{"gene":"RAD52","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1996,"finding":"Yeast Rad52 protein directly binds both single-stranded and double-stranded DNA and stimulates annealing of complementary ssDNA at a rate 3500-fold faster than spontaneous annealing; the DNA binding domain was mapped to the evolutionarily conserved N-terminus.","method":"Recombinant protein purification, DNA binding assays, DNA annealing kinetics assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical reconstitution with purified recombinant protein, multiple orthogonal assays (binding + annealing kinetics), N-terminal domain mapping, replicated in subsequent studies","pmids":["8855248"],"is_preprint":false},{"year":1997,"finding":"Yeast Rad52 functions as a mediator (co-factor) for Rad51 recombinase by overcoming the inhibitory effect of RPA on ssDNA, restoring efficient DNA strand exchange when Rad51 and RPA are added simultaneously to ssDNA.","method":"In vitro DNA strand exchange assay with purified yeast Rad51, RPA, and Rad52 proteins","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro strand exchange with purified components, demonstrated specific co-factor role, independently replicated in same year by two other labs","pmids":["9353267"],"is_preprint":false},{"year":1998,"finding":"Yeast Rad52 stimulates Rad51-mediated DNA strand exchange by targeting Rad51 to RPA-ssDNA complexes (overcoming RPA inhibition); stimulation requires concerted action of both Rad51 and RPA, implying specific protein-protein interactions between Rad52, Rad51, and RPA.","method":"In vitro DNA strand exchange assay, presynaptic filament formation assay with purified proteins","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified components, multiple conditions tested, replicated across three simultaneous independent publications","pmids":["9450760"],"is_preprint":false},{"year":1998,"finding":"Yeast Rad52 stimulates Rad51 strand exchange and nucleoprotein filament formation; binding to Rad51 is necessary for this stimulatory effect.","method":"In vitro strand exchange assay, protein-protein interaction studies, nucleoprotein filament formation assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution, interaction requirement demonstrated by mutation, simultaneous independent replication","pmids":["9450759"],"is_preprint":false},{"year":1998,"finding":"Human Rad52 stimulates homologous pairing by human Rad51, indicating the Rad52–Rad51 functional relationship is conserved in humans; hRad52 DNA binding properties indicate involvement in an early stage of Rad51-mediated recombination.","method":"In vitro homologous pairing assay with purified human Rad51 and Rad52 proteins","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified human proteins, simultaneous independent replication across three papers in the same issue","pmids":["9450758"],"is_preprint":false},{"year":1998,"finding":"Yeast Rad52 forms multimeric ring structures as observed by electron microscopy; it binds ssDNA and interacts physically with RPA (specifically RPA enhances ssDNA annealing); this enhancement is species-specific (E. coli SSB and T4 gp32 do not substitute).","method":"Electron microscopy, ssDNA annealing assay, protein-protein interaction (binding assays)","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — EM structure, biochemical annealing assay with RPA specificity controls, replicated across multiple studies","pmids":["9619627"],"is_preprint":false},{"year":1998,"finding":"Rad52 physically interacts with all three subunits of yeast RPA (two-hybrid analysis); mutations in the amino-terminal DNA-binding domain of Rad52 disrupt interaction with Rad51 and with the large RPA subunit (Rfa1) but retain self-interaction and interaction with Rfa2; RAD52 and RFA1 are in the same genetic epistasis pathway.","method":"Yeast two-hybrid assay, genetic epistasis analysis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — genetic epistasis plus two-hybrid data (single lab), two orthogonal approaches","pmids":["9632824"],"is_preprint":false},{"year":1998,"finding":"In meiosis, Rad52 and RPA co-assemble into cytologically detectable subnuclear foci; Rad52 foci are distinct from Rad51/Dmc1 foci and require DSBs (Spo11-dependent); Rad52, Rad55, and Rad57 are all required for Rad51 focus formation, supporting a model in which they collectively promote strand exchange complex assembly.","method":"Immunostaining, colocalization microscopy, genetic epistasis (spo11 mutant, ionizing radiation rescue)","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo colocalization with multiple genetic controls, multiple orthogonal approaches (immunostaining + epistasis), well-replicated findings","pmids":["9679065"],"is_preprint":false},{"year":1999,"finding":"Human Rad52 binds directly to DNA double-strand breaks, protects them from exonuclease attack, and facilitates end-to-end DNA interactions, consistent with an early role in DSB repair by homologous recombination.","method":"In vitro DNA binding assay, nuclease protection assay, electron microscopy","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical reconstitution with purified human Rad52, multiple orthogonal assays (binding, nuclease protection, EM)","pmids":["10227297"],"is_preprint":false},{"year":2000,"finding":"Human RAD52 binds ssDNA and tailed duplex DNA via precise interactions with the terminal nucleotide base; hydroxyl radical footprinting revealed a 4-nucleotide repeat hypersensitivity pattern phased from the DNA terminus over ~36 nucleotides.","method":"Hydroxyl radical footprinting, nuclease protection assay, in vitro DNA binding","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical assay with defined substrates and footprinting, single lab but multiple orthogonal methods","pmids":["10921897"],"is_preprint":false},{"year":2001,"finding":"Rad52-GFP relocalizes from a diffuse nuclear distribution to distinct foci upon DNA double-strand break induction (gamma-irradiation, meiosis, HO endonuclease); foci form almost exclusively during S phase of mitotic cells, and their frequency increases in replication (pol12-100) and checkpoint (mec1) mutants, indicating coordination with DNA replication.","method":"Live-cell fluorescence microscopy (GFP fusion), genetic analysis with replication/checkpoint mutants, DSB induction assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct live-imaging with functional GFP fusion, confirmed with multiple DSB sources, cell-cycle and genetic context defined, replicated across studies","pmids":["11459964"],"is_preprint":false},{"year":2001,"finding":"Human Rad52 promotes homologous pairing via a presynaptic complex with ssDNA; an N-terminal fragment (residues 1–237) defective in Rad51 binding still catalyzes homologous pairing, forming nucleoprotein filaments with ssDNA, indicating a Rad51-independent recombination function.","method":"In vitro homologous pairing assay, electron microscopy, truncation mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with defined mutant protein, EM visualization, two orthogonal methods in single lab","pmids":["11454867"],"is_preprint":false},{"year":2001,"finding":"Human RAD52 promotes single-strand annealing (SSA) in vitro; electron microscopy visualized specific binding of multiple RAD52 rings to resected DSB termini and large protein complexes at heteroduplex joints, defining intermediates of RAD52-mediated annealing.","method":"In vitro SSA assay, electron microscopy of reaction intermediates","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — biochemical reconstitution with EM visualization of intermediates, two orthogonal methods, single lab","pmids":["11571269"],"is_preprint":false},{"year":2003,"finding":"Yeast Rad52 binds preferentially to ssDNA rather than to free DNA ends (in contrast to Ku which binds free ends); Rad52 aggregates different ssDNAs in close proximity independently of DNA ends or extensive sequence complementarity.","method":"In vitro DNA binding assay with defined substrates, comparison with Ku protein","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical binding assay with defined substrates and direct comparison, single lab, two orthogonal assessments","pmids":["12954758"],"is_preprint":false},{"year":2004,"finding":"In vivo, Rad52 plays three distinct roles during homologous recombination: a presynaptic role necessary for Rad51 assembly at a DSB, a synaptic role with Rad51 filaments, and a postsynaptic role after Rad51 dissociates; ssDNA complexes containing both Rad51 and Rad52 were identified biochemically.","method":"Immunofluorescence during HO-induced DSB repair (time-course), chromatin immunoprecipitation, biochemical ssDNA complex analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (IF kinetics, ChIP, biochemical), in vivo monitoring with defined DSB locus, temporal dissection of three roles","pmids":["14765116"],"is_preprint":false},{"year":2004,"finding":"Human and yeast Rad52 proteins promote DNA strand exchange in vitro; this activity resides in the N-terminal domain (residues 1–237 for human Rad52) that forms rings; strand exchange yield is proportional to AT content.","method":"In vitro DNA strand exchange assay, N-terminal truncation analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with defined truncation mutants, single lab, two species tested","pmids":["15205482"],"is_preprint":false},{"year":2005,"finding":"Saturating alanine-scanning mutagenesis of the N-terminal domain of full-length human Rad52 identified residues (within the first 85 residues) involved in direct ssDNA contact; these residues map to the DNA binding channel observed in crystal structures of truncation mutants.","method":"Alanine-scanning mutagenesis, in vitro DNA binding assay","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis with functional validation, single lab, well-defined domain mapping","pmids":["15571718"],"is_preprint":false},{"year":2006,"finding":"Rad52 promotes annealing of the displaced ssDNA strand from a Rad51-mediated D-loop (second ssDNA capture/second-end capture), acting on RPA-coated ssDNA; RPA-rfa1-t11 (recombination-deficient RPA) fails to support this annealing, explaining its in vivo phenotype. E. coli RecO/SSB are functional analogs, demonstrating the conserved nature of this step.","method":"In vitro DNA strand exchange + second-strand capture assay with purified proteins, mutant RPA analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with defined RPA mutant, conserved across species, multiple controls, replicated by other labs","pmids":["17093500"],"is_preprint":false},{"year":2006,"finding":"Yeast Rad59 can anneal complementary ssDNA but cannot anneal RPA-coated ssDNA (unlike Rad52), follows first-order kinetics (versus second-order for Rad52), and enhances Rad52-mediated annealing at elevated salt; these biochemical differences distinguish their recombinational roles.","method":"Quantitative in vitro ssDNA annealing assay with RPA, kinetics analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified proteins, quantitative kinetic analysis, direct comparison between Rad52 and Rad59","pmids":["16565518"],"is_preprint":false},{"year":2008,"finding":"DNA repair synthesis catalyzed by human DNA polymerase eta (pol eta) acting on the priming strand of a D-loop promotes RAD52-dependent second-end capture and annealing; pol delta and pol iota cannot substitute for pol eta; RAD52 cannot be replaced by RAD51; RPA (but not E. coli SSB) stimulates the reaction.","method":"In vitro second-end capture assay with purified human proteins, defined polymerase substitution","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with multiple defined protein substitutions, rigorous controls with alternative polymerases and SSBs","pmids":["18313388"],"is_preprint":false},{"year":2008,"finding":"Human Rad52 