molecule reconstitution with quantitative kinetic measurements; rigorous controls for specificity\",\n      \"pmids\": [\"30420424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Hop2 physically interacts with ATF4 transcription factor via its Zip domain (identified by yeast two-hybrid and confirmed by interaction assays); Hop2 enhances ATF4-dependent transcription; Hop2-/- mice exhibit an osteopenic phenotype similar to Atf4-/- mice with decreased Osteocalcin mRNA and reduced type I collagen synthesis; compound heterozygous Atf4+/-:Hop2+/- mice display the same skeletal defects as Hop2-/- mice.\",\n      \"method\": \"Yeast two-hybrid, deletional mapping, transcription reporter assay, Hop2 knockout mouse skeletal phenotype, genetic epistasis (compound heterozygotes)\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid with domain mapping plus in vivo genetic epistasis and KO mouse phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"31433867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Hop2 physically interacts with CEBPα (confirmed by pull-down with recombinant proteins and co-immunoprecipitation of endogenous proteins from preadipocytes and adipocytes); Hop2 suppresses CEBPα-mediated transactivation; Hop2 stable overexpression inhibits adipocyte differentiation; Hop2-/- mice exhibit increased adiposity and adipogenic marker gene expression; ChIP shows higher CEBPα binding to PPARγ promoter in Hop2-/- adipose-derived MSCs.\",\n      \"method\": \"Pull-down, co-immunoprecipitation, transcription reporter assay, stable overexpression, Hop2 knockout mouse, ChIP\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal endogenous Co-IP, KO mouse, ChIP, multiple functional assays; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34600885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Oct4 A transcriptionally regulates PSMC3IP expression; knockdown of PSMC3IP reduces HNSCC self-renewal capacity and clonogenic cell survival after irradiation, indicating PSMC3IP contributes to homologous recombination-mediated radioresistance and cancer stem cell phenotype.\",\n      \"method\": \"Knockdown of PSMC3IP, clonogenic survival assay, self-renewal assay, PARP inhibitor combination studies\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — KD with defined cellular phenotypes in multiple assays; transcriptional regulation shown but upstream mechanism less rigorously defined\",\n      \"pmids\": [\"34079088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Depletion of PSMC3IP or MND1 in mitotic cells causes sensitivity to PARP inhibitors and ionizing radiation, independently of alternative lengthening of telomeres; depleted cells accumulate toxic RAD51 foci and show impaired homology-directed DNA repair; PARPi sensitivity occurs even in BRCA1/TP53BP1-deficient cells; wild-type PSMC3IP reverses PARPi sensitivity but the p.Glu201del ovarian dysgenesis mutant does not, linking the D-loop formation function to PARPi sensitivity.\",\n      \"method\": \"Genome-scale CRISPR screens, PSMC3IP/MND1 depletion, RAD51 foci immunofluorescence, HR reporter assay, PARP inhibitor sensitivity assays, rescue with wild-type vs mutant PSMC3IP\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screens plus targeted depletion, multiple functional assays including structure-function rescue; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37163373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Fission yeast Hop2-Mnd1 and Swi5-Sfr1 stimulate Dmc1 filament assembly by distinct mechanisms: Hop2-Mnd1 enhances the binding rate (nucleation) of Dmc1 at ssDNA/dsDNA junctions by binding DNA first to recruit Dmc1, while Swi5-Sfr1 specifically reduces the Dmc1 dissociation rate during nucleation; both proteins together allow further stimulation.\",\n      \"method\": \"Single-molecule FRET (smFRET), tethered particle motion (TPM), order-of-addition experiments with purified proteins\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — single-molecule reconstitution (smFRET + TPM) with purified proteins, kinetic dissection of mechanism; single lab\",\n      \"pmids\": [\"37395447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Hop2-Mnd1 acts as a DNA sequence fidelity switch for Dmc1: it upregulates Dmc1 activity with fully homologous or mismatch-containing substrates, but suppresses illegitimate recombination between substrates with only microhomology; suppression of illegitimate recombination requires the Dmc1 filament interaction attributable to Hop2-Mnd1 but not its DNA binding activity, as demonstrated by separation-of-function variants.