{"gene":"RAD23B","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1996,"finding":"HHR23B (RAD23B) stimulates XPC protein activity in nucleotide excision repair (NER) in vitro. In a reconstituted repair system lacking endogenous XPC and HHR23B, recombinant XPC alone weakly corrected NER defects, while co-addition of recombinant HHR23B significantly enhanced repair activity for both UV- and N-acetoxy-2-acetylfluorene-induced lesions on naked plasmid and SV40 minichromosomes.","method":"Reconstituted in vitro NER assay with recombinant proteins in fractionated XP-C cell extracts","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro assay with purified recombinant proteins, replicated across multiple DNA substrates and lesion types","pmids":["8756644"],"is_preprint":false},{"year":1997,"finding":"A 56-amino-acid XPC-binding domain in hHR23B (residues covering this region) is both necessary and sufficient for binding XPC and stimulating NER in vitro. The domain has predominantly amphipathic alpha-helical character and binds XPC via hydrophobic interactions.","method":"Deletion mutagenesis, nickel-chelating Sepharose pulldown with His-tagged fragments, in vitro NER stimulation assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — domain mapping by deletion mutagenesis combined with in vitro NER reconstitution, multiple orthogonal methods","pmids":["9372923"],"is_preprint":false},{"year":1997,"finding":"XPC interacts in vivo with both HHR23B and HHR23A via the same conserved region in the C-terminal half of XPC, and an N-terminal region of HHR23B contains the XPC-interaction site. XPC mutants deficient in binding both RAD23 homologs are also highly defective in complementing XPC cells in vivo.","method":"Yeast two-hybrid system, domain mapping","journal":"Mutation research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid with domain mapping, functional correlation in vivo, single lab","pmids":["9164480"],"is_preprint":false},{"year":2000,"finding":"The XPC-HR23B complex interacts with general transcription factor IIH (TFIIH) both in vivo and in vitro, mediated through XPC affinity for TFIIH subunits XPB and/or p62. XPC-HR23B is required for efficient association of TFIIH with damaged DNA in cell-free extracts, establishing its role in recruiting TFIIH to sites of damage in global genome NER.","method":"Co-immunoprecipitation (in vivo and in vitro), cell-free repair reconstitution with XP-C and XP-A extracts","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP in vivo and in vitro, functional reconstitution with complementation extracts showing TFIIH recruitment defect","pmids":["10734143"],"is_preprint":false},{"year":2000,"finding":"Ataxin-3 interacts with the ubiquitin-like (UbL) domain at the N-terminus of HHR23B (and HHR23A). In 293 cells, mutant polyQ-expanded ataxin-3 recruits HHR23A to intranuclear inclusions via this interaction.","method":"Yeast two-hybrid screen, domain interaction mapping, immunofluorescence in transfected cells","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus cell-based localization, single lab, two orthogonal methods","pmids":["10915768"],"is_preprint":false},{"year":2002,"finding":"The XPC-HR23B complex binds damaged DNA with high affinity (KD ~1–3 nM) and high specificity, showing ~30-fold preference for 6,4-photoproducts over cyclobutane dimers. The complex binds with high specificity over undamaged DNA (specificity factor 100–3000).","method":"Fluorescence anisotropy equilibrium binding assay, stoichiometric titration, competition with undamaged/damaged plasmid","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative in vitro binding assay with defined substrates, multiple lesion types tested","pmids":["12022861"],"is_preprint":false},{"year":2003,"finding":"XPC-HR23B induces a bend in DNA upon binding, and this bend is stabilized at the site of damage. DNA bending is proposed as an architectural feature exploited for assembly of subsequent NER complexes.","method":"Scanning force microscopy (SFM) of protein-DNA complexes","journal":"DNA repair","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct visualization by SFM, single lab, single method","pmids":["12547395"],"is_preprint":false},{"year":2003,"finding":"The NMR structure of the UbL domain of hHR23B was determined. The UBA domains of hHR23B bind to ubiquitin at Lys-48, inhibiting multiubiquitin assembly, and an intramolecular UbL-UBA interaction was identified. The UbL domain binds the polyubiquitin-binding site 2 (PUbS2) of proteasome subunit S5a, mimicking ubiquitin.","method":"NMR structure determination, chemical shift perturbation binding mapping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure with functional binding surface mapping via chemical shift perturbation, multiple domain interactions characterized","pmids":["12832454"],"is_preprint":false},{"year":2003,"finding":"Crystal/NMR structure of the ubiquitin-interacting motif (UIM) of proteasome subunit S5a bound to the UbL domain of HR23B was determined, revealing one hydrophobic and two polar contact sites. The UbL domain mimics ubiquitin in binding UIM; a histidine residue in ubiquitin confers pH-dependent binding differences.","method":"NMR structure of UIM:UbL complex, mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural determination with mutagenesis validation, defines molecular basis for proteasome targeting","pmids":["14585839"],"is_preprint":false},{"year":2005,"finding":"Solution NMR structure of the XPC-binding domain (XPCB, residues 275–342) of hHR23B was determined. The domain forms kinked alpha-helices with periodic prolines; the N-terminal region (residues 275–283) is more flexible than the corresponding region of hHR23A, potentially contributing to functional differences between the two paralogs.","method":"NMR structure determination, 15N relaxation backbone dynamics","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with backbone dynamics, single lab","pmids":["15885096"],"is_preprint":false},{"year":2005,"finding":"XPC-hHR23B recognizes psoralen interstrand crosslinks with high affinity and specificity. XPC-hHR23B and XPA-RPA can bind psoralen ICLs simultaneously, forming a multimeric complex on damaged DNA.","method":"Electrophoretic mobility shift assay, simultaneous binding assay with multiple purified NER proteins","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay with purified proteins, simultaneous complex formation demonstrated, single lab","pmids":["15914671"],"is_preprint":false},{"year":2005,"finding":"hHR23B localizes to both nucleus and cytoplasm during G1 phase; nuclear levels decrease during S-phase; during mitosis, hHR23B relocalizes entirely to the cytoplasm without association with chromatin. This distribution is cell cycle dependent.","method":"Immunofluorescence across cell cycle phases","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — immunofluorescence localization across cell cycle, single lab, single method","pmids":["16253613"],"is_preprint":false},{"year":2006,"finding":"XPC-hHR23B displays faster association rate (kon) for cisplatin- and UV-damaged duplex DNA than for undamaged DNA. XPC-hHR23B has high affinity for undamaged single-stranded DNA mainly through a high kon; cisplatin damage on ssDNA reduces binding ~7-fold via effects on both kon and koff. Damage discrimination is driven primarily by structural changes in DNA, not adduct chemistry.","method":"Stopped-flow fluorescence pre-steady-state kinetics","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — pre-steady-state kinetic analysis with stopped-flow, quantitative rate constants determined, single lab","pmids":["16460043"],"is_preprint":false},{"year":2006,"finding":"hHR23A and hHR23B form distinct interactions with proteasomes and multiubiquitinated proteins. Threonine-79 in hHR23A weakens its proteasome binding relative to hHR23B (which has proline at that position); T79P mutation in hHR23A increases proteasome interaction. Both paralogs bind Ataxin-3 similarly but co-purify with unique proteolytic factors in