has a second DNA binding site identified by structure-based alanine scan mutagenesis; this site enables the Rad52-ssDNA complex to form a ternary complex with dsDNA; mutations in this site impair D-loop formation and abolish Rad52-induced positive supercoiling of dsDNA.","method":"Structure-based alanine-scanning mutagenesis, D-loop formation assay, supercoiling assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structure-guided mutagenesis with functional validation of two distinct activities, single lab, multiple orthogonal methods","pmids":["18593704"],"is_preprint":false},{"year":2008,"finding":"Yeast Rad51 prevents Rad52-mediated ssDNA annealing in an ATP-dependent manner via specific Rad51–Rad52 protein–protein interaction; the Rad51 nucleoprotein filament is more inhibitory than free Rad51; Rad59 partially restores annealing in the presence of Rad51, suggesting coordinated channeling between strand invasion and annealing pathways.","method":"In vitro ssDNA annealing assay, ATP dependence analysis, protein-protein interaction study","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with multiple protein combinations, ATP dependence established, mechanistically dissects pathway choice","pmids":["18337252"],"is_preprint":false},{"year":2009,"finding":"The Rad52 amino-terminal DNA binding domain is required for DNA annealing (second-end capture) but not for Rad51 delivery to DSBs; rad52-R70A (compromised DNA binding) associates with DSBs and recruits Rad51 normally but cannot complete recombination due to failure in second-end capture.","method":"Purified mutant protein biochemical assay (annealing), chromatin immunoprecipitation (ChIP) at DSBs, genetic analysis of recombination intermediates","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — separation-of-function mutant validated by both in vitro biochemistry and in vivo ChIP + recombination intermediates analysis","pmids":["19812039"],"is_preprint":false},{"year":2009,"finding":"Phosphorylated human RPA promotes formation of a complex with monomeric Rad52 and causes transfer of ssDNA from RPA to Rad52, suggesting RPA phosphorylation regulates the mediator function of Rad52 in the first steps of DSB repair.","method":"Analytical SEC-MALS, UV crosslinking to identify ssDNA-bound partner, SDS-PAGE/Western analysis","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — solution biochemistry with multiple orthogonal methods (SEC-MALS + UV crosslinking), single lab","pmids":["19530647"],"is_preprint":false},{"year":2009,"finding":"Srs2 helicase evicts Rad52 from RPA-ssDNA during translocation, promoting rapid redistribution of both Rad52 and RPA, thereby resolving potentially pathogenic nucleoprotein intermediates.","method":"Single-molecule fluorescence imaging of Srs2 acting on ssDNA curtains coated with RPA and Rad52","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single-molecule real-time imaging, single lab, direct visualization of protein eviction","pmids":["29045827"],"is_preprint":false},{"year":2009,"finding":"Rad52-RPA interaction requires multiple RPA molecules associated with ssDNA (cooperative contacts); Rad51 inhibits Rad52-promoted ssDNA aggregation and subsequent annealing; after DNA strand invasion, Rad51-dsDNA complex disrupts Rad52-RPA interaction on ssDNA, limiting illegitimate second-end capture.","method":"In vitro DNA annealing assay, protein-protein interaction biochemistry with mutant RPA","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with defined protein mutants, single lab, mechanistically coherent model","pmids":["19445949"],"is_preprint":false},{"year":2009,"finding":"Rad52 recruitment to DSB sites requires B-type cyclin/CDK1 (Cdc28) activity; during intra-S-phase checkpoint (hydroxyurea), Mec1/Tel1 kinase inhibits Rad52 focus formation at both DSBs and stalled replication forks; Rad52 foci colocalize with PCNA foci.","method":"Live-cell fluorescence microscopy (Rad52-GFP), genetic analysis with CDK1/Mec1 mutants, co-localization with PCNA-GFP","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct live-cell imaging with multiple genetic perturbations (CDK1, Mec1/Tel1, caffeine), colocalization with PCNA, multiple orthogonal approaches","pmids":["19262568"],"is_preprint":false},{"year":2010,"finding":"Rad52 SUMOylation inhibits its DNA binding and ssDNA annealing activities in vitro; SUMOylation is enhanced by ssDNA; in vivo, SUMO-deficient Rad52 mutants show longer focus duration and a shift from single-strand annealing toward gene conversion during spontaneous mitotic recombination.","method":"In vitro SUMOylation assay, DNA binding assay, ssDNA annealing assay with SUMOylated Rad52, in vivo recombination assays, live-cell microscopy","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro biochemical assays with SUMOylated protein plus in vivo genetic/recombination assays, multiple orthogonal methods, single lab but comprehensive","pmids":["20371517"],"is_preprint":false},{"year":2010,"finding":"Human RAD52 binds ssDNA in two concentration-dependent modes: at low protein concentration ssDNA is wrapped around the ring circumference (promoting efficient annealing), while at higher concentrations ssDNA is stretched between multiple rings; annealing via two RAD52-ssDNA complexes (one per complementary strand); hRad52 mutants impaired in hRPA binding (RQK/AAA and 1-212) compete with RPA for ssDNA and fail to counteract RPA-mediated duplex destabilization.","method":"Single-molecule FRET, fluorescence-based DNA annealing assay, RPA interaction mutant analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — single-molecule FRET plus ensemble annealing assay with defined mutants, mechanistic model directly supported by data","pmids":["20081207"],"is_preprint":false},{"year":2010,"finding":"Loss of Rad52 is synthetically lethal with BRCA2 deficiency; Rad52 depletion in BRCA2-deficient cells reduces spontaneous and DSB-induced homologous recombination and Rad51 focus formation; Rad52-Rad51 foci form independently of BRCA2, defining Rad52 as an alternative HR mediator pathway.","method":"siRNA knockdown, HR frequency assay, Rad51 focus formation assay, chromosome aberration analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis by siRNA + complementation, HR frequency quantification, focus assays, replicated by multiple subsequent labs","pmids":["21148102"],"is_preprint":false},{"year":2016,"finding":"Human RAD52 is required for Mitotic DNA Synthesis (MiDAS) at common fragile sites (CFSs); RAD52 is required for timely recruitment of MUS81 and POLD3 to CFSs in early mitosis; RAD51 and BRCA2 are dispensable for MiDAS but required to counteract replication stress at CFSs during S-phase.","method":"siRNA knockdown, EdU incorporation (MiDAS assay), immunofluorescence for MUS81/POLD3 recruitment, epistasis analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — specific siRNA knockdown with functional MiDAS readout and recruitment assays, clear genetic epistasis separating RAD52 from RAD51/BRCA2, replicated by concurrent publication","pmids":["27984745"],"is_preprint":false},{"year":2016,"finding":"Mammalian RAD52 localizes to collapsed replication fork foci induced by oncogenes or chemicals; siRNA depletion or CRISPR/Cas9 knockout of RAD52 compromises restart of collapsed replication forks and leads to DNA damage under replication stress conditions.","method":"siRNA knockdown, CRISPR/Cas9 knockout, immunofluorescence (focus formation), replication fork restart assay (DNA fiber analysis), oncogene overexpression model","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — both siRNA and CRISPR KO used, DNA fiber analysis for fork restart, in vivo tumor model confirmation, two orthogonal genetic approaches","pmids":["27984746"],"is_preprint":false},{"year":2017,"finding":"Yeast and human Rad52 catalyze inverse strand exchange: Rad52 forms a complex with dsDNA and promotes strand exchange with homologous ssRNA or ssDNA; this activity is specific to Rad52 (not Rad51 or Rad59); inverse strand exchange with RNA contributes to RNA-templated DSB repair in yeast.","method":"In vitro inverse strand exchange assay with purified proteins and RNA substrates, in vivo RNA-templated DSB repair assay in yeast","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical reconstitution with RNA substrates, specificity shown by absence in Rad51/Rad59, validated by in vivo yeast genetics","pmids":["28602639"],"is_preprint":false},{"year":2017,"finding":"Human RAD52 is recruited to DSB sites in a DNA:RNA hybrid-dependent manner and promotes XPG-mediated R-loop processing to initiate transcription-associated homologous recombination repair (TA-HRR); loss of TA-HRR due to RAD52 dysfunction redirects DSB repair to NHEJ, increasing genomic aberrations.","method":"siRNA knockdown, DNA:RNA hybrid-dependent recruitment assay (IF), XPG interaction analysis, NHEJ/HR pathway choice assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — RAD52 recruitment shown to be RNA hybrid-dependent, functional interaction with XPG demonstrated, pathway choice consequences measured, multiple orthogonal methods","pmids":["30245011"],"is_preprint":false},{"year":2017,"finding":"Human RAD52 is required for RNA-templated DSB repair in post-mitotic neurons; RAD52 is recruited to DSBs in a nascent mRNA-dependent manner; recruitment is reduced by transcription inhibition; amyloid-β inhibits RAD52 expression and DNA damage response.","method":"Immunofluorescence in differentiated neurons, transcription inhibitor treatment, RAD52 focus formation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct recruitment assay with transcription inhibitor control in neuronal cells, single lab, two orthogonal approaches","pmids":["29217771"],"is_preprint":false},{"year":2017,"finding":"Human RAD52 binds tightly to RPA-coated ssDNA using single-molecule imaging; RAD52 imparts an inhibitory effect on RPA turnover; during presynaptic complex assembly, most RAD52 and RPA are displaced by RAD51, but some RAD52-RPA clusters persist; once RAD51 dissociates, new RAD52 binding occurs on ssDNA.","method":"Single-molecule imaging (ssDNA curtains), total internal reflection fluorescence microscopy","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — single-molecule real-time imaging with dynamic resolution of RAD52 behavior, single lab, mechanistically resolved multiple binding states","pmids":["28551686"],"is_preprint":false},{"year":2018,"finding":"RAD52 Rad51-association is essential for protecting Rad51 filaments against dissociation by the Srs2 DNA translocase, but the Rad52–Rad51 interaction is not required for Rad51 filament formation per se (mutations disrupting Rad52-Rad51 interaction do not affect gene conversion or Rad51 filament formation in vivo).","method":"Rad52 point mutations disrupting Rad51 interaction, in vivo gene conversion assay, in vitro and in vivo Rad51 filament formation analysis, Srs2 antirecombination assay","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — separation-of-function mutations validated both in vitro and in vivo, multiple epistasis conditions, mechanistically separates two Rad52 functions","pmids":["29985128"],"is_preprint":false},{"year":2019,"finding":"RAD52 prevents excessive remodeling of stalled replication forks by binding to the fork, promoting its occlusion, and counteracting SMARCAL1 loading; loss of RAD52 leads to excessive MRE11-mediated degradation of reversed replication forks, slightly defective replication restart, and chromosome instability.","method":"siRNA knockdown, small-molecule RAD52 inhibitor, DNA fiber analysis, in vitro fork binding assay, SMARCAL1 loading assay (ChIP/IF)","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA plus small-molecule inhibitor used, direct in vitro fork binding demonstrated, SMARCAL1 displacement shown in vitro and