\",\n      \"method\": \"In vitro strand exchange assays with Hop2-Mnd1 separation-of-function variants, DNA substrates with defined mismatches/microhomology\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with structure-function variants, multiple substrate types; rigorous mechanistic dissection\",\n      \"pmids\": [\"39463417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GDF15 overexpression upregulates Hop2/PSMC3IP expression in pre-adipocytes; Hop2 mediates GDF15-induced suppression of C/EBPα expression and inhibition of adipogenesis, as Hop2 knockdown during GDF15 overexpression abolishes the suppression of C/EBPα.\",\n      \"method\": \"GDF15 overexpression, Hop2 knockdown, adipogenesis assay, gene expression analysis\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — epistasis by genetic KD, functional adipogenesis assay, consistent with prior Hop2-CEBPα mechanism\",\n      \"pmids\": [\"39814165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Human DMC1-ssDNA presynaptic complex employs diffusion-based homology search generating a migrating DNA bubble; HOP2-MND1 codiffuses with the DMC1-ssDNA presynaptic complex, clamps the ssDNA-dsDNA junctions, and maintains an expanded DNA bubble to enable homology recognition that cannot occur without HOP2-MND1 or free DMC1.\",\n      \"method\": \"Single-molecule imaging of human proteins, reconstituted in vitro system\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — single-molecule reconstitution with human proteins, rigorous mechanistic dissection; most recent mechanistic study\",\n      \"pmids\": [\"41746729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Mouse TBPIP (ortholog of PSMC3IP) was cloned as a TBP-1-interacting protein; it co-localizes with TBP-1 in vivo and enhances TBP-1's inhibitory action on Tat-mediated transactivation of HIV replication in vitro.\",\n      \"method\": \"Protein-protein interaction cloning, co-localization, transactivation reporter assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single interaction and reporter assay, mouse protein, single lab\",\n      \"pmids\": [\"9345291\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMC3IP (also known as HOP2, GT198, TBPIP) is a multifunctional nuclear protein that, as part of the HOP2-MND1 heterodimer, acts as an essential cofactor for the DMC1 and RAD51 recombinases in meiotic (and mitotic) homologous recombination: it stabilizes the recombinase-ssDNA presynaptic filament, captures duplex DNA to promote synaptic complex formation, suppresses illegitimate recombination, and codiffuses with the DMC1-ssDNA complex to enable homology recognition; structurally, HOP2-MND1 forms a V-shaped/curved rod with a winged-helix DNA-binding domain and leucine zipper coiled-coil, with distinct regions mediating dsDNA capture, ssDNA filament stabilization, and recombinase interaction via the C-terminal helical bundle; outside of recombination, PSMC3IP functions as a tissue-specific nuclear receptor coactivator (interacting with DBDs of ER, AR, GR, PR, TRβ) and interacts with ATF4 to promote osteoblast differentiation and with CEBPα to suppress adipogenesis, while disease-associated mutations (p.Glu201del causing XX gonadal dysgenesis; truncating mutations in breast/ovarian cancer) disrupt its coactivation of estrogen-driven transcription and its stimulation of RAD51/DMC1-mediated D-loop formation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PSMC3IP (HOP2/GT198/TBPIP) is a nuclear protein that functions principally as an essential cofactor for the DMC1 and RAD51 recombinases during homologous recombination, while also serving as a tissue-specific transcriptional regulator. In meiosis it localizes to chromosomes before and during synapsis and is required to repair programmed double-strand breaks and to prevent synaptonemal complex formation between nonhomologous chromosomes [#0, #2]. It acts as a stable heterodimer with MND1, whose chromatin localization depends on HOP2 [#1]; this heterodimer binds DNA—preferring duplex and three-stranded branch intermediates—and stimulates DMC1- and RAD51-mediated strand invasion and exchange up to 35-fold [#4, #5, #6]. Mechanistically, HOP2-MND1 acts through a bipartite scheme: it stabilizes the recombinase-ssDNA presynaptic filament and facilitates capture of duplex DNA to nucleate the synaptic complex [#9, #10], and it codiffuses with the DMC1-ssDNA complex, clamping ssDNA-dsDNA junctions and maintaining an expanded DNA bubble to enable homology recognition [#34]. The heterodimer additionally serves as a sequence-fidelity switch that suppresses illegitimate recombination between microhomologous substrates via its recombinase-interaction surface [#32]. Structurally HOP2-MND1 forms a curved/V-shaped rod with juxtaposed winged-helix DNA-binding domains, leucine-zipper coiled coils, and a C-terminal helical bundle that engages the recombinase nucleofilament [#19, #21, #22]. Independent of recombination, PSMC3IP acts as a nuclear-receptor coactivator that binds the DNA-binding domains of ERα/β, AR, GR, PR, and TRβ1 and potentiates their transcription [#12], interacts with the proteasomal ATPase PSMC3/TBP-1 to augment AR-driven transcription [#13], and modulates osteoblast and adipocyte differentiation through interactions with ATF4 and CEBPα [#27, #28]. A homozygous in-frame deletion (p.Glu201del) in the C-terminal acidic domain causes XX gonadal dysgenesis by abolishing estrogen-driven coactivation and impairing recombinase stimulation [#15, #23], and the recombination function underlies PARP-inhibitor and irradiation sensitivity in mitotic and cancer cells [#30].