vivo.","method":"Mutagenesis, co-purification from human breast cancer tissue, binding assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with functional binding assay and in vivo co-purification, single lab","pmids":["16712842"],"is_preprint":false},{"year":2006,"finding":"hHR23B is required for genotoxin-induced stabilization and activation of p53. siRNA depletion of hHR23B abrogated accumulation of ubiquitinated p53, attenuated p53/p21/bax induction, and suppressed apoptosis after DNA damage. K48-linked p53-ubiquitin conjugates were specifically induced after genotoxic stress, and hHR23B accumulated with ubiquitinated p53 in chromatin and at the p21 promoter.","method":"siRNA knockdown, chromatin immunoprecipitation, ubiquitin lysine-mutant expression constructs, flow cytometry for apoptosis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (siRNA, ChIP, ubiquitin mutants) in single lab","pmids":["16924240"],"is_preprint":false},{"year":2007,"finding":"XPC/HR23B exhibits distinct helix-opening patterns on three stereoisomeric benzo[a]pyrene-N2-dG lesions, as revealed by permanganate footprinting. The extent of helix opening and overall XPC/HR23B binding correlates with dual incision efficiency by reconstituted NER, demonstrating that lesion stereochemistry determines XPC binding and NER efficiency.","method":"Permanganate footprinting, in vitro NER reconstitution with purified factors, cell-free extract NER","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted NER with purified factors, footprinting, and cell-free extracts all corroborating, single lab with multiple orthogonal methods","pmids":["17525733"],"is_preprint":false},{"year":2007,"finding":"Photocrosslinking assays with damaged DNA substrates demonstrated that XPC is the subunit of XPC-HR23B that directly contacts DNA (both damaged and complementary strands), while Rad23B interaction with DNA is largely indirect via XPC. XPC-Rad23B complex preferentially crosslinks 5' of the cisplatin adduct, suggesting orientation-specific binding.","method":"Photocrosslinking with photoreactive dNMP analogues, denaturing immunoprecipitation of protein-DNA complexes","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — photocrosslinking with purified proteins and site-specific probes, single lab","pmids":["17320292"],"is_preprint":false},{"year":2010,"finding":"HR23B governs the sensitivity of CTCL cells to HDAC inhibitors. HR23B depletion reduces HDAC inhibitor-induced apoptosis, and HDAC inhibitor treatment deregulates proteasome activity through a mechanism dependent on HR23B.","method":"Genome-wide loss-of-function screen, siRNA knockdown, cell death assays in CTCL lines","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide screen plus targeted knockdown with apoptosis readout, single lab","pmids":["20308564"],"is_preprint":false},{"year":2010,"finding":"XPC-Rad23B makes direct contact with both the cisplatin-damaged DNA strand and the complementary undamaged strand. Rad23B's interaction with DNA is largely indirect, mediated through XPC. The complex shows orientation-specific binding, preferentially crosslinking 5' of the cisplatin adduct.","method":"Photo-crosslinking with FAP-dCMP analogue at defined positions, immunoprecipitation after denaturation","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific photocrosslinking with purified complex, defined positional analysis, single lab","pmids":["20028083"],"is_preprint":false},{"year":2013,"finding":"HDAC6 interacts with HR23B and downregulates HR23B protein levels independently of its deacetylase activity, reducing ubiquitinated substrates targeted to the proteasome and desensitizing cells to apoptosis. HSP90 was identified as a key effector mediating HDAC6's effect on HR23B levels.","method":"Co-immunoprecipitation, HDAC6 interactome analysis (MS), overexpression/knockdown with apoptosis/autophagy readouts, deacetylase-inactive mutant","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, interactome analysis, deacetylase mutant, single lab with multiple methods","pmids":["23703321"],"is_preprint":false},{"year":2013,"finding":"Rad23b-null mice are proficient in NER (due to redundancy with Rad23a) but show defective erythropoiesis. The majority of Rad23b-interacting proteins identified by unbiased proteomics are associated with the ubiquitin-proteasome system (UPS). Loss of Rad23b reduces cell proliferation in fibroblasts, causes accumulation of early erythroid progenitors, and blocks erythroid maturation in fetal liver. Proteasome inhibition recapitulates Rad23b loss in erythroid cells.","method":"Knockout mouse model, unbiased proteomics of Rad23b interactors, cell proliferation assays, flow cytometry of erythroid differentiation, siRNA knockdown","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse combined with proteomics, multiple cellular assays and pharmacological validation across labs","pmids":["23897431"],"is_preprint":false},{"year":2015,"finding":"Both XPC and RAD23B subunits of the XPC-RAD23B complex are poly(ADP-ribosyl)ated by PARP1 in vitro. Free PAR competes with DNA for XPC-RAD23B binding in an affinity-dependent manner. The efficiency of PARylation of XPC-RAD23B increases after UV irradiation of DNA substrate.","method":"32P-labeled NAD+ incorporation assay, immunoblotting, competitive binding assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical demonstration of PARylation with multiple methods, single lab","pmids":["26170451"],"is_preprint":false},{"year":2015,"finding":"YB-1 and XPC-HR23B mutually stimulate each other's binding to DNA containing bulky lesions or clustered lesions (bulky lesion plus abasic site), suggesting YB-1 functions as a modulator of NER damage recognition.","method":"Photocrosslinking and binding assays with purified proteins and defined damaged DNA substrates","journal":"Biochemistry (Biokhimiia)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (photocrosslinking/binding), no mutagenesis or in vivo validation","pmids":["25756536"],"is_preprint":false},{"year":2016,"finding":"The dissociation rate (koff) of XPC-RAD23B from damaged DNA inversely correlates with NER efficiency; XPC retention on clustered adducts is much longer than on mono-adducts, making dissociation a rate-limiting step for NER of certain lesions.","method":"Surface plasmon resonance (real-time kinetics), comparison of mono- vs di-AAF-modified substrates","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — quantitative kinetic analysis by SPR, single lab, single method","pmids":["27327897"],"is_preprint":false},{"year":2017,"finding":"PAQR3 directly associates with RAD23B and tethers it to the Golgi apparatus, reducing nuclear RAD23B levels. This reduces the amount of RAD23B available to stabilize XPC, leading to enhanced polyubiquitination and degradation of XPC and diminished NER capacity. Subcellular compartmentation of RAD23B thus controls XPC stability.","method":"Co-immunoprecipitation, subcellular fractionation, ubiquitination assay, siRNA knockdown/overexpression, γ-H2AX immunoblotting for DNA damage","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, fractionation, and functional consequence (XPC degradation, DNA damage) with multiple methods, single lab","pmids":["28473198"],"is_preprint":false},{"year":2018,"finding":"PolyQ-expanded huntingtin and ataxin-3 sequester hHR23B into inclusions through the UBA domains of hHR23B binding conjugated ubiquitin on the aggregated proteins. This sequestration reduces available hHR23B and consequently decreases XPC protein levels.","method":"Cell transfection, immunofluorescence, Western blotting, domain mutant analysis","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — cell-based with domain mutants and functional consequence on XPC, single lab, multiple methods","pmids":["29401586"],"is_preprint":false},{"year":2019,"finding":"Single-molecule imaging revealed that XPC-RAD23B diffuses along DNA via hopping (one-dimensional motion), allowing it to bypass protein obstacles during damage search. XPC-RAD23B makes futile attempts to bind CPDs (consistent with