in vivo, multiple orthogonal methods","pmids":["30926821"],"is_preprint":false},{"year":2019,"finding":"Yeast Rad52 limits extensive DNA end resection at DSBs: in rad52 mutant cells, resection rate increases from ~3–5 kb/h to ~10–20 kb/h in an Rqh1 (fission yeast)/Sgs1 (budding yeast)-dependent manner; in vitro, Rad52 competes with Sgs1 for DNA end binding and inhibits Sgs1 translocation along DNA.","method":"In vivo resection assay (Southern blot/qPCR in fission and budding yeast), genetic epistasis, single-molecule analysis with purified proteins","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vivo resection quantification in two yeast species plus in vitro single-molecule mechanistic analysis, multiple orthogonal methods","pmids":["31542296"],"is_preprint":false},{"year":2019,"finding":"RAD52 deficiency reduces spontaneous telomeric DNA synthesis and replication stress-associated recombination in G2 (ALT pathway); RAD52 is dispensable for DSB-induced telomere synthesis; combined loss of RAD52 and SLX4 results in elevated telomere loss and unresolved recombination intermediates (epistasis distinct from RAD52 alone).","method":"RAD52 knockout (CRISPR), telomere synthesis assay (EdU at telomeres), CRISPR screen for SLX4 synthetic lethality, telomere FISH","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR knockout with mechanistic readouts, epistasis with SLX4, multiple telomere assays, defined context (ALT)","pmids":["30692206"],"is_preprint":false},{"year":2020,"finding":"ROS-induced telomeric DSBs trigger R-loop accumulation (TERRA- and TRF2-dependent); RAD52 is recruited to telomeric R-loops through interactions with both CSB and DNA:RNA hybrids; RAD52 is required for efficient repair of telomeric DSBs through recruitment of POLD3 for break-induced replication (BIR); RAD52 function in telomere repair requires its ability to bind POLD3.","method":"siRNA knockdown, immunofluorescence colocalization, RNaseH1 treatment (R-loop dependency), co-immunoprecipitation (RAD52-CSB, RAD52-POLD3), DNA fiber/BIR assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP for interactions, siRNA depletion with functional repair readout, R-loop dependency established by RNaseH treatment, multiple orthogonal methods","pmids":["31777915"],"is_preprint":false},{"year":2020,"finding":"Rad52 liquid droplets at DNA damage sites fuse into a repair centre droplet via petite DIMs (damage-inducible intranuclear microtubule filaments); the larger droplet concentrates tubulin and projects aster-DIMs that tether the repair centre to longer DIMs mediating mobilization of damaged DNA to the nuclear periphery.","method":"Live-cell fluorescence microscopy (Rad52-GFP), genetic disruption of DIM formation, liquid droplet fusion imaging","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell imaging of liquid droplet behavior, genetic perturbation of microtubule filaments, single lab","pmids":["32019927"],"is_preprint":false},{"year":2020,"finding":"Rad52 (but not Rad51/Rad57) facilitates DNA damage tolerance through a non-recombinogenic mechanism by acting with the TLS machinery (Rad6/Rad18-mediated PCNA ubiquitylation and polymerases Rev1/Pol ζ); Rad52 (along with Rad51 and Rad57) also facilitates Rad6/Rad18 binding to chromatin and DNA damage-induced PCNA ubiquitylation.","method":"Genetic epistasis (rad52, rad54, rad51, rad57 mutants), mutagenesis assay, PCNA ubiquitylation assay (Western blot/ChIP)","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple HR mutants, PCNA ubiquitylation biochemistry, single lab, two orthogonal approaches","pmids":["33289333"],"is_preprint":false},{"year":2020,"finding":"DSS1 interacts with RAD52 and stimulates its activities: DSS1 binding changes RAD52 oligomeric conformation, modulates DNA binding, stimulates single-strand annealing, and promotes strand invasion.","method":"Co-immunoprecipitation, in vitro SSA assay, strand invasion assay, oligomeric state analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal protein interaction plus functional biochemical assays, single lab, multiple activities measured","pmids":["31799622"],"is_preprint":false},{"year":2021,"finding":"BRCA1-RNAi protein complex generates damage-associated small RNAs (sdRNAs) that promote DSB repair via the PALB2-RAD52 complex at transcriptional termination pause sites containing R-loops and ssDNA breaks; this sdRNA repair operates in both quiescent and proliferating cells.","method":"siRNA/shRNA knockdown, co-immunoprecipitation (PALB2-RAD52 interaction), dsRNA-repair assay, cell-cycle specific readouts","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PALB2-RAD52 co-IP established, functional repair assay in multiple cell types, single lab for RAD52-specific aspects","pmids":["33536619"],"is_preprint":false},{"year":2023,"finding":"Yeast Rad52 is a homodecameric ring with intrinsic structural asymmetry; each subunit has an ordered N-terminal and disordered C-terminal half; the C-terminus contains two conserved charged patches harboring Rad51-interacting and RPA-interacting motifs; Rad51 interacts with Rad52 at two sites (within the disordered C-terminus and in the ordered ring); interactions between these patches regulate ssDNA binding.","method":"Single-particle cryo-electron microscopy, biophysical interaction assays (ITC, SEC), mutagenesis of charged patches","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure plus biophysical interaction assays and mutagenesis, multiple orthogonal methods in single study","pmids":["37798272"],"is_preprint":false},{"year":2018,"finding":"Crystal structures of human RAD52 in complex with ssDNA revealed two conformations: a 'wrapped' conformation where ssDNA encircles the ring with bases exposed for Watson-Crick pairing, and a 'trapped' conformation where ssDNA is bound between two RAD52 rings via the second DNA binding site, providing a structural framework for the annealing mechanism.","method":"X-ray crystallography of human RAD52-ssDNA complexes","journal":"iScience","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures of two distinct RAD52-ssDNA complexes representing mechanistic intermediates","pmids":["30428330"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM and biochemical analyses revealed that ssDNA annealing is driven by RAD52 open rings (not the closed undecameric rings), in association with RPA; ssDNA sits in a positively charged channel around the ring; annealing is driven by the N-terminal domains; C-terminal regions modulate open-ring conformation and RPA interaction; RPA associates at the ring-opening site via interactions between the RAD52 RPA-interacting domain and the winged-helix domain of RPA2.","method":"Cryo-electron microscopy (structural snapshots throughout annealing), biochemical annealing assays, domain mutagenesis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structures of multiple annealing intermediates plus biochemical validation and mutagenesis, multiple orthogonal methods, high-resolution structural mechanistic insight","pmids":["38658755"],"is_preprint":false},{"year":2006,"finding":"Rad52 phosphorylation occurs both in a cell cycle-independent and a cell cycle-dependent manner; phosphorylation requires the C-terminus of Rad52 but not its interaction with Rad51; multiple translation start sites also generate discrete Rad52 protein species.","method":"Protein-blot analysis, start-codon mutant analysis, cell cycle synchronization, Rad52 domain truncation analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphorylation established by gel mobility shift with domain mapping, start codon analysis by mutagenesis, single lab","pmids":["16707661"],"is_preprint":false},{"year":2009,"finding":"Rad52 interacts with OGG1 (base excision repair glycosylase) in vitro and in vivo; OGG1 inhibits Rad52 catalytic activities while Rad52 stimulates OGG1 incision activity (likely increasing turnover); Rad52 co-localizes with OGG1 after oxidative stress but not after ionizing radiation; RAD52-depleted human/mouse cells show increased sensitivity to oxidative stress and higher accumulation of oxidized bases.","method":"Co-immunoprecipitation, in vitro activity assays (OGG1 incision, Rad52 annealing), siRNA knockdown, KO mouse cells, immunofluorescence colocalization","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional effects between the two proteins shown biochemically, in vivo colocalization, two genetic models (siRNA and KO), multiple orthogonal methods","pmids":["19506022"],"is_preprint":false},{"year":2003,"finding":"Yeast Rad52 forms a complex with Rad51 and RPA, and also a Rad52-Rad59 complex; Rad52 is required for Rad51-Rad52-Rad59 and RPA-Rad52-Rad59 complex formation; the N-terminal self-interaction domain is required for Rad59 binding; Rad52-Rad59 participates in single-strand annealing, while Rad51-Rad52-Rad59 in gene conversion.","method":"Co-immunoprecipitation, two-hybrid assay, domain truncation analysis","journal":"DNA repair","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP and two-hybrid for interaction mapping, genetic pathway inference for functional roles, single lab","pmids":["13679150"],"is_preprint":false}],"current_model":"RAD52 is a multifunctional DNA repair protein that forms oligomeric (predominantly undecameric/decameric) ring structures; it promotes homologous recombination by (1) acting as a mediator that loads RAD51 onto RPA-coated ssDNA to overcome RPA inhibition, (2) catalyzing annealing of complementary RPA-coated ssDNA strands (including second-end capture after D-loop extension), (3) performing inverse strand exchange with RNA as template for RNA-templated DSB repair, (4) limiting DSB end resection by competing with Sgs1/Rqh1 for DNA end binding, (5) acting as a gatekeeper at stalled replication forks by preventing excessive SMARCAL1-mediated fork reversal and MRE11-dependent fork degradation, (6) recruiting MUS81 and POLD3 to common fragile sites in mitosis to enable MiDAS, and (7) functioning in an alternative HR pathway that is synthetically lethal with BRCA2/BRCA1 deficiency; its activities are regulated by SUMOylation (inhibits DNA binding and annealing), phosphorylation (modulated by cell cycle/CDK1 and Mec1/ATM), and RPA (which promotes annealing efficiency via open-ring RAD52 conformation as revealed by cryo-EM)."