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established that HOP2 is a meiotic chromosome factor required for repair of double-strand breaks and for fidelity of synapsis, distinguishing it from break-formation machinery.\",\n      \"evidence\": \"Genetic analysis and immunofluorescence of hop2 mutant yeast meiotic chromosome spreads\",\n      \"pmids\": [\"9708739\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No biochemical activity defined\", \"Partner proteins unknown\", \"Molecular basis of synapsis defect not resolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified MND1 as HOP2's obligate partner, defining the functional unit as a heterodimer and showing HOP2 directs MND1 to chromatin.\",\n      \"evidence\": \"Co-immunoprecipitation, immunofluorescence and genetic epistasis in meiotic cells\",\n      \"pmids\": [\"11940665\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical mechanism of the complex unknown\", \"Direct DNA/recombinase activities not yet shown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Revealed a recombination-independent role: PSMC3IP/GT198 is a tissue-specific coactivator binding nuclear-receptor DNA-binding domains and is regulated by phosphorylation.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, reporter and in vitro kinase assays\",\n      \"pmids\": [\"11739747\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of each receptor interaction not established\", \"Coactivation mechanism (chromatin/cofactor recruitment) undefined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Confirmed in mammals that HOP2 is required for homologous chromosome synapsis and meiotic DSB repair without affecting break formation.\",\n      \"evidence\": \"Hop2 knockout mouse cytological analysis of spermatocytes\",\n      \"pmids\": [\"14667414\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular substrate not defined in vivo\", \"Relationship to recombinase activity not yet biochemically shown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrated direct biochemical activity: purified HOP2 binds dsDNA and stimulates DMC1-mediated pairing, and the HOP2-MND1 heterodimer stimulates DMC1 strand assimilation, placing HOP2/MND1/DMC1 in one pathway.\",\n      \"evidence\": \"Reconstituted in vitro pairing/strand assimilation assays, deletion analysis, genetic epistasis\",\n      \"pmids\": [\"15192114\", \"15249670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RAD51 specificity unresolved across species\", \"Structural basis of recombinase stimulation unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed that MND1 binding switches off HOP2's intrinsic D-loop activity and creates the interface enabling the heterodimer to physically engage and strongly stimulate both RAD51 and DMC1.\",\n      \"evidence\": \"In vitro D-loop and strand invasion assays, co-immunoprecipitation\",\n      \"pmids\": [\"15834424\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational change not structurally defined\", \"Division of labor between subunits unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined the bipartite/conformational logic of the complex—coiled-coil-mediated dimerization, MND1-induced HOP2 conformational change, C-terminal DNA binding, and recombinase stimulation—and extended activity to human proteins.\",\n      \"evidence\": \"Purified protein biochemistry, mutagenesis, strand exchange assays, sedimentation analysis (human and yeast)\",\n      \"pmids\": [\"16407260\", \"16675459\", \"16581767\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic structure still lacking\", \"Quantitative kinetics of stimulation unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Dissected the dual mechanism: HOP2-MND1 both stabilizes the recombinase-ssDNA presynaptic filament and promotes duplex DNA capture for synaptic complex assembly, with HOP2 as the DNA-binding and MND1 as the RAD51-interacting subunit.\",\n      \"evidence\": \"Reconstituted filament-stability and duplex-capture assays, interaction mapping, EM (yeast and mouse)\",\n      \"pmids\": [\"17639081\", \"17639080\", \"17426123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural arrangement on the filament not resolved\", \"Cross-species recombinase specificity differences unexplained\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected the coactivator role to the proteasomal ATPase PSMC3/TBP-1, which binds the HOP2 N-terminal leucine zipper and augments androgen-receptor transcription at target promoters.