low CPD recognition efficiency) and binds CPDs in biphasic states — stable for lesion recognition and transient for lesion interrogation.","method":"High-throughput single-molecule imaging (DNA curtain assay), diffusion coefficient analysis under varying ionic strengths","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — single-molecule imaging with quantitative analysis, multiple DNA substrates and conditions, mechanistic model validated","pmids":["31372632"],"is_preprint":false},{"year":2020,"finding":"XPC-RAD23B (XPC) competes with the BER glycosylase NEIL1 for binding to hydantoin DNA lesions (spiroiminodihydantoin and 5-guanidinohydantoin). XPC displaces non-covalently bound NEIL1 from these lesions at [XPC]/[NEIL1] ratios >0.2, inhibiting NEIL1 BER activity, with lesion incision only resuming after XPC dissociation.","method":"Competition binding assay with purified proteins, single-turnover NEIL1 incision kinetics in the presence of varying XPC concentrations","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — quantitative kinetic biochemistry with purified proteins, single lab","pmids":["32302101"],"is_preprint":false},{"year":2020,"finding":"Deleting a single cytosine opposite a bulky B[a]P-dG lesion in a 50-mer duplex fully abrogates XPC-RAD23B binding. XPC shows slightly lower affinity (2.5–3.6-fold higher KD) for G*:deletion duplexes than for undamaged G:deletion duplexes — a lesion-avoidance effect attributed to thermodynamic stabilization by base stacking of the B[a]P aromatic ring system preventing DNA distortion required for XPC's BHD2/BHD3 hairpin binding.","method":"Fluorescence binding assay with competitor DNA to determine accurate KD values, structural modeling","journal":"DNA repair","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — quantitative binding assays with defined substrates and competitor DNA, single lab","pmids":["33035795"],"is_preprint":false},{"year":2021,"finding":"PSMD7, a deubiquitinase, directly interacts with RAD23B and prevents its ubiquitination and proteasomal degradation, thereby stabilizing RAD23B and the RAD23B-XPC complex. PSMD7 knockdown enhances ubiquitination and degradation of RAD23B in gastric cancer cells and reduces cisplatin resistance.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, xenograft mouse model","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, in vivo xenograft, single lab, multiple methods","pmids":["34512150"],"is_preprint":false},{"year":2021,"finding":"RAD23B interacts and co-localizes with CORO1C in the cytoplasm of colorectal cancer cells. Overexpression of RAD23B and/or CORO1C increases invadopodia formation and matrix degradation, while RAD23B knockdown suppresses the talin1/2-integrin/FAK/RhoA/Rac1/CORO1C signaling axis and inhibits invasion and metastasis.","method":"Co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown, invasion/migration assays in vitro and xenograft","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with in vitro and in vivo functional validation, single lab","pmids":["34062216"],"is_preprint":false},{"year":2024,"finding":"HDAC6 inhibition releases HR23B from HDAC6 sequestration via the HDAC6 ubiquitin-binding domain, allowing HR23B to shuttle ubiquitinylated cargo to proteasomes. Silencing HDAC6 or HR23B in myeloma cells abolishes the effect of HDAC6 inhibitors on proteasome activity, antigen presentation, and T-cell cytotoxicity.","method":"Pharmacologic HDAC6 domain inhibition, siRNA knockdown, proteasome activity assay, MHC-I antigen presentation assay, T-cell cytotoxicity assay","journal":"Cancer research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacologic and genetic loss-of-function with functional proteasomal and immunological readouts, single lab","pmids":["38747592"],"is_preprint":false},{"year":2024,"finding":"FMNL3 directly interacts with Twist1 and suppresses Twist1 ubiquitin-dependent degradation by inhibiting the interaction between Twist1 and RAD23B, the ubiquitin transfer protein for Twist1, thereby promoting EMT and breast cancer cell invasion.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown/overexpression, invasion assay","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay supporting RAD23B as ubiquitin adaptor for Twist1, single lab","pmids":["39582466"],"is_preprint":false},{"year":2025,"finding":"XPC-RAD23B enhances UV-DDB binding to DNA by forming a UV-DDB/XPC-RAD23B (UX) complex. The UX-complex increases UV-DDB affinity for undamaged DNA and facilitates UV-DDB one-dimensional diffusion along DNA for CPD search. UV-DDB and XPC-RAD23B can bind CPDs as a complex, facilitating lesion transfer.","method":"Biochemical binding assays, single-molecule DNA curtain assay, 1D diffusion analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — single-molecule and biochemical assays with multiple orthogonal methods demonstrating complex formation and functional consequence on damage search","pmids":["40530698"],"is_preprint":false},{"year":2025,"finding":"RAD23B acquires an allosteric H274/H323 copper-binding site in the transition from amphibians to reptiles, enabling it to transfer copper from CTR1 to all known copper metallochaperone pathways while making its canonical DNA repair functions copper-dependent.","method":"Structural and biochemical characterization of copper binding, evolutionary comparative analysis, metabolic and DNA repair functional assays","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structural and biochemical data supporting metalloadaptor function, single study, novel function requiring replication","pmids":["40972527"],"is_preprint":false},{"year":2025,"finding":"OTUD1 deubiquitinase promotes degradation of the RAD23B-XPC complex by cleaving K63-linked ubiquitin chains on RAD23B and XPC and enhancing PRKN-mediated K48-linked ubiquitination, leading to proteasomal degradation. Loss of OTUD1 (via promoter methylation) stabilizes RAD23B-XPC and confers cisplatin resistance in NSCLC.","method":"Co-immunoprecipitation, ubiquitin linkage-specific analysis, overexpression/knockdown, in vitro and in vivo cisplatin sensitivity assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with ubiquitin linkage analysis and functional cisplatin resistance readout, single lab","pmids":["41286308"],"is_preprint":false},{"year":2025,"finding":"Rad23b directly interacts with mutant ataxin-3 (mATXN3), promotes its ubiquitination, and facilitates delivery to the proteasome; however, Rad23b paradoxically disrupts proteasome catalytic activity, preventing mATXN3 degradation and exacerbating aggregate formation. Rad23b knockdown/knockout reduces mATXN3 aggregates and neuronal cell death.","method":"Overexpression and knockdown/knockout functional assays, ubiquitination assay, co-immunoprecipitation, proteasome activity assay, immunohistochemistry in SCA3 transgenic mice","journal":"Neurotherapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays with transgenic mouse validation, single lab","pmids":["42172862"],"is_preprint":false},{"year":2025,"finding":"The EF-hand insertion domain of MINDY3 deubiquitinase specifically binds the UbL domain of RAD23B (and RAD23A), but not other UBL-domain proteins. This interaction mediates MINDY3 recruitment to DNA damage sites. MINDY3 can form a ternary complex with RAD23A/B and polyubiquitin, and may deubiquitylate RAD23A/B-bound clients.","method":"Crystal structure of MINDY3 EF-hand:RAD23A UbL complex, Co-IP in cells, biochemical binding assays, DNA damage localization assay","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — crystal structure with cell-based and biochemical validation, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.07.16.665128"],"is_preprint":true},{"year":2025,"finding":"RAD23B is necessary for the formation of transient aggregate-associated proteasome condensates (TAADs) that co-localize with cytosolic alpha-synuclein aggregates to facilitate their clearance via the ubiquitin-proteasome system.","method":"Quantitative live-cell imaging, siRNA knockdown, proteasome activity