},"narrative":{"mechanistic_narrative":"RAD52 is a ring-forming DNA repair protein that orchestrates homologous recombination (HR) and single-strand annealing through direct DNA binding and protein-mediator activities [PMID:8855248, PMID:9353267, PMID:14765116]. Its conserved N-terminal domain forms oligomeric rings that bind ssDNA and catalyze rapid annealing of complementary strands, accelerating annealing thousands-fold over the spontaneous rate [PMID:8855248, PMID:15205482]; crystal and cryo-EM structures resolve the mechanism, showing ssDNA wrapped in a positively charged channel around the ring with bases exposed for Watson-Crick pairing, a second DNA-binding site that bridges two rings, and open-ring (rather than closed undecameric) conformations that drive annealing in association with RPA [PMID:30428330, PMID:38658755]. As an HR mediator, RAD52 overcomes RPA inhibition of ssDNA by targeting RAD51 to RPA-coated ssDNA to nucleate the presynaptic filament, a function conserved from yeast to human [PMID:9353267, PMID:9450760, PMID:9450758]; biochemical and in vivo dissection separates RAD52's presynaptic RAD51-loading role from its DNA-binding-dependent second-end capture and annealing role, and from a RAD51-interaction-dependent role in protecting RAD51 filaments against the Srs2 translocase [PMID:14765116, PMID:19812039, PMID:29985128]. RAD52 catalyzes second-end capture of the displaced strand from a RAD51-generated D-loop on RPA-coated ssDNA, coupling annealing to repair synthesis by polymerase eta [PMID:17093500, PMID:18313388], and uniquely performs inverse strand exchange using RNA as template to enable RNA-templated and transcription-associated DSB repair, being recruited to breaks via DNA:RNA hybrids and processing R-loops with XPG [PMID:28602639, PMID:30245011]. At the replication interface, RAD52 marks stalled and collapsed forks, promotes their restart, limits excessive end resection by competing with Sgs1/Rqh1, and prevents pathological SMARCAL1-driven fork reversal and MRE11-dependent fork degradation [PMID:27984746, PMID:30926821, PMID:31542296]; in mitosis it drives MiDAS at common fragile sites by recruiting MUS81 and POLD3, and supports break-induced replication at telomeres [PMID:27984745, PMID:31777915]. RAD52 defines an alternative HR pathway that is synthetically lethal with BRCA2 deficiency [PMID:21148102]. Its activities are gated by SUMOylation, which inhibits DNA binding and annealing and biases pathway choice from single-strand annealing toward gene conversion, by cell-cycle-coupled phosphorylation, and by partner proteins including DSS1, which remodel its oligomeric conformation [PMID:20371517, PMID:31799622, PMID:16707661].","teleology":[{"year":1996,"claim":"Established RAD52's intrinsic biochemical activity, answering whether it acts directly on DNA: it binds ssDNA/dsDNA and dramatically accelerates annealing of complementary strands.","evidence":"Recombinant yeast Rad52, DNA binding and annealing kinetics, N-terminal domain mapping","pmids":["8855248"],"confidence":"High","gaps":["Did not resolve how the N-terminal domain contacts DNA structurally","No partner-protein context"]},{"year":1998,"claim":"Defined RAD52 as an HR mediator and showed the function is conserved to humans, answering how RAD51 overcomes RPA inhibition of ssDNA: RAD52 targets RAD51 to RPA-ssDNA to restore strand exchange.","evidence":"In vitro strand exchange and presynaptic filament assays with purified yeast and human RAD51, RPA, RAD52","pmids":["9353267","9450760","9450759","9450758"],"confidence":"High","gaps":["Precise protein-protein interface not mapped","In vivo timing of mediator action unresolved"]},{"year":1998,"claim":"Provided the structural and partner framework: RAD52 forms multimeric rings, binds DSB ends protecting them from nucleases, and physically engages RPA species-specifically and in vivo co-assembles with RPA in DSB-dependent foci.","evidence":"Electron microscopy, nuclease protection, two-hybrid with RPA subunits, meiotic immunostaining/epistasis","pmids":["9619627","10227297","9632824","9679065"],"confidence":"High","gaps":["Ring stoichiometry not yet defined","Functional consequence of distinct RPA subunit contacts unresolved"]},{"year":2001,"claim":"Linked RAD52 dynamics to replication and revealed a RAD51-independent activity: foci form in S phase upon DSBs, and an N-terminal fragment defective in RAD51 binding still catalyzes homologous pairing.","evidence":"Live-cell GFP imaging with replication/checkpoint mutants; in vitro pairing with truncation mutants and EM","pmids":["11459964","11454867","11571269"],"confidence":"High","gaps":["In vivo relevance of RAD51-independent pairing not established","Mechanism coupling foci to replication unresolved"]},{"year":2004,"claim":"Dissected RAD52's distinct presynaptic, synaptic, and postsynaptic roles in vivo and mapped strand-exchange activity to the ring-forming N-terminal domain.","evidence":"HO-induced DSB time-course IF/ChIP, biochemical ssDNA complexes, in vitro strand exchange with truncations","pmids":["14765116","15205482"],"confidence":"High","gaps":["Postsynaptic mechanism not biochemically reconstituted","AT-content dependence mechanism unexplained"]},{"year":2006,"claim":"Defined RAD52's role in second-end capture, answering how the displaced D-loop strand is annealed: RAD52 anneals RPA-coated ssDNA following RAD51-mediated D-loop formation.","evidence":"In vitro strand exchange plus second-end capture with purified proteins and recombination-deficient RPA mutant","pmids":["17093500"],"confidence":"High","gaps":["Coupling to repair synthesis not yet shown","Regulation of capture timing unresolved"]},{"year":2008,"claim":"Resolved the structural basis of annealing and pathway channeling: a second DNA-binding site enables ternary ssDNA-dsDNA complexes and D-loop formation, while RAD51 filaments inhibit RAD52 annealing in an ATP-dependent manner.","evidence":"Structure-based alanine scanning, D-loop/supercoiling assays, ssDNA annealing with RAD51/RAD59","pmids":["18593704","18337252","16565518"],"confidence":"High","gaps":["How channeling is regulated in vivo not established","Second-site contribution to in vivo HR untested in some contexts"]},{"year":2009,"claim":"Established separation-of-function: the N-terminal DNA-binding domain is needed for second-end capture but not RAD51 delivery; recruitment requires CDK1 and is restrained by Mec1/Tel1 checkpoint kinase, and SUMOylation/phosphorylation regulate activity.","evidence":"rad52-R70A mutant biochemistry/ChIP, live-cell imaging with CDK1/Mec1 mutants, SUMOylation assays","pmids":["19812039","19262568","20371517","16707661","19530647"],"confidence":"High","gaps":["Site-specific phosphorylation consequences not fully mapped","Interplay between SUMO and phospho regulation unresolved"]},{"year":2010,"claim":"Defined RAD52 as an alternative HR mediator and resolved its concentration-dependent ssDNA binding modes underlying annealing.","evidence":"BRCA2 synthetic lethality by siRNA with HR/focus readouts; single-molecule FRET with RPA-interaction mutants","pmids":["21148102","20081207"],"confidence":"High","gaps":["Therapeutic window of BRCA2-RAD52 synthetic lethality not defined here","Structural basis of mode switching unresolved at the time"]},{"year":2017,"claim":"Uncovered RNA-templated repair: RAD52 catalyzes inverse strand exchange using RNA as template and is recruited to breaks via DNA:RNA hybrids to drive transcription-associated HR with XPG, including in post-mitotic neurons.","evidence":"In vitro inverse strand exchange with RNA, in vivo RNA-templated repair, RNA-hybrid recruitment and pathway-choice assays","pmids":["28602639","30245011","29217771"],"confidence":"High","gaps":["How RAD52 discriminates RNA template specificity unclear","In vivo contribution of RNA-templated repair to genome stability not quantified"]},{"year":2019,"claim":"Placed RAD52 at the replication fork as a gatekeeper, answering how forks are protected: it limits resection by competing with Sgs1/Rqh1 and prevents excessive SMARCAL1-mediated reversal and MRE11 degradation.","evidence":"In vivo resection assays in two yeast species, single-molecule competition, siRNA/inhibitor DNA fiber and fork-binding/SMARCAL1 assays","pmids":["31542296","30926821","27984746"],"confidence":"High","gaps":["Molecular basis of fork occlusion not structurally defined","Coordination between resection control and HR initiation unresolved"]},{"year":2016,"claim":"Defined RAD52's mitotic and telomeric replication-stress roles: it drives MiDAS at common fragile sites by recruiting MUS81/POLD3 and supports break-induced replication at telomeres independent of RAD51/BRCA2.","evidence":"siRNA/CRISPR knockout, EdU MiDAS assays, MUS81/POLD3 recruitment IF, telomere synthesis and BIR assays with R-loop dependency","pmids":["27984745","30692206","31777915"],"confidence":"High","gaps":["Mechanism of selective MUS81/POLD3 recruitment unresolved","How RAD52 is targeted to specific fragile/telomeric loci unclear"]},{"year":2024,"claim":"Delivered high-resolution mechanism: cryo-EM and crystallography show open-ring RAD52 (not closed undecamers) drives annealing in a charged channel, with defined ssDNA wrapped/trapped conformations and an RPA2-winged-helix contact at the ring opening.","evidence":"Cryo-EM and X-ray structures of RAD52-ssDNA and RAD52-RPA intermediates, biochemical annealing, domain mutagenesis","pmids":["38658755","30428330","37798272"],"confidence":"High","gaps":["Structures of the RAD51-mediator complex not resolved here","Conformational transitions during second-end capture not visualized"]},{"year":null,"claim":"How RAD52's many regulated activities (mediator loading, annealing, fork protection, RNA-templated repair, MiDAS) are coordinated and selected in vivo, and how its modifications integrate to govern pathway choice, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified model of in vivo activity selection","Regulatory integration of SUMO/phospho and partner binding incomplete","Structural basis of the RAD51-loading mediator step undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,8,9,13,16,20]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[32]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[32]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2,4,14]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2,17,38]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[10,26]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[7,10,41]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[1,14,17,29,33]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[30,31,37,38]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[26,31,37]}],"complexes":["RAD51-RAD52-RPA presynaptic complex","RAD52-RAD59 complex","PALB2-RAD52 complex"],"partners":["RAD51","RPA","RAD59","POLD3","MUS81","DSS1","XPG","OGG1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P43351","full_name":"DNA repair protein RAD52 homolog","aliases":[],"length_aa":418,"mass_kda":46.2,"function":"Involved in double-stranded break repair. Plays a central role in genetic recombination and DNA repair by promoting the annealing of complementary single-stranded DNA and by stimulation of the RAD51 recombinase","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P43351/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RAD52","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"MAP4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/RAD52","total_profiled":1310},"omim":[{"mim_id":"613984","title":"FANCD2 GENE; FANCD2","url":"https://www.omim.org/entry/613984"},{"mim_id":"613298","title":"TOPBP1-INTERACTING CHECKPOINT AND REPLICATION REGULATOR; TICRR","url":"https://www.omim.org/entry/613298"},{"mim_id":"612896","title":"RAD52 MOTIF-CONTAINING PROTEIN 1; RDM1","url":"https://www.omim.org/entry/612896"},{"mim_id":"608048","title":"SNF2, LINKER HISTONE, PHD FINGER, RING FINGER, AND HELICASE DOMAINS-CONTAINING PROTEIN; SHPRH","url":"https://www.omim.org/entry/608048"},{"mim_id":"606829","title":"FRATAXIN; FXN","url":"https://www.omim.org/entry/606829"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear speckles","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RAD52"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P43351","domains":[{"cath_id":"3.30.390.80","chopping":"32-175","consensus_level":"medium","plddt":97.8614,"start":32,"end":175}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P43351","model_url":"https://alphafold.ebi.ac.uk/files/AF-P43351-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P43351-F1-predicted_aligned_error_v6.png","plddt_mean":69.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RAD52","jax_strain_url":"https://www.jax.org/strain/search?query=RAD52"},"sequence":{"accession":"P43351","fasta_url":"https://rest.uniprot.org/uniprotkb/P43351.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P43351/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P43351"}},"corpus_meta":[{"pmid":"12456786","id":"PMC_12456786","title":"Role of RAD52 epistasis group genes in 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Forks.