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP in LNCaP cells, reporter assays and ChIP\",\n      \"pmids\": [\"19325002\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking proteasome ATPase to transcription unclear\", \"Generality beyond AR/PSA promoter untested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided a human disease link, showing that a C-terminal acidic-domain deletion (p.Glu201del) causes XX gonadal dysgenesis by abolishing estrogen-driven coactivation.\",\n      \"evidence\": \"Homozygosity mapping, exome sequencing, cell-based reporter assay\",\n      \"pmids\": [\"21963259\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single functional readout (reporter only)\", \"Effect on recombinase function not tested in this study\", \"How a coactivation defect produces dysgenesis unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Refined subunit autonomy and disease association: HOP2 alone has ATP-independent recombinase activity partly active in vivo, while truncating GT198 mutations and dominant-negative splice variants disrupt RAD51 foci, coactivation, and promote tumor growth.\",\n      \"evidence\": \"In vitro strand exchange, Mnd1 knockout mouse, germline mutation screening, RAD51 foci assays, xenografts\",\n      \"pmids\": [\"24304900\", \"23946868\", \"23946869\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cancer-association statistics limited to single-lab cohorts\", \"Dominant-negative mechanism not structurally defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established structural and mechanistic detail: HOP2's N-terminal winged-helix DNA-binding fold, and HOP2-MND1-induced conformational changes that reprogram RAD51 nucleotide/DNA-binding behavior during filament formation and homology search.\",\n      \"evidence\": \"NMR solution structure with mutagenesis; in vitro strand exchange and nucleotide/DNA-binding assays with RAD51 mutants\",\n      \"pmids\": [\"24711446\", \"24943459\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full heterodimer structure not yet solved\", \"Conformational change in RAD51 not visualized directly\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Delivered the architecture and disease mechanism: a curved rod with juxtaposed winged-helix domains and a recombinase-engaging helical bundle, and direct evidence that p.Glu201del weakens RAD51/DMC1 association and stimulation.\",\n      \"evidence\": \"Crystal structure and SAXS/EM, deletion analysis, modeling onto the nucleofilament; mutant protein interaction and strand-invasion assays\",\n      \"pmids\": [\"24150939\", \"25740648\", \"25820426\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cryo-EM of the complex on a filament not available\", \"How disease mutant affects both transcription and recombination jointly unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended GT198 to angiogenesis and tumor-cell-of-origin biology by linking its activation to VEGF expression and tube formation.\",\n      \"evidence\": \"Cell culture activation/overexpression, VEGF reporter and tube-formation assays, xenograft models\",\n      \"pmids\": [\"28881671\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular pathway to VEGF undefined\", \"Single-lab evidence\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Quantified the specificity of recombinase engagement in budding yeast, showing rapid high-affinity binding to DMC1-ssDNA filaments but not RAD51- or RPA-ssDNA.\",\n      \"evidence\": \"Single-molecule DNA-curtain real-time binding measurements\",\n      \"pmids\": [\"30420424\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Species divergence in RAD51 vs DMC1 specificity unresolved\", \"Structural basis of selective binding unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a coactivator role in bone: HOP2 binds ATF4 via its Zip domain and enhances ATF4-dependent transcription, with KO and compound-heterozygote mice phenocopying osteopenia.\",\n      \"evidence\": \"Yeast two-hybrid, deletion mapping, reporter assays, knockout mouse skeletal phenotype, genetic epistasis\",\n      \"pmids\": [\"31433867\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct chromatin co-occupancy of HOP2-ATF4 not shown\", \"Relationship to recombination function in osteoblasts unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined an opposing differentiation role in fat: HOP2 binds CEBPα and suppresses its transactivation to inhibit adipogenesis, with KO mice showing increased adiposity.