assay, proteomics","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, functional imaging assay without detailed mechanistic dissection of RAD23B's specific role","pmids":["bio_10.1101_2025.09.15.676044"],"is_preprint":true},{"year":2025,"finding":"Rad23B inhibits Ataxin-3 droplet maturation (liquid-to-solid phase transition) through heterotypic interactions but does not inhibit amyloid formation under dilute conditions, suggesting aggregation via misfolding is distinct from condensation pathway.","method":"In vitro LLPS assay, Thioflavin-T binding, co-incubation of purified proteins","journal":"Journal of molecular biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — in vitro LLPS assay with purified proteins, single lab, single method, limited mechanistic detail in abstract","pmids":["40684934"],"is_preprint":false}],"current_model":"RAD23B functions as a multidomain adaptor protein that (1) stabilizes XPC and stimulates damage recognition in global genome nucleotide excision repair by forming a tight complex with XPC, recruiting TFIIH to damaged DNA via XPC–XPB/p62 contacts, and enabling high-affinity, specificity-driven DNA lesion binding through hopping-based 1D diffusion; (2) serves as a ubiquitin-proteasome shuttling factor by presenting ubiquitinated substrates to the 26S proteasome via its N-terminal UbL domain interacting with S5a/PSMD4, while its UBA domains bind and inhibit polyubiquitin assembly; (3) is itself regulated by post-translational modifications including PARP1-mediated PARylation (reducing DNA binding), PSMD7-mediated deubiquitination (stabilization), and OTUD1-dependent ubiquitin chain editing (promoting degradation); and (4) its subcellular localization (nuclear vs. cytoplasmic/Golgi) is spatially controlled by interactors such as PAQR3 and HDAC6, which modulate XPC stability, proteasome activity, and cellular responses to genotoxic and HDAC inhibitor treatments."},"narrative":{"mechanistic_narrative":"RAD23B is a multidomain adaptor that bridges global-genome nucleotide excision repair (NER) and the ubiquitin-proteasome system [PMID:8756644, PMID:23897431]. In NER, it forms a tight complex with XPC, stimulating XPC-dependent damage recognition through a 56-residue amphipathic XPC-binding domain that is necessary and sufficient for both binding and repair stimulation [PMID:9372923, PMID:15885096]. The XPC-RAD23B complex binds diverse bulky and helix-distorting lesions with nanomolar affinity and high specificity over undamaged DNA, with damage discrimination driven primarily by DNA structural distortion rather than adduct chemistry [PMID:12022861, PMID:16460043, PMID:17525733]; within the complex XPC makes the direct DNA contacts while RAD23B interacts with DNA largely indirectly [PMID:17320292]. Recognition proceeds through hopping-based one-dimensional diffusion that allows lesion search and interrogation [PMID:31372632], with dissociation kinetics being rate-limiting for repair of certain lesions [PMID:27327897], and the complex recruits TFIIH to damaged DNA via XPC contacts with XPB/p62 to nucleate downstream repair assembly [PMID:10734143]. In its second role, RAD23B acts as a proteasome shuttle factor: its N-terminal ubiquitin-like (UbL) domain mimics ubiquitin to bind the proteasome subunit S5a, while its UBA domains engage K48-linked polyubiquitin and inhibit chain extension, with an intramolecular UbL-UBA interaction modulating these contacts [PMID:12832454, PMID:14585839]. Consistent with this, the majority of RAD23B interactors are ubiquitin-proteasome components, and loss of Rad23b in mice impairs erythropoiesis through a proteasome-dependent mechanism while NER remains intact owing to redundancy with Rad23a [PMID:23897431]. RAD23B levels and activity are tuned by post-translational and spatial control: PARP1 PARylates the complex to reduce DNA binding [PMID:26170451], PSMD7 stabilizes RAD23B by preventing its degradation [PMID:34512150], OTUD1 directs RAD23B-XPC for proteasomal degradation through ubiquitin-chain editing [PMID:41286308], and the localization regulators PAQR3 and HDAC6 sequester RAD23B at the Golgi or cytoplasm to limit XPC stabilization and proteasome cargo shuttling [PMID:28473198, PMID:23703321, PMID:38747592]. RAD23B also engages polyglutamine disease proteins, binding ataxin-3 via its UbL domain and being sequestered into polyQ inclusions through its UBA domains, linking it to substrate handling in neurodegeneration [PMID:10915768, PMID:29401586]. Beyond these core roles, individual studies implicate RAD23B in p53 stabilization after genotoxic stress, cancer-cell invasion via CORO1C, and a vertebrate-derived copper-binding metalloadaptor function [PMID:16924240, PMID:34062216, PMID:40972527].","teleology":[{"year":1996,"claim":"Established that RAD23B is a functional cofactor of XPC rather than an isolated repair factor, defining its primary role in stimulating global-genome NER.","evidence":"Reconstituted in vitro NER assay with recombinant proteins in fractionated XP-C extracts across multiple lesion types","pmids":["8756644"],"confidence":"High","gaps":["Did not map the interaction interface","In vitro stimulation did not address in vivo requirement given Rad23a redundancy"]},{"year":1997,"claim":"Mapped the molecular basis of the XPC interaction, showing a discrete amphipathic helical domain is necessary and sufficient for XPC binding and NER stimulation.","evidence":"Deletion mutagenesis, His-tagged pulldowns, in vitro NER stimulation, and yeast two-hybrid domain mapping","pmids":["9372923","9164480"],"confidence":"High","gaps":["Two-hybrid functional correlation was indirect","Did not resolve how the domain stabilizes XPC"]},{"year":2000,"claim":"Connected the XPC-RAD23B complex to downstream repair assembly by showing it recruits TFIIH to damaged DNA, and identified UbL binding to disease protein ataxin-3.","evidence":"Reciprocal Co-IP and cell-free reconstitution showing TFIIH recruitment defect; yeast two-hybrid plus immunofluorescence for ataxin-3","pmids":["10734143","10915768"],"confidence":"High","gaps":["TFIIH contact attributed to XPC, not RAD23B directly","Ataxin-3 interaction functional consequence not established at this stage"]},{"year":2002,"claim":"Quantified the affinity and specificity of damage recognition, demonstrating lesion preference and strong discrimination against undamaged DNA.","evidence":"Fluorescence anisotropy equilibrium binding and competition with defined damaged substrates","pmids":["12022861"],"confidence":"High","gaps":["Did not resolve whether specificity arises from chemistry or DNA distortion","Kinetic basis of discrimination not addressed"]},{"year":2003,"claim":"Defined the structural and proteasome-targeting roles of the UbL/UBA domains, showing UbL mimics ubiquitin to bind S5a while UBA inhibits chain assembly.","evidence":"NMR structures of UbL and UIM:UbL complexes with chemical-shift and mutagenesis mapping; SFM of DNA bending","pmids":["12832454","14585839","12547395"],"confidence":"High","gaps":["Did not connect proteasome shuttling to specific in vivo substrates","DNA bending role inferred, not functionally tested"]},{"year":2006,"claim":"Resolved damage discrimination kinetics and began distinguishing paralog-specific proteasome behavior and a role in damage-induced p53 stabilization.","evidence":"Stopped-flow pre-steady-state kinetics; paralog mutagenesis and co-purification; siRNA, ChIP and ubiquitin-mutant analysis of p53","pmids":["16460043","16712842","16924240"],"confidence":"Medium","gaps":["p53 role from single lab without reciprocal validation","Mechanism linking RAD23B to p53 ubiquitin accumulation unresolved"]},{"year":2007,"claim":"Established that lesion stereochemistry and helix-opening govern XPC-RAD23B binding and NER efficiency, and showed XPC is the direct DNA-contacting subunit.","evidence":"Permanganate footprinting with reconstituted NER; site-specific photocrosslinking with denaturing IP","pmids":["17525733","17320292"],"confidence":"High","gaps":["RAD23B's contribution to DNA contact remained indirect/unclear","Orientation specificity