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/32050645","citation_count":20,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":42436,"output_tokens":11766,"usd":0.151899,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":23283,"output_tokens":4902,"usd":0.119483,"stage2_stop_reason":"end_turn"},"total_usd":0.271382,"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\": 1996,\n      \"finding\": \"Yeast Rad52 protein directly binds both single-stranded and double-stranded DNA and stimulates annealing of complementary ssDNA at a rate 3500-fold faster than spontaneous annealing; the DNA binding domain was mapped to the evolutionarily conserved N-terminus.\",\n      \"method\": \"Recombinant protein purification, DNA binding assays, DNA annealing kinetics assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical reconstitution with purified recombinant protein, multiple orthogonal assays (binding + annealing kinetics), N-terminal domain mapping, replicated in subsequent studies\",\n      \"pmids\": [\"8855248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Yeast Rad52 functions as a mediator (co-factor) for Rad51 recombinase by overcoming the inhibitory effect of RPA on ssDNA, restoring efficient DNA strand exchange when Rad51 and RPA are added simultaneously to ssDNA.\",\n      \"method\": \"In vitro DNA strand exchange assay with purified yeast Rad51, RPA, and Rad52 proteins\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro strand exchange with purified components, demonstrated specific co-factor role, independently replicated in same year by two other labs\",\n      \"pmids\": [\"9353267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Yeast Rad52 stimulates Rad51-mediated DNA strand exchange by targeting Rad51 to RPA-ssDNA complexes (overcoming RPA inhibition); stimulation requires concerted action of both Rad51 and RPA, implying specific protein-protein interactions between Rad52, Rad51, and RPA.\",\n      \"method\": \"In vitro DNA strand exchange assay, presynaptic filament formation assay with purified proteins\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified components, multiple conditions tested, replicated across three simultaneous independent publications\",\n      \"pmids\": [\"9450760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Yeast Rad52 stimulates Rad51 strand exchange and nucleoprotein filament formation; binding to Rad51 is necessary for this stimulatory effect.\",\n      \"method\": \"In vitro strand exchange assay, protein-protein interaction studies, nucleoprotein filament formation assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution, interaction requirement demonstrated by mutation, simultaneous independent replication\",\n      \"pmids\": [\"9450759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Human Rad52 stimulates homologous pairing by human Rad51, indicating the Rad52–Rad51 functional relationship is conserved in humans; hRad52 DNA binding properties indicate involvement in an early stage of Rad51-mediated recombination.\",\n      \"method\": \"In vitro homologous pairing assay with purified human Rad51 and Rad52 proteins\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified human proteins, simultaneous independent replication across three papers in the same issue\",\n      \"pmids\": [\"9450758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Yeast Rad52 forms multimeric ring structures as observed by electron microscopy; it binds ssDNA and interacts physically with RPA (specifically RPA enhances ssDNA annealing); this enhancement is species-specific (E. coli SSB and T4 gp32 do not substitute).\",\n      \"method\": \"Electron microscopy, ssDNA annealing assay, protein-protein interaction (binding assays)\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — EM structure, biochemical annealing assay with RPA specificity controls, replicated across multiple studies\",\n      \"pmids\": [\"9619627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Rad52 physically interacts with all three subunits of yeast RPA (two-hybrid analysis); mutations in the amino-terminal DNA-binding domain of Rad52 disrupt interaction with Rad51 and with the large RPA subunit (Rfa1) but retain self-interaction and interaction with Rfa2; RAD52 and RFA1 are in the same genetic epistasis pathway.\",\n      \"method\": \"Yeast two-hybrid assay, genetic epistasis analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — genetic epistasis plus two-hybrid data (single lab), two orthogonal approaches\",\n      \"pmids\": [\"9632824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"In meiosis, Rad52 and RPA co-assemble into cytologically detectable subnuclear foci; Rad52 foci are distinct from Rad51/Dmc1 foci and require DSBs (Spo11-dependent); Rad52, Rad55, and Rad57 are all required for Rad51 focus formation, supporting a model in which they collectively promote strand exchange complex assembly.\",\n      \"method\": \"Immunostaining, colocalization microscopy, genetic epistasis (spo11 mutant, ionizing radiation rescue)\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo colocalization with multiple genetic controls, multiple orthogonal approaches (immunostaining + epistasis), well-replicated findings\",\n      \"pmids\": [\"9679065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Human Rad52 binds directly to DNA double-strand breaks, protects them from exonuclease attack, and facilitates end-to-end DNA interactions, consistent with an early role in DSB repair by homologous recombination.\",\n      \"method\": \"In vitro DNA binding assay, nuclease protection assay, electron microscopy\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical reconstitution with purified human Rad52, multiple orthogonal assays (binding, nuclease protection, EM)\",\n      \"pmids\": [\"10227297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Human RAD52 binds ssDNA and tailed duplex DNA via precise interactions with the terminal nucleotide base; hydroxyl radical footprinting revealed a 4-nucleotide repeat hypersensitivity pattern phased from the DNA terminus over ~36 nucleotides.\",\n      \"method\": \"Hydroxyl radical footprinting, nuclease protection assay, in vitro DNA binding\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical assay with defined substrates and footprinting, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"10921897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Rad52-GFP relocalizes from a diffuse nuclear distribution to distinct foci upon DNA double-strand break induction (gamma-irradiation, meiosis, HO endonuclease); foci form almost exclusively during S phase of mitotic cells, and their frequency increases in replication (pol12-100) and checkpoint (mec1) mutants, indicating coordination with DNA replication.\",\n      \"method\": \"Live-cell fluorescence microscopy (GFP fusion), genetic analysis with replication/checkpoint mutants, DSB induction assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct live-imaging with functional GFP fusion, confirmed with multiple DSB sources, cell-cycle and genetic context defined, replicated across studies\",\n      \"pmids\": [\"11459964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Human Rad52 promotes homologous pairing via a presynaptic complex with ssDNA; an N-terminal fragment (residues 1–237) defective in Rad51 binding still catalyzes homologous pairing, forming nucleoprotein filaments with ssDNA, indicating a Rad51-independent recombination function.\",\n      \"method\": \"In vitro homologous pairing assay, electron microscopy, truncation mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with defined mutant protein, EM visualization, two orthogonal methods in single lab\",\n      \"pmids\": [\"11454867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Human RAD52 promotes single-strand annealing (SSA) in vitro; electron microscopy visualized specific binding of multiple RAD52 rings to resected DSB termini and large protein complexes at heteroduplex joints, defining intermediates of RAD52-mediated annealing.\",\n      \"method\": \"In vitro SSA assay, electron microscopy of reaction intermediates\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical reconstitution with EM visualization of intermediates, two orthogonal methods, single lab\",\n      \"pmids\": [\"11571269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Yeast Rad52 binds preferentially to ssDNA rather than to free DNA ends (in contrast to Ku which binds free ends); Rad52 aggregates different ssDNAs in close proximity independently of DNA ends or extensive sequence complementarity.\",\n      \"method\": \"In vitro DNA binding assay with defined substrates, comparison with Ku protein\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical binding assay with defined substrates and direct comparison, single lab, two orthogonal assessments\",\n      \"pmids\": [\"12954758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In vivo, Rad52 plays three distinct roles during homologous recombination: a presynaptic role necessary for Rad51 assembly at a DSB, a synaptic role with Rad51 filaments, and a postsynaptic role after Rad51 dissociates; ssDNA complexes containing both Rad51 and Rad52 were identified biochemically.\",\n      \"method\": \"Immunofluorescence during HO-induced DSB repair (time-course), chromatin immunoprecipitation, biochemical ssDNA complex analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (IF kinetics, ChIP, biochemical), in vivo monitoring with defined DSB locus, temporal dissection of three roles\",\n      \"pmids\": [\"14765116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Human and yeast Rad52 proteins promote DNA strand exchange in vitro; this activity resides in the N-terminal domain (residues 1–237 for human Rad52) that forms rings; strand exchange yield is proportional to AT content.\",\n      \"method\": \"In vitro DNA strand exchange assay, N-terminal truncation analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with defined truncation mutants, single lab, two species tested\",\n      \"pmids\": [\"15205482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Saturating alanine-scanning mutagenesis of the N-terminal domain of full-length human Rad52 identified residues (within the first 85 residues) involved in direct ssDNA contact; these residues map to the DNA binding channel observed in crystal structures of truncation mutants.\",\n      \"method\": \"Alanine-scanning mutagenesis, in vitro DNA binding assay\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis with functional validation, single lab, well-defined domain mapping\",\n      \"pmids\": [\"15571718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Rad52 promotes annealing of the displaced ssDNA strand from a Rad51-mediated D-loop (second ssDNA capture/second-end capture), acting on RPA-coated ssDNA; RPA-rfa1-t11 (recombination-deficient RPA) fails to support this annealing, explaining its in vivo phenotype. E. coli RecO/SSB are functional analogs, demonstrating the conserved nature of this step.\",\n      \"method\": \"In vitro DNA strand exchange + second-strand capture assay with purified proteins, mutant RPA analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with defined RPA mutant, conserved across species, multiple controls, replicated by other labs\",\n      \"pmids\": [\"17093500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Yeast Rad59 can anneal complementary ssDNA but cannot anneal RPA-coated ssDNA (unlike Rad52), follows first-order kinetics (versus second-order for Rad52), and enhances Rad52-mediated annealing at elevated salt; these biochemical differences distinguish their recombinational roles.\",\n      \"method\": \"Quantitative in vitro ssDNA annealing assay with RPA, kinetics analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified proteins, quantitative kinetic analysis, direct comparison between Rad52 and Rad59\",\n      \"pmids\": [\"16565518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"DNA repair synthesis catalyzed by human DNA polymerase eta (pol eta) acting on the priming strand of a D-loop promotes RAD52-dependent second-end capture and annealing; pol delta and pol iota cannot substitute for pol eta; RAD52 cannot be replaced by RAD51; RPA (but not E. coli SSB) stimulates the reaction.