\",\n      \"evidence\": \"Pull-down, endogenous Co-IP, reporter assays, stable overexpression, knockout mouse, ChIP\",\n      \"pmids\": [\"34600885\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How HOP2 suppresses rather than coactivates here is unexplained\", \"Tissue-specific switch between coactivation and repression undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked PSMC3IP-dependent HR to cancer radioresistance and stemness, with Oct4A upstream regulation.\",\n      \"evidence\": \"Knockdown, clonogenic and self-renewal assays, PARP inhibitor combinations in HNSCC\",\n      \"pmids\": [\"34079088\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream Oct4A regulation mechanism not rigorously defined\", \"Direct HR contribution vs indirect effects not separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established PSMC3IP/MND1 as targetable HR factors in mitotic cells: their loss causes toxic RAD51 foci, HR defects and PARPi/IR sensitivity even in BRCA1/53BP1-deficient cells, with rescue dependent on the intact D-loop function lost in p.Glu201del.\",\n      \"evidence\": \"Genome-scale CRISPR screens, depletion, RAD51 foci, HR reporter, PARPi assays, WT vs mutant rescue\",\n      \"pmids\": [\"37163373\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Therapeutic window in patient tumors untested\", \"Source of toxic RAD51 foci not fully mechanistically defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved the kinetic mechanism of DMC1 filament stimulation: HOP2-MND1 binds DNA first to recruit DMC1 and enhance nucleation rate, distinct from Swi5-Sfr1 which slows dissociation.\",\n      \"evidence\": \"Single-molecule FRET and TPM with order-of-addition experiments (fission yeast)\",\n      \"pmids\": [\"37395447\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conservation of nucleation mechanism in human proteins not shown here\", \"Coordination with other mediators in vivo unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a fidelity-switch function: HOP2-MND1 promotes recombination on homologous/mismatched substrates but suppresses illegitimate recombination on microhomology via its recombinase-interaction surface, not DNA binding.\",\n      \"evidence\": \"In vitro strand exchange with separation-of-function variants and defined mismatch/microhomology substrates\",\n      \"pmids\": [\"39463417\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of fidelity switch untested\", \"Structural basis of microhomology discrimination unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed HOP2 downstream of GDF15 in adipogenic control, where it mediates GDF15-induced CEBPα suppression.\",\n      \"evidence\": \"GDF15 overexpression with HOP2 knockdown and adipogenesis assays\",\n      \"pmids\": [\"39814165\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct GDF15-HOP2 signaling link not defined\", \"Single functional epistasis readout\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Captured the homology-search mechanism in human proteins: HOP2-MND1 codiffuses with the DMC1-ssDNA complex, clamps ssDNA-dsDNA junctions and maintains an expanded migrating DNA bubble enabling homology recognition.\",\n      \"evidence\": \"Single-molecule imaging of reconstituted human DMC1/HOP2-MND1 system\",\n      \"pmids\": [\"41746729\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coupling of bubble maintenance to downstream strand exchange not resolved\", \"Structure of the migrating complex not solved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PSMC3IP is partitioned between its recombination and transcriptional-coactivator/repressor roles in different tissues, and what regulatory signals (e.g. phosphorylation) toggle these functions, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue-specific control of dual function undefined\", \"No structural model unifying coactivation and recombination domains\", \"Direct chromatin-targeting mechanism of the coactivator role unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [3, 4, 10, 19, 21]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [5, 9, 10, 20]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 9, 23, 32]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [12, 13, 27, 28]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [5, 6, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [12, 13, 35]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [17, 30]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0, 2, 15]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [12, 13, 27, 28]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [27, 28]}\n    ],\n    \"complexes\": [\"HOP2-MND1 heterodimer\"],\n    \"partners\": [\"MND1\", \"DMC1\", \"RAD51\", \"PSMC3\", \"ATF4\", \"CEBPA\", \"AR\", \"ESR1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}