mechanism not structurally resolved"]},{"year":2013,"claim":"Demonstrated an in vivo proteasome-shuttling role distinct from NER, with the Rad23b interactome dominated by UPS components and erythropoiesis defects upon loss.","evidence":"Rad23b-null mouse with unbiased interactor proteomics, erythroid differentiation flow cytometry, and proteasome inhibition; HDAC6 Co-IP and interactome","pmids":["23897431","23703321"],"confidence":"High","gaps":["Specific ubiquitinated cargoes in erythropoiesis not identified","HDAC6 regulation deacetylase-independent mechanism only partly defined"]},{"year":2015,"claim":"Identified PARylation as a post-translational regulator of DNA binding, with PAR competing with DNA for the complex.","evidence":"32P-NAD+ incorporation, immunoblotting, and competitive binding assays","pmids":["26170451"],"confidence":"Medium","gaps":["In vivo relevance of PARylation not established","Single-lab biochemistry without structural mapping of modified sites"]},{"year":2017,"claim":"Showed that subcellular compartmentation controls function: Golgi tethering by PAQR3 sequesters RAD23B and destabilizes XPC, reducing NER capacity.","evidence":"Co-IP, subcellular fractionation, ubiquitination and γ-H2AX assays with knockdown/overexpression","pmids":["28473198"],"confidence":"Medium","gaps":["Single lab","Physiological trigger for PAQR3-mediated sequestration unknown"]},{"year":2019,"claim":"Defined the search mechanism of XPC-RAD23B at single-molecule resolution, showing hopping-based 1D diffusion and biphasic lesion interrogation.","evidence":"High-throughput DNA curtain single-molecule imaging with diffusion analysis","pmids":["31372632"],"confidence":"High","gaps":["RAD23B-specific contribution to diffusion not isolated","Did not address handoff to downstream factors"]},{"year":2020,"claim":"Refined lesion-recognition rules by demonstrating competition with base-excision repair and a lesion-avoidance effect for stably stacked adducts.","evidence":"Competition binding with NEIL1 and single-turnover kinetics; fluorescence KD measurement with structural modeling; SPR koff analysis","pmids":["32302101","33035795","27327897"],"confidence":"Medium","gaps":["In vivo pathway competition with BER not tested","Structural models not experimentally validated"]},{"year":2021,"claim":"Established RAD23B as a regulated node in cancer through stabilization by PSMD7 and as an adaptor in invasion signaling via CORO1C.","evidence":"Co-IP, ubiquitination assays, knockdown, and xenografts in gastric and colorectal cancer models","pmids":["34512150","34062216"],"confidence":"Medium","gaps":["Direct deubiquitination of RAD23B by PSMD7 not biochemically reconstituted","CORO1C axis mechanism is correlative"]},{"year":2024,"claim":"Extended the HDAC6 axis and adaptor function, showing HDAC6-inhibitor-released RAD23B shuttles cargo affecting antigen presentation, and RAD23B serves as the ubiquitin adaptor for Twist1.","evidence":"Pharmacologic HDAC6 domain inhibition with proteasome, antigen-presentation and T-cell assays; Co-IP and ubiquitination assays for Twist1","pmids":["38747592","39582466"],"confidence":"Medium","gaps":["Direct cargo identity in immune context incompletely defined","Twist1 adaptor role from single lab"]},{"year":2025,"claim":"Diversified the functional landscape with new partners (UV-DDB handoff, MINDY3, OTUD1), a copper-binding metalloadaptor function, and roles in aggregate clearance and phase separation.","evidence":"Single-molecule and biochemical UX-complex assays; crystal structure of MINDY3 UbL complex (preprint); ubiquitin-linkage analysis for OTUD1; structural/biochemical copper-binding and evolutionary analysis; live-cell imaging and LLPS assays","pmids":["40530698","bio_10.1101_2025.07.16.665128","41286308","40972527","42172862","bio_10.1101_2025.09.15.676044","40684934"],"confidence":"Medium","gaps":["Copper metalloadaptor function is a single novel study requiring replication","Phase-separation and condensate roles are preprint/low-confidence","Integration of new partners into a unified regulatory model incomplete"]},{"year":null,"claim":"How RAD23B's two functions — NER damage recognition and proteasomal substrate shuttling — are coordinated within a cell, and which determinants partition it between these roles, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking spatial regulation, PTMs, and substrate choice","RAD23B-specific in vivo proteasome substrates largely unidentified","Physiological relevance of copper-binding and phase-separation functions in humans untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,3,7,8,20]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[5,12,16,26]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,8,29]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[11,14,24]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[11,19,30]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[24]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0,1,3,5,15,26]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[7,8,20,29,35]}],"complexes":["XPC-RAD23B complex","UV-DDB/XPC-RAD23B (UX) complex"],"partners":["XPC","TFIIH","PSMD4","PAQR3","HDAC6","PSMD7","OTUD1","ATXN3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P54727","full_name":"Lysine-specific demethylase RAD23B","aliases":["UV excision repair protein RAD23 homolog B","HR23B","hHR23B","XP-C repair-complementing complex 58 kDa protein","p58"],"length_aa":409,"mass_kda":43.2,"function":"Multifunctional protein that participates in histone H4K20 demethylation, DNA repair, ubiquitin-dependent protein degradation and transcriptional regulation (PubMed:10488153, PubMed:32209475, PubMed:9372924). Specifically demethylates mono-, di- and trimethylated 'Lys-20' of histone H4 (H4K20me1, H4K20me2, H4K20me3, respectively) into unmethylated forms. Activates the transcription of coding genes by demethylating H4K20me1 and the transcription of repetitive elements by demethylating H4K20me3 (PubMed:32209475). Multiubiquitin chain receptor involved in modulation of proteasomal degradation. Binds to polyubiquitin chains. Proposed to be capable to bind simultaneously to the 26S proteasome and to polyubiquitinated substrates and to deliver ubiquitinated proteins to the proteasome (PubMed:10488153, PubMed:19435460). May play a role in endoplasmic reticulum-associated degradation (ERAD) of misfolded glycoproteins by association with PNGase and delivering deglycosylated proteins to the proteasome (PubMed:15358861). Involved in global genome nucleotide excision repair (GG-NER) by acting as component of the XPC complex, a nucleotide-excision repair complex that is involved in damage sensing during global genome nucleotide excision repair. In vitro, the XPC:RAD23B dimer is sufficient to initiate NER; it preferentially binds to cisplatin and UV-damaged double-stranded DNA. Recognizes a wide spectrum of damaged DNA characterized by distortions of the DNA helix including single-stranded loops, mismatched bubbles or single-stranded overhangs. Cooperatively with CETN2 appears to stabilize XPC (PubMed:10873465, PubMed:12815074, PubMed:9372924)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P54727/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RAD23B","classification":"Not Classified","n_dependent_lines":48,"n_total_lines":1208,"dependency_fraction":0.039735099337748346},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CDK7","stoichiometry":10.0},{"gene":"CETN2","stoichiometry":10.0},{"gene":"CBX1","stoichiometry":0.2},{"gene":"CDC7","stoichiometry":0.2},{"gene":"PSMC2","stoichiometry":0.2},{"gene":"PSMC4","stoichiometry":0.2},{"gene":"PSMD3","stoichiometry":0.2},{"gene":"SEM1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/RAD23B","total_profiled":1310},"omim":[{"mim_id":"613984","title":"FANCD2 GENE; FANCD2","url":"https://www.omim.org/entry/613984"},{"mim_id":"611153","title":"XPA, DNA DAMAGE RECOGNITION AND REPAIR FACTOR; XPA","url":"https://www.omim.org/entry/611153"},{"mim_id":"608780","title":"GENERAL TRANSCRIPTION FACTOR IIH, POLYPEPTIDE 5; GTF2H5","url":"https://www.omim.org/entry/608780"},{"mim_id":"607047","title":"ATAXIN 3; ATXN3","url":"https://www.omim.org/entry/607047"},{"mim_id":"601023","title":"VALOSIN-CONTAINING PROTEIN; VCP","url":"https://www.omim.org/entry/601023"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RAD23B"},"hgnc":{"alias_symbol":["HHR23B","P58","HR23B"],"prev_symbol":[]},"alphafold":{"accession":"P54727","domains":[{"cath_id":"3.10.20.90","chopping":"1-73","consensus_level":"high","plddt":88.0179,"start":1,"end":73},{"cath_id":"1.10.8.10","chopping":"186-234","consensus_level":"high","plddt":82.8208,"start":186,"end":234},{"cath_id":"1.10.10.540","chopping":"276-328","consensus_level":"high","plddt":82.8877,"start":276,"end":328},{"cath_id":"1.10.8.10","chopping":"363-404","consensus_level":"high","plddt":87.064,"start":363,"end":404}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P54727","model_url":"https://alphafold.ebi.ac.uk/files/AF-P54727-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P54727-F1-predicted_aligned_error_v6.png","plddt_mean":67.