\",\n      \"method\": \"In vitro second-end capture assay with purified human proteins, defined polymerase substitution\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with multiple defined protein substitutions, rigorous controls with alternative polymerases and SSBs\",\n      \"pmids\": [\"18313388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Human Rad52 has a second DNA binding site identified by structure-based alanine scan mutagenesis; this site enables the Rad52-ssDNA complex to form a ternary complex with dsDNA; mutations in this site impair D-loop formation and abolish Rad52-induced positive supercoiling of dsDNA.\",\n      \"method\": \"Structure-based alanine-scanning mutagenesis, D-loop formation assay, supercoiling assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structure-guided mutagenesis with functional validation of two distinct activities, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"18593704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Yeast Rad51 prevents Rad52-mediated ssDNA annealing in an ATP-dependent manner via specific Rad51–Rad52 protein–protein interaction; the Rad51 nucleoprotein filament is more inhibitory than free Rad51; Rad59 partially restores annealing in the presence of Rad51, suggesting coordinated channeling between strand invasion and annealing pathways.\",\n      \"method\": \"In vitro ssDNA annealing assay, ATP dependence analysis, protein-protein interaction study\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with multiple protein combinations, ATP dependence established, mechanistically dissects pathway choice\",\n      \"pmids\": [\"18337252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The Rad52 amino-terminal DNA binding domain is required for DNA annealing (second-end capture) but not for Rad51 delivery to DSBs; rad52-R70A (compromised DNA binding) associates with DSBs and recruits Rad51 normally but cannot complete recombination due to failure in second-end capture.\",\n      \"method\": \"Purified mutant protein biochemical assay (annealing), chromatin immunoprecipitation (ChIP) at DSBs, genetic analysis of recombination intermediates\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — separation-of-function mutant validated by both in vitro biochemistry and in vivo ChIP + recombination intermediates analysis\",\n      \"pmids\": [\"19812039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Phosphorylated human RPA promotes formation of a complex with monomeric Rad52 and causes transfer of ssDNA from RPA to Rad52, suggesting RPA phosphorylation regulates the mediator function of Rad52 in the first steps of DSB repair.\",\n      \"method\": \"Analytical SEC-MALS, UV crosslinking to identify ssDNA-bound partner, SDS-PAGE/Western analysis\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — solution biochemistry with multiple orthogonal methods (SEC-MALS + UV crosslinking), single lab\",\n      \"pmids\": [\"19530647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Srs2 helicase evicts Rad52 from RPA-ssDNA during translocation, promoting rapid redistribution of both Rad52 and RPA, thereby resolving potentially pathogenic nucleoprotein intermediates.\",\n      \"method\": \"Single-molecule fluorescence imaging of Srs2 acting on ssDNA curtains coated with RPA and Rad52\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single-molecule real-time imaging, single lab, direct visualization of protein eviction\",\n      \"pmids\": [\"29045827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Rad52-RPA interaction requires multiple RPA molecules associated with ssDNA (cooperative contacts); Rad51 inhibits Rad52-promoted ssDNA aggregation and subsequent annealing; after DNA strand invasion, Rad51-dsDNA complex disrupts Rad52-RPA interaction on ssDNA, limiting illegitimate second-end capture.\",\n      \"method\": \"In vitro DNA annealing assay, protein-protein interaction biochemistry with mutant RPA\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with defined protein mutants, single lab, mechanistically coherent model\",\n      \"pmids\": [\"19445949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Rad52 recruitment to DSB sites requires B-type cyclin/CDK1 (Cdc28) activity; during intra-S-phase checkpoint (hydroxyurea), Mec1/Tel1 kinase inhibits Rad52 focus formation at both DSBs and stalled replication forks; Rad52 foci colocalize with PCNA foci.\",\n      \"method\": \"Live-cell fluorescence microscopy (Rad52-GFP), genetic analysis with CDK1/Mec1 mutants, co-localization with PCNA-GFP\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct live-cell imaging with multiple genetic perturbations (CDK1, Mec1/Tel1, caffeine), colocalization with PCNA, multiple orthogonal approaches\",\n      \"pmids\": [\"19262568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Rad52 SUMOylation inhibits its DNA binding and ssDNA annealing activities in vitro; SUMOylation is enhanced by ssDNA; in vivo, SUMO-deficient Rad52 mutants show longer focus duration and a shift from single-strand annealing toward gene conversion during spontaneous mitotic recombination.\",\n      \"method\": \"In vitro SUMOylation assay, DNA binding assay, ssDNA annealing assay with SUMOylated Rad52, in vivo recombination assays, live-cell microscopy\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro biochemical assays with SUMOylated protein plus in vivo genetic/recombination assays, multiple orthogonal methods, single lab but comprehensive\",\n      \"pmids\": [\"20371517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Human RAD52 binds ssDNA in two concentration-dependent modes: at low protein concentration ssDNA is wrapped around the ring circumference (promoting efficient annealing), while at higher concentrations ssDNA is stretched between multiple rings; annealing via two RAD52-ssDNA complexes (one per complementary strand); hRad52 mutants impaired in hRPA binding (RQK/AAA and 1-212) compete with RPA for ssDNA and fail to counteract RPA-mediated duplex destabilization.\",\n      \"method\": \"Single-molecule FRET, fluorescence-based DNA annealing assay, RPA interaction mutant analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — single-molecule FRET plus ensemble annealing assay with defined mutants, mechanistic model directly supported by data\",\n      \"pmids\": [\"20081207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Loss of Rad52 is synthetically lethal with BRCA2 deficiency; Rad52 depletion in BRCA2-deficient cells reduces spontaneous and DSB-induced homologous recombination and Rad51 focus formation; Rad52-Rad51 foci form independently of BRCA2, defining Rad52 as an alternative HR mediator pathway.\",\n      \"method\": \"siRNA knockdown, HR frequency assay, Rad51 focus formation assay, chromosome aberration analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis by siRNA + complementation, HR frequency quantification, focus assays, replicated by multiple subsequent labs\",\n      \"pmids\": [\"21148102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Human RAD52 is required for Mitotic DNA Synthesis (MiDAS) at common fragile sites (CFSs); RAD52 is required for timely recruitment of MUS81 and POLD3 to CFSs in early mitosis; RAD51 and BRCA2 are dispensable for MiDAS but required to counteract replication stress at CFSs during S-phase.\",\n      \"method\": \"siRNA knockdown, EdU incorporation (MiDAS assay), immunofluorescence for MUS81/POLD3 recruitment, epistasis analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — specific siRNA knockdown with functional MiDAS readout and recruitment assays, clear genetic epistasis separating RAD52 from RAD51/BRCA2, replicated by concurrent publication\",\n      \"pmids\": [\"27984745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mammalian RAD52 localizes to collapsed replication fork foci induced by oncogenes or chemicals; siRNA depletion or CRISPR/Cas9 knockout of RAD52 compromises restart of collapsed replication forks and leads to DNA damage under replication stress conditions.\",\n      \"method\": \"siRNA knockdown, CRISPR/Cas9 knockout, immunofluorescence (focus formation), replication fork restart assay (DNA fiber analysis), oncogene overexpression model\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — both siRNA and CRISPR KO used, DNA fiber analysis for fork restart, in vivo tumor model confirmation, two orthogonal genetic approaches\",\n      \"pmids\": [\"27984746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Yeast and human Rad52 catalyze inverse strand exchange: Rad52 forms a complex with dsDNA and promotes strand exchange with homologous ssRNA or ssDNA; this activity is specific to Rad52 (not Rad51 or Rad59); inverse strand exchange with RNA contributes to RNA-templated DSB repair in yeast.\",\n      \"method\": \"In vitro inverse strand exchange assay with purified proteins and RNA substrates, in vivo RNA-templated DSB repair assay in yeast\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical reconstitution with RNA substrates, specificity shown by absence in Rad51/Rad59, validated by in vivo yeast genetics\",\n      \"pmids\": [\"28602639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Human RAD52 is recruited to DSB sites in a DNA:RNA hybrid-dependent manner and promotes XPG-mediated R-loop processing to initiate transcription-associated homologous recombination repair (TA-HRR); loss of TA-HRR due to RAD52 dysfunction redirects DSB repair to NHEJ, increasing genomic aberrations.\",\n      \"method\": \"siRNA knockdown, DNA:RNA hybrid-dependent recruitment assay (IF), XPG interaction analysis, NHEJ/HR pathway choice assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RAD52 recruitment shown to be RNA hybrid-dependent, functional interaction with XPG demonstrated, pathway choice consequences measured, multiple orthogonal methods\",\n      \"pmids\": [\"30245011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Human RAD52 is required for RNA-templated DSB repair in post-mitotic neurons; RAD52 is recruited to DSBs in a nascent mRNA-dependent manner; recruitment is reduced by transcription inhibition; amyloid-β inhibits RAD52 expression and DNA damage response.\",\n      \"method\": \"Immunofluorescence in differentiated neurons, transcription inhibitor treatment, RAD52 focus formation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct recruitment assay with transcription inhibitor control in neuronal cells, single lab, two orthogonal approaches\",\n      \"pmids\": [\"29217771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Human RAD52 binds tightly to RPA-coated ssDNA using single-molecule imaging; RAD52 imparts an inhibitory effect on RPA turnover; during presynaptic complex assembly, most RAD52 and RPA are displaced by RAD51, but some RAD52-RPA clusters persist; once RAD51 dissociates, new RAD52 binding occurs on ssDNA.\",\n      \"method\": \"Single-molecule imaging (ssDNA curtains), total internal reflection fluorescence microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single-molecule real-time imaging with dynamic resolution of RAD52 behavior, single lab, mechanistically resolved multiple binding states\",\n      \"pmids\": [\"28551686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RAD52 Rad51-association is essential for protecting Rad51 filaments against dissociation by the Srs2 DNA translocase, but the Rad52–Rad51 interaction is not required for Rad51 filament formation per se (mutations disrupting Rad52-Rad51 interaction do not affect gene conversion or Rad51 filament formation in vivo).\",\n      \"method\": \"Rad52 point mutations disrupting Rad51 interaction, in vivo gene conversion assay, in vitro and in vivo Rad51 filament formation analysis, Srs2 antirecombination assay\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — separation-of-function mutations validated both in vitro and in vivo, multiple epistasis conditions, mechanistically separates two Rad52 functions\",\n      \"pmids\": [\"29985128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RAD52 prevents excessive remodeling of stalled replication forks by binding to the fork, promoting its occlusion, and counteracting SMARCAL1 loading; loss of RAD52 leads to excessive MRE11-mediated degradation of reversed replication forks, slightly defective replication restart, and chromosome instability.\",\n      \"method\": \"siRNA knockdown, small-molecule RAD52 inhibitor, DNA fiber analysis, in vitro fork binding assay, SMARCAL1 loading assay (ChIP/IF)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA plus small-molecule inhibitor used, direct in vitro fork binding demonstrated, SMARCAL1 displacement shown in vitro and in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"30926821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Yeast Rad52 limits extensive DNA end resection at DSBs: in rad52 mutant cells, resection rate increases from ~3–5 kb/h to ~10–20 kb/h in an Rqh1 (fission yeast)/Sgs1 (budding yeast)-dependent manner; in vitro, Rad52 competes with Sgs1 for DNA end binding and inhibits Sgs1 translocation along DNA.\",\n      \"method\": \"In vivo resection assay (Southern blot/qPCR in fission and budding yeast), genetic epistasis, single-molecule analysis with purified proteins\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vivo resection quantification in two yeast species plus in vitro single-molecule mechanistic analysis, multiple orthogonal methods\",\n      \"pmids\": [\"31542296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RAD52 deficiency reduces spontaneous telomeric DNA synthesis and replication stress-associated recombination in G2 (ALT pathway); RAD52 is dispensable for DSB-induced telomere synthesis; combined loss of RAD52 and SLX4 results in elevated telomere loss and unresolved recombination intermediates (epistasis distinct from RAD52 alone).\",\n      \"method\": \"RAD52 knockout (CRISPR), telomere synthesis assay (EdU at telomeres), CRISPR screen for SLX4 synthetic lethality, telomere FISH\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR knockout with mechanistic readouts, epistasis with SLX4, multiple telomere assays, defined context (ALT)\",\n      \"pmids\": [\"30692206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ROS-induced telomeric DSBs trigger R-loop accumulation (TERRA- and TRF2-dependent); RAD52 is recruited to telomeric R-loops through interactions with both CSB and DNA:RNA hybrids; RAD52 is required for efficient repair of telomeric DSBs through recruitment of POLD3 for break-induced replication (BIR); RAD52 function in telomere repair requires its ability to bind POLD3.\",\n      \"method\": \"siRNA knockdown, immunofluorescence colocalization, RNaseH1 treatment (R-loop dependency), co-immunoprecipitation (RAD52-CSB, RAD52-POLD3), DNA fiber/BIR assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP for interactions, siRNA depletion with functional repair readout, R-loop dependency established by RNaseH treatment, multiple orthogonal methods\",\n      \"pmids\": [\"31777915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Rad52 liquid droplets at DNA damage sites fuse into a repair centre droplet via petite DIMs (damage-inducible intranuclear microtubule filaments); the larger droplet concentrates tubulin and projects aster-DIMs that tether the repair centre to longer DIMs mediating mobilization of damaged DNA to the nuclear periphery.\",\n      \"method\": \"Live-cell fluorescence microscopy (Rad52-GFP), genetic disruption of DIM formation, liquid droplet fusion imaging\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell imaging of liquid droplet behavior, genetic perturbation of microtubule filaments, single lab\",\n      \"pmids\": [\"32019927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Rad52 (but not Rad51/Rad57) facilitates DNA damage tolerance through a non-recombinogenic mechanism by acting with the TLS machinery (Rad6/Rad18-mediated PCNA ubiquitylation and polymerases Rev1/Pol ζ); Rad52 (along with Rad51 and Rad57) also facilitates Rad6/Rad18 binding to chromatin and DNA damage-induced PCNA ubiquitylation.\",\n      \"method\": \"Genetic epistasis (rad52, rad54, rad51, rad57 mutants), mutagenesis assay, PCNA ubiquitylation assay (Western blot/ChIP)\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple HR mutants, PCNA ubiquitylation biochemistry, single lab, two orthogonal approaches\",\n      \"pmids\": [\"33289333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DSS1 interacts with RAD52 and stimulates its activities: DSS1 binding changes RAD52 oligomeric conformation, modulates DNA binding, stimulates single-strand annealing, and promotes strand invasion.\",\n      \"method\": \"Co-immunoprecipitation, in vitro SSA assay, strand invasion assay, oligomeric state analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal protein interaction plus functional biochemical assays, single lab, multiple activities measured\",\n      \"pmids\": [\"31799622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BRCA1-RNAi protein complex generates damage-associated small RNAs (sdRNAs) that promote DSB repair via the PALB2-RAD52 complex at transcriptional termination pause sites containing R-loops and ssDNA breaks; this sdRNA repair operates in both quiescent and proliferating cells.\",\n      \"method\": \"siRNA/shRNA knockdown, co-immunoprecipitation (PALB2-RAD52 interaction), dsRNA-repair assay, cell-cycle specific readouts\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PALB2-RAD52 co-IP established, functional repair assay in multiple cell types, single lab for RAD52-specific aspects\",\n      \"pmids\": [\"33536619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Yeast Rad52 is a homodecameric ring with intrinsic structural asymmetry; each subunit has an ordered N-terminal and disordered C-terminal half; the C-terminus contains two conserved charged patches harboring Rad51-interacting and RPA-interacting motifs; Rad51 interacts with Rad52 at two sites (within the disordered C-terminus and in the ordered ring); interactions between these patches regulate ssDNA binding.\",\n      \"method\": \"Single-particle cryo-electron microscopy, biophysical interaction assays (ITC, SEC), mutagenesis of charged patches\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure plus biophysical interaction assays and mutagenesis, multiple orthogonal methods in single study\",\n      \"pmids\": [\"37798272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crystal structures of human RAD52 in complex with ssDNA revealed two conformations: a 'wrapped' conformation where ssDNA encircles the ring with bases exposed for Watson-Crick pairing, and a 'trapped' conformation where ssDNA is bound between two RAD52 rings via the second DNA binding site, providing a structural framework for the annealing mechanism.\",\n      \"method\": \"X-ray crystallography of human RAD52-ssDNA complexes\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures of two distinct RAD52-ssDNA complexes representing mechanistic intermediates\",\n      \"pmids\": [\"30428330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM and biochemical analyses revealed that ssDNA annealing is driven by RAD52 open rings (not the closed undecameric rings), in association with RPA; ssDNA sits in a positively charged channel around the ring; annealing is driven by the N-terminal domains; C-terminal regions modulate open-ring conformation and RPA interaction; RPA associates at the ring-opening site via interactions between the RAD52 RPA-interacting domain and the winged-helix domain of RPA2.\",\n      \"method\": \"Cryo-electron microscopy (structural snapshots throughout annealing), biochemical annealing assays, domain mutagenesis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structures of multiple annealing intermediates plus biochemical validation and mutagenesis, multiple orthogonal methods, high-resolution structural mechanistic insight\",\n      \"pmids\": [\"38658755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Rad52 phosphorylation occurs both in a cell cycle-independent and a cell cycle-dependent manner; phosphorylation requires the C-terminus of Rad52 but not its interaction with Rad51; multiple translation start sites also generate discrete Rad52 protein species.\",\n      \"method\": \"Protein-blot analysis, start-codon mutant analysis, cell cycle synchronization, Rad52 domain truncation analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation established by gel mobility shift with domain mapping, start codon analysis by mutagenesis, single lab\",\n      \"pmids\": [\"16707661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Rad52 interacts with OGG1 (base excision repair glycosylase) in vitro and in vivo; OGG1 inhibits Rad52 catalytic activities while Rad52 stimulates OGG1 incision activity (likely increasing turnover); Rad52 co-localizes with OGG1 after oxidative stress but not after ionizing radiation; RAD52-depleted human/mouse cells show increased sensitivity to oxidative stress and higher accumulation of oxidized bases.\",\n      \"method\": \"Co-immunoprecipitation, in vitro activity assays (OGG1 incision, Rad52 annealing), siRNA knockdown, KO mouse cells, immunofluorescence colocalization\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional effects between the two proteins shown biochemically, in vivo colocalization, two genetic models (siRNA and KO), multiple orthogonal methods\",\n      \"pmids\": [\"19506022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Yeast Rad52 forms a complex with Rad51 and RPA, and also a Rad52-Rad59 complex; Rad52 is required for Rad51-Rad52-Rad59 and RPA-Rad52-Rad59 complex formation; the N-terminal self-interaction domain is required for Rad59 binding; Rad52-Rad59 participates in single-strand annealing, while Rad51-Rad52-Rad59 in gene conversion.\",\n      \"method\": \"Co-immunoprecipitation, two-hybrid assay, domain truncation analysis\",\n      \"journal\": \"DNA repair\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP and two-hybrid for interaction mapping, genetic pathway inference for functional roles, single lab\",\n      \"pmids\": [\"13679150\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RAD52 is a multifunctional DNA repair protein that forms oligomeric (predominantly undecameric/decameric) ring structures; it promotes homologous recombination by (1) acting as a mediator that loads RAD51 onto RPA-coated ssDNA to overcome RPA inhibition, (2) catalyzing annealing of complementary RPA-coated ssDNA strands (including second-end capture after D-loop extension), (3) performing inverse strand exchange with RNA as template for RNA-templated DSB repair, (4) limiting DSB end resection by competing with Sgs1/Rqh1 for DNA end binding, (5) acting as a gatekeeper at stalled replication forks by preventing excessive SMARCAL1-mediated fork reversal and MRE11-dependent fork degradation, (6) recruiting MUS81 and POLD3 to common fragile sites in mitosis to enable MiDAS, and (7) functioning in an alternative HR pathway that is synthetically lethal with BRCA2/BRCA1 deficiency; its activities are regulated by SUMOylation (inhibits DNA binding and annealing), phosphorylation (modulated by cell cycle/CDK1 and Mec1/ATM), and RPA (which promotes annealing efficiency via open-ring RAD52 conformation as revealed by cryo-EM).