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RAD23B","jax_strain_url":"https://www.jax.org/strain/search?query=RAD23B"},"sequence":{"accession":"P54727","fasta_url":"https://rest.uniprot.org/uniprotkb/P54727.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P54727/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P54727"}},"corpus_meta":[{"pmid":"10734143","id":"PMC_10734143","title":"The 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In a reconstituted repair system lacking endogenous XPC and HHR23B, recombinant XPC alone weakly corrected NER defects, while co-addition of recombinant HHR23B significantly enhanced repair activity for both UV- and N-acetoxy-2-acetylfluorene-induced lesions on naked plasmid and SV40 minichromosomes.\",\n      \"method\": \"Reconstituted in vitro NER assay with recombinant proteins in fractionated XP-C cell extracts\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro assay with purified recombinant proteins, replicated across multiple DNA substrates and lesion types\",\n      \"pmids\": [\"8756644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"A 56-amino-acid XPC-binding domain in hHR23B (residues covering this region) is both necessary and sufficient for binding XPC and stimulating NER in vitro. The domain has predominantly amphipathic alpha-helical character and binds XPC via hydrophobic interactions.\",\n      \"method\": \"Deletion mutagenesis, nickel-chelating Sepharose pulldown with His-tagged fragments, in vitro NER stimulation assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — domain mapping by deletion mutagenesis combined with in vitro NER reconstitution, multiple orthogonal methods\",\n      \"pmids\": [\"9372923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"XPC interacts in vivo with both HHR23B and HHR23A via the same conserved region in the C-terminal half of XPC, and an N-terminal region of HHR23B contains the XPC-interaction site. XPC mutants deficient in binding both RAD23 homologs are also highly defective in complementing XPC cells in vivo.\",\n      \"method\": \"Yeast two-hybrid system, domain mapping\",\n      \"journal\": \"Mutation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid with domain mapping, functional correlation in vivo, single lab\",\n      \"pmids\": [\"9164480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The XPC-HR23B complex interacts with general transcription factor IIH (TFIIH) both in vivo and in vitro, mediated through XPC affinity for TFIIH subunits XPB and/or p62. XPC-HR23B is required for efficient association of TFIIH with damaged DNA in cell-free extracts, establishing its role in recruiting TFIIH to sites of damage in global genome NER.\",\n      \"method\": \"Co-immunoprecipitation (in vivo and in vitro), cell-free repair reconstitution with XP-C and XP-A extracts\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP in vivo and in vitro, functional reconstitution with complementation extracts showing TFIIH recruitment defect\",\n      \"pmids\": [\"10734143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Ataxin-3 interacts with the ubiquitin-like (UbL) domain at the N-terminus of HHR23B (and HHR23A). In 293 cells, mutant polyQ-expanded ataxin-3 recruits HHR23A to intranuclear inclusions via this interaction.\",\n      \"method\": \"Yeast two-hybrid screen, domain interaction mapping, immunofluorescence in transfected cells\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus cell-based localization, single lab, two orthogonal methods\",\n      \"pmids\": [\"10915768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The XPC-HR23B complex binds damaged DNA with high affinity (KD ~1–3 nM) and high specificity, showing ~30-fold preference for 6,4-photoproducts over cyclobutane dimers. The complex binds with high specificity over undamaged DNA (specificity factor 100–3000).\",\n      \"method\": \"Fluorescence anisotropy equilibrium binding assay, stoichiometric titration, competition with undamaged/damaged plasmid\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative in vitro binding assay with defined substrates, multiple lesion types tested\",\n      \"pmids\": [\"12022861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"XPC-HR23B induces a bend in DNA upon binding, and this bend is stabilized at the site of damage. DNA bending is proposed as an architectural feature exploited for assembly of subsequent NER complexes.\",\n      \"method\": \"Scanning force microscopy (SFM) of protein-DNA complexes\",\n      \"journal\": \"DNA repair\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct visualization by SFM, single lab, single method\",\n      \"pmids\": [\"12547395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The NMR structure of the UbL domain of hHR23B was determined. The UBA domains of hHR23B bind to ubiquitin at Lys-48, inhibiting multiubiquitin assembly, and an intramolecular UbL-UBA interaction was identified. The UbL domain binds the polyubiquitin-binding site 2 (PUbS2) of proteasome subunit S5a, mimicking ubiquitin.\",\n      \"method\": \"NMR structure determination, chemical shift perturbation binding mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure with functional binding surface mapping via chemical shift perturbation, multiple domain interactions characterized\",\n      \"pmids\": [\"12832454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Crystal/NMR structure of the ubiquitin-interacting motif (UIM) of proteasome subunit S5a bound to the UbL domain of HR23B was determined, revealing one hydrophobic and two polar contact sites. The UbL domain mimics ubiquitin in binding UIM; a histidine residue in ubiquitin confers pH-dependent binding differences.\",\n      \"method\": \"NMR structure of UIM:UbL complex, mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural determination with mutagenesis validation, defines molecular basis for proteasome targeting\",\n      \"pmids\": [\"14585839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Solution NMR structure of the XPC-binding domain (XPCB, residues 275–342) of hHR23B was determined. The domain forms kinked alpha-helices with periodic prolines; the N-terminal region (residues 275–283) is more flexible than the corresponding region of hHR23A, potentially contributing to functional differences between the two paralogs.\",\n      \"method\": \"NMR structure determination, 15N relaxation backbone dynamics\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with backbone dynamics, single lab\",\n      \"pmids\": [\"15885096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"XPC-hHR23B recognizes psoralen interstrand crosslinks with high affinity and specificity. XPC-hHR23B and XPA-RPA can bind psoralen ICLs simultaneously, forming a multimeric complex on damaged DNA.