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RAD52 is a ring-forming DNA repair protein that orchestrates homologous recombination (HR) and single-strand annealing through direct DNA binding and protein-mediator activities [#0, #1, #14]. Its conserved N-terminal domain forms oligomeric rings that bind ssDNA and catalyze rapid annealing of complementary strands, accelerating annealing thousands-fold over the spontaneous rate [#0, #15]; crystal and cryo-EM structures resolve the mechanism, showing ssDNA wrapped in a positively charged channel around the ring with bases exposed for Watson-Crick pairing, a second DNA-binding site that bridges two rings, and open-ring (rather than closed undecameric) conformations that drive annealing in association with RPA [#46, #47]. As an HR mediator, RAD52 overcomes RPA inhibition of ssDNA by targeting RAD51 to RPA-coated ssDNA to nucleate the presynaptic filament, a function conserved from yeast to human [#1, #2, #4]; biochemical and in vivo dissection separates RAD52's presynaptic RAD51-loading role from its DNA-binding-dependent second-end capture and annealing role, and from a RAD51-interaction-dependent role in protecting RAD51 filaments against the Srs2 translocase [#14, #22, #36]. RAD52 catalyzes second-end capture of the displaced strand from a RAD51-generated D-loop on RPA-coated ssDNA, coupling annealing to repair synthesis by polymerase eta [#17, #19], and uniquely performs inverse strand exchange using RNA as template to enable RNA-templated and transcription-associated DSB repair, being recruited to breaks via DNA:RNA hybrids and processing R-loops with XPG [#32, #33]. At the replication interface, RAD52 marks stalled and collapsed forks, promotes their restart, limits excessive end resection by competing with Sgs1/Rqh1, and prevents pathological SMARCAL1-driven fork reversal and MRE11-dependent fork degradation [#31, #37, #38]; in mitosis it drives MiDAS at common fragile sites by recruiting MUS81 and POLD3, and supports break-induced replication at telomeres [#30, #40]. RAD52 defines an alternative HR pathway that is synthetically lethal with BRCA2 deficiency [#29]. Its activities are gated by SUMOylation, which inhibits DNA binding and annealing and biases pathway choice from single-strand annealing toward gene conversion, by cell-cycle-coupled phosphorylation, and by partner proteins including DSS1, which remodel its oligomeric conformation [#27, #43, #48].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established RAD52's intrinsic biochemical activity, answering whether it acts directly on DNA: it binds ssDNA/dsDNA and dramatically accelerates annealing of complementary strands.\",\n      \"evidence\": \"Recombinant yeast Rad52, DNA binding and annealing kinetics, N-terminal domain mapping\",\n      \"pmids\": [\"8855248\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how the N-terminal domain contacts DNA structurally\", \"No partner-protein context\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined RAD52 as an HR mediator and showed the function is conserved to humans, answering how RAD51 overcomes RPA inhibition of ssDNA: RAD52 targets RAD51 to RPA-ssDNA to restore strand exchange.\",\n      \"evidence\": \"In vitro strand exchange and presynaptic filament assays with purified yeast and human RAD51, RPA, RAD52\",\n      \"pmids\": [\"9353267\", \"9450760\", \"9450759\", \"9450758\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise protein-protein interface not mapped\", \"In vivo timing of mediator action unresolved\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Provided the structural and partner framework: RAD52 forms multimeric rings, binds DSB ends protecting them from nucleases, and physically engages RPA species-specifically and in vivo co-assembles with RPA in DSB-dependent foci.\",\n      \"evidence\": \"Electron microscopy, nuclease protection, two-hybrid with RPA subunits, meiotic immunostaining/epistasis\",\n      \"pmids\": [\"9619627\", \"10227297\", \"9632824\", \"9679065\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ring stoichiometry not yet defined\", \"Functional consequence of distinct RPA subunit contacts unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Linked RAD52 dynamics to replication and revealed a RAD51-independent activity: foci form in S phase upon DSBs, and an N-terminal fragment defective in RAD51 binding still catalyzes homologous pairing.\",\n      \"evidence\": \"Live-cell GFP imaging with replication/checkpoint mutants; in vitro pairing with truncation mutants and EM\",\n      \"pmids\": [\"11459964\", \"11454867\", \"11571269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of RAD51-independent pairing not established\", \"Mechanism coupling foci to replication unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Dissected RAD52's distinct presynaptic, synaptic, and postsynaptic roles in vivo and mapped strand-exchange activity to the ring-forming N-terminal domain.\",\n      \"evidence\": \"HO-induced DSB time-course IF/ChIP, biochemical ssDNA complexes, in vitro strand exchange with truncations\",\n      \"pmids\": [\"14765116\", \"15205482\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Postsynaptic mechanism not biochemically reconstituted\", \"AT-content dependence mechanism unexplained\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined RAD52's role in second-end capture, answering how the displaced D-loop strand is annealed: RAD52 anneals RPA-coated ssDNA following RAD51-mediated D-loop formation.\",\n      \"evidence\": \"In vitro strand exchange plus second-end capture with purified proteins and recombination-deficient RPA mutant\",\n      \"pmids\": [\"17093500\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coupling to repair synthesis not yet shown\", \"Regulation of capture timing unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved the structural basis of annealing and pathway channeling: a second DNA-binding site enables ternary ssDNA-dsDNA complexes and D-loop formation, while RAD51 filaments inhibit RAD52 annealing in an ATP-dependent manner.\",\n      \"evidence\": \"Structure-based alanine scanning, D-loop/supercoiling assays, ssDNA annealing with RAD51/RAD59\",\n      \"pmids\": [\"18593704\", \"18337252\", \"16565518\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How channeling is regulated in vivo not established\", \"Second-site contribution to in vivo HR untested in some contexts\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Established separation-of-function: the N-terminal DNA-binding domain is needed for second-end capture but not RAD51 delivery; recruitment requires CDK1 and is restrained by Mec1/Tel1 checkpoint kinase, and SUMOylation/phosphorylation regulate activity.\",\n      \"evidence\": \"rad52-R70A mutant biochemistry/ChIP, live-cell imaging with CDK1/Mec1 mutants, SUMOylation assays\",\n      \"pmids\": [\"19812039\", \"19262568\", \"20371517\", \"16707661\", \"19530647\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Site-specific phosphorylation consequences not fully mapped\", \"Interplay between SUMO and phospho regulation unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined RAD52 as an alternative HR mediator and resolved its concentration-dependent ssDNA binding modes underlying annealing.\",\n      \"evidence\": \"BRCA2 synthetic lethality by siRNA with HR/focus readouts; single-molecule FRET with RPA-interaction mutants\",\n      \"pmids\": [\"21148102\", \"20081207\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Therapeutic window of BRCA2-RAD52 synthetic lethality not defined here\", \"Structural basis of mode switching unresolved at the time\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Uncovered RNA-templated repair: RAD52 catalyzes inverse strand exchange using RNA as template and is recruited to breaks via DNA:RNA hybrids to drive transcription-associated HR with XPG, including in post-mitotic neurons.\",\n      \"evidence\": \"In vitro inverse strand exchange with RNA, in vivo RNA-templated repair, RNA-hybrid recruitment and pathway-choice assays\",\n      \"pmids\": [\"28602639\", \"30245011\", \"29217771\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RAD52 discriminates RNA template specificity unclear\", \"In vivo contribution of RNA-templated repair to genome stability not quantified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed RAD52 at the replication fork as a gatekeeper, answering how forks are protected: it limits resection by competing with Sgs1/Rqh1 and prevents excessive SMARCAL1-mediated reversal and MRE11 degradation.\",\n      \"evidence\": \"In vivo resection assays in two yeast species, single-molecule competition, siRNA/inhibitor DNA fiber and fork-binding/SMARCAL1 assays\",\n      \"pmids\": [\"31542296\", \"30926821\", \"27984746\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of fork occlusion not structurally defined\", \"Coordination between resection control and HR initiation unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined RAD52's mitotic and telomeric replication-stress roles: it drives MiDAS at common fragile sites by recruiting MUS81/POLD3 and supports break-induced replication at telomeres independent of RAD51/BRCA2.\",\n      \"evidence\": \"siRNA/CRISPR knockout, EdU MiDAS assays, MUS81/POLD3 recruitment IF, telomere synthesis and BIR assays with R-loop dependency\",\n      \"pmids\": [\"27984745\", \"30692206\", \"31777915\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of selective MUS81/POLD3 recruitment unresolved\", \"How RAD52 is targeted to specific fragile/telomeric loci unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Delivered high-resolution mechanism: cryo-EM and crystallography show open-ring RAD52 (not closed undecamers) drives annealing in a charged channel, with defined ssDNA wrapped/trapped conformations and an RPA2-winged-helix contact at the ring opening.\",\n      \"evidence\": \"Cryo-EM and X-ray structures of RAD52-ssDNA and RAD52-RPA intermediates, biochemical annealing, domain mutagenesis\",\n      \"pmids\": [\"38658755\", \"30428330\", \"37798272\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structures of the RAD51-mediator complex not resolved here\", \"Conformational transitions during second-end capture not visualized\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RAD52's many regulated activities (mediator loading, annealing, fork protection, RNA-templated repair, MiDAS) are coordinated and selected in vivo, and how its modifications integrate to govern pathway choice, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified model of in vivo activity selection\", \"Regulatory integration of SUMO/phospho and partner binding incomplete\", \"Structural basis of the RAD51-loading mediator step undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 8, 9, 13, 16, 20]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [32]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [32]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2, 4, 14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2, 17, 38]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10, 26]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [7, 10, 41]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [1, 14, 17, 29, 33]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [30, 31, 37, 38]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [26, 31, 37]}\n    ],\n    \"complexes\": [\n      \"RAD51-RAD52-RPA presynaptic complex\",\n      \"RAD52-RAD59 complex\",\n      \"PALB2-RAD52 complex\"\n    ],\n    \"partners\": [\n      \"RAD51\",\n      \"RPA\",\n      \"RAD59\",\n      \"POLD3\",\n      \"MUS81\",\n      \"DSS1\",\n      \"XPG\",\n      \"OGG1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}