\",\n      \"method\": \"Electrophoretic mobility shift assay, simultaneous binding assay with multiple purified NER proteins\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay with purified proteins, simultaneous complex formation demonstrated, single lab\",\n      \"pmids\": [\"15914671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"hHR23B localizes to both nucleus and cytoplasm during G1 phase; nuclear levels decrease during S-phase; during mitosis, hHR23B relocalizes entirely to the cytoplasm without association with chromatin. This distribution is cell cycle dependent.\",\n      \"method\": \"Immunofluorescence across cell cycle phases\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — immunofluorescence localization across cell cycle, single lab, single method\",\n      \"pmids\": [\"16253613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"XPC-hHR23B displays faster association rate (kon) for cisplatin- and UV-damaged duplex DNA than for undamaged DNA. XPC-hHR23B has high affinity for undamaged single-stranded DNA mainly through a high kon; cisplatin damage on ssDNA reduces binding ~7-fold via effects on both kon and koff. Damage discrimination is driven primarily by structural changes in DNA, not adduct chemistry.\",\n      \"method\": \"Stopped-flow fluorescence pre-steady-state kinetics\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — pre-steady-state kinetic analysis with stopped-flow, quantitative rate constants determined, single lab\",\n      \"pmids\": [\"16460043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"hHR23A and hHR23B form distinct interactions with proteasomes and multiubiquitinated proteins. Threonine-79 in hHR23A weakens its proteasome binding relative to hHR23B (which has proline at that position); T79P mutation in hHR23A increases proteasome interaction. Both paralogs bind Ataxin-3 similarly but co-purify with unique proteolytic factors in vivo.\",\n      \"method\": \"Mutagenesis, co-purification from human breast cancer tissue, binding assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with functional binding assay and in vivo co-purification, single lab\",\n      \"pmids\": [\"16712842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"hHR23B is required for genotoxin-induced stabilization and activation of p53. siRNA depletion of hHR23B abrogated accumulation of ubiquitinated p53, attenuated p53/p21/bax induction, and suppressed apoptosis after DNA damage. K48-linked p53-ubiquitin conjugates were specifically induced after genotoxic stress, and hHR23B accumulated with ubiquitinated p53 in chromatin and at the p21 promoter.\",\n      \"method\": \"siRNA knockdown, chromatin immunoprecipitation, ubiquitin lysine-mutant expression constructs, flow cytometry for apoptosis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (siRNA, ChIP, ubiquitin mutants) in single lab\",\n      \"pmids\": [\"16924240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"XPC/HR23B exhibits distinct helix-opening patterns on three stereoisomeric benzo[a]pyrene-N2-dG lesions, as revealed by permanganate footprinting. The extent of helix opening and overall XPC/HR23B binding correlates with dual incision efficiency by reconstituted NER, demonstrating that lesion stereochemistry determines XPC binding and NER efficiency.\",\n      \"method\": \"Permanganate footprinting, in vitro NER reconstitution with purified factors, cell-free extract NER\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted NER with purified factors, footprinting, and cell-free extracts all corroborating, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"17525733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Photocrosslinking assays with damaged DNA substrates demonstrated that XPC is the subunit of XPC-HR23B that directly contacts DNA (both damaged and complementary strands), while Rad23B interaction with DNA is largely indirect via XPC. XPC-Rad23B complex preferentially crosslinks 5' of the cisplatin adduct, suggesting orientation-specific binding.\",\n      \"method\": \"Photocrosslinking with photoreactive dNMP analogues, denaturing immunoprecipitation of protein-DNA complexes\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — photocrosslinking with purified proteins and site-specific probes, single lab\",\n      \"pmids\": [\"17320292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"HR23B governs the sensitivity of CTCL cells to HDAC inhibitors. HR23B depletion reduces HDAC inhibitor-induced apoptosis, and HDAC inhibitor treatment deregulates proteasome activity through a mechanism dependent on HR23B.\",\n      \"method\": \"Genome-wide loss-of-function screen, siRNA knockdown, cell death assays in CTCL lines\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide screen plus targeted knockdown with apoptosis readout, single lab\",\n      \"pmids\": [\"20308564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"XPC-Rad23B makes direct contact with both the cisplatin-damaged DNA strand and the complementary undamaged strand. Rad23B's interaction with DNA is largely indirect, mediated through XPC. The complex shows orientation-specific binding, preferentially crosslinking 5' of the cisplatin adduct.\",\n      \"method\": \"Photo-crosslinking with FAP-dCMP analogue at defined positions, immunoprecipitation after denaturation\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific photocrosslinking with purified complex, defined positional analysis, single lab\",\n      \"pmids\": [\"20028083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HDAC6 interacts with HR23B and downregulates HR23B protein levels independently of its deacetylase activity, reducing ubiquitinated substrates targeted to the proteasome and desensitizing cells to apoptosis. HSP90 was identified as a key effector mediating HDAC6's effect on HR23B levels.\",\n      \"method\": \"Co-immunoprecipitation, HDAC6 interactome analysis (MS), overexpression/knockdown with apoptosis/autophagy readouts, deacetylase-inactive mutant\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, interactome analysis, deacetylase mutant, single lab with multiple methods\",\n      \"pmids\": [\"23703321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Rad23b-null mice are proficient in NER (due to redundancy with Rad23a) but show defective erythropoiesis. The majority of Rad23b-interacting proteins identified by unbiased proteomics are associated with the ubiquitin-proteasome system (UPS). Loss of Rad23b reduces cell proliferation in fibroblasts, causes accumulation of early erythroid progenitors, and blocks erythroid maturation in fetal liver. Proteasome inhibition recapitulates Rad23b loss in erythroid cells.\",\n      \"method\": \"Knockout mouse model, unbiased proteomics of Rad23b interactors, cell proliferation assays, flow cytometry of erythroid differentiation, siRNA knockdown\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse combined with proteomics, multiple cellular assays and pharmacological validation across labs\",\n      \"pmids\": [\"23897431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Both XPC and RAD23B subunits of the XPC-RAD23B complex are poly(ADP-ribosyl)ated by PARP1 in vitro. Free PAR competes with DNA for XPC-RAD23B binding in an affinity-dependent manner. The efficiency of PARylation of XPC-RAD23B increases after UV irradiation of DNA substrate.\",\n      \"method\": \"32P-labeled NAD+ incorporation assay, immunoblotting, competitive binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical demonstration of PARylation with multiple methods, single lab\",\n      \"pmids\": [\"26170451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"YB-1 and XPC-HR23B mutually stimulate each other's binding to DNA containing bulky lesions or clustered lesions (bulky lesion plus abasic site), suggesting YB-1 functions as a modulator of NER damage recognition.\",\n      \"method\": \"Photocrosslinking and binding assays with purified proteins and defined damaged DNA substrates\",\n      \"journal\": \"Biochemistry (Biokhimiia)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (photocrosslinking/binding), no mutagenesis or in vivo validation\",\n      \"pmids\": [\"25756536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The dissociation rate (koff) of XPC-RAD23B from damaged DNA inversely correlates with NER efficiency; XPC retention on clustered adducts is much longer than on mono-adducts, making dissociation a rate-limiting step for NER of certain lesions.\",\n      \"method\": \"Surface plasmon resonance (real-time kinetics), comparison of mono- vs di-AAF-modified substrates\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative kinetic analysis by SPR, single lab, single method\",\n      \"pmids\": [\"27327897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PAQR3 directly associates with RAD23B and tethers it to the Golgi apparatus, reducing nuclear RAD23B levels. This reduces the amount of RAD23B available to stabilize XPC, leading to enhanced polyubiquitination and degradation of XPC and diminished NER capacity. Subcellular compartmentation of RAD23B thus controls XPC stability.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, ubiquitination assay, siRNA knockdown/overexpression, γ-H2AX immunoblotting for DNA damage\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, fractionation, and functional consequence (XPC degradation, DNA damage) with multiple methods, single lab\",\n      \"pmids\": [\"28473198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PolyQ-expanded huntingtin and ataxin-3 sequester hHR23B into inclusions through the UBA domains of hHR23B binding conjugated ubiquitin on the aggregated proteins. This sequestration reduces available hHR23B and consequently decreases XPC protein levels.\",\n      \"method\": \"Cell transfection, immunofluorescence, Western blotting, domain mutant analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — cell-based with domain mutants and functional consequence on XPC, single lab, multiple methods\",\n      \"pmids\": [\"29401586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Single-molecule imaging revealed that XPC-RAD23B diffuses along DNA via hopping (one-dimensional motion), allowing it to bypass protein obstacles during damage search. XPC-RAD23B makes futile attempts to bind CPDs (consistent with low CPD recognition efficiency) and binds CPDs in biphasic states — stable for lesion recognition and transient for lesion interrogation.\",\n      \"method\": \"High-throughput single-molecule imaging (DNA curtain assay), diffusion coefficient analysis under varying ionic strengths\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — single-molecule imaging with quantitative analysis, multiple DNA substrates and conditions, mechanistic model validated\",\n      \"pmids\": [\"31372632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"XPC-RAD23B (XPC) competes with the BER glycosylase NEIL1 for binding to hydantoin DNA lesions (spiroiminodihydantoin and 5-guanidinohydantoin). XPC displaces non-covalently bound NEIL1 from these lesions at [XPC]/[NEIL1] ratios >0.2, inhibiting NEIL1 BER activity, with lesion incision only resuming after XPC dissociation.\",\n      \"method\": \"Competition binding assay with purified proteins, single-turnover NEIL1 incision kinetics in the presence of varying XPC concentrations\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative kinetic biochemistry with purified proteins, single lab\",\n      \"pmids\": [\"32302101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Deleting a single cytosine opposite a bulky B[a]P-dG lesion in a 50-mer duplex fully abrogates XPC-RAD23B binding. XPC shows slightly lower affinity (2.5–3.6-fold higher KD) for G*:deletion duplexes than for undamaged G:deletion duplexes — a lesion-avoidance effect attributed to thermodynamic stabilization by base stacking of the B[a]P aromatic ring system preventing DNA distortion required for XPC's BHD2/BHD3 hairpin binding.\",\n      \"method\": \"Fluorescence binding assay with competitor DNA to determine accurate KD values, structural modeling\",\n      \"journal\": \"DNA repair\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative binding assays with defined substrates and competitor DNA, single lab\",\n      \"pmids\": [\"33035795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PSMD7, a deubiquitinase, directly interacts with RAD23B and prevents its ubiquitination and proteasomal degradation, thereby stabilizing RAD23B and the RAD23B-XPC complex. PSMD7 knockdown enhances ubiquitination and degradation of RAD23B in gastric cancer cells and reduces cisplatin resistance.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, xenograft mouse model\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, in vivo xenograft, single lab, multiple methods\",\n      \"pmids\": [\"34512150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RAD23B interacts and co-localizes with CORO1C in the cytoplasm of colorectal cancer cells. Overexpression of RAD23B and/or CORO1C increases invadopodia formation and matrix degradation, while RAD23B knockdown suppresses the talin1/2-integrin/FAK/RhoA/Rac1/CORO1C signaling axis and inhibits invasion and metastasis.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown, invasion/migration assays in vitro and xenograft\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with in vitro and in vivo functional validation, single lab\",\n      \"pmids\": [\"34062216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HDAC6 inhibition releases HR23B from HDAC6 sequestration via the HDAC6 ubiquitin-binding domain, allowing HR23B to shuttle ubiquitinylated cargo to proteasomes. Silencing HDAC6 or HR23B in myeloma cells abolishes the effect of HDAC6 inhibitors on proteasome activity, antigen presentation, and T-cell cytotoxicity.\",\n      \"method\": \"Pharmacologic HDAC6 domain inhibition, siRNA knockdown, proteasome activity assay, MHC-I antigen presentation assay, T-cell cytotoxicity assay\",\n      \"journal\": \"Cancer research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacologic and genetic loss-of-function with functional proteasomal and immunological readouts, single lab\",\n      \"pmids\": [\"38747592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FMNL3 directly interacts with Twist1 and suppresses Twist1 ubiquitin-dependent degradation by inhibiting the interaction between Twist1 and RAD23B, the ubiquitin transfer protein for Twist1, thereby promoting EMT and breast cancer cell invasion.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown/overexpression, invasion assay\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay supporting RAD23B as ubiquitin adaptor for Twist1, single lab\",\n      \"pmids\": [\"39582466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"XPC-RAD23B enhances UV-DDB binding to DNA by forming a UV-DDB/XPC-RAD23B (UX) complex. The UX-complex increases UV-DDB affinity for undamaged DNA and facilitates UV-DDB one-dimensional diffusion along DNA for CPD search. UV-DDB and XPC-RAD23B can bind CPDs as a complex, facilitating lesion transfer.\",\n      \"method\": \"Biochemical binding assays, single-molecule DNA curtain assay, 1D diffusion analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — single-molecule and biochemical assays with multiple orthogonal methods demonstrating complex formation and functional consequence on damage search\",\n      \"pmids\": [\"40530698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RAD23B acquires an allosteric H274/H323 copper-binding site in the transition from amphibians to reptiles, enabling it to transfer copper from CTR1 to all known copper metallochaperone pathways while making its canonical DNA repair functions copper-dependent.\",\n      \"method\": \"Structural and biochemical characterization of copper binding, evolutionary comparative analysis, metabolic and DNA repair functional assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structural and biochemical data supporting metalloadaptor function, single study, novel function requiring replication\",\n      \"pmids\": [\"40972527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OTUD1 deubiquitinase promotes degradation of the RAD23B-XPC complex by cleaving K63-linked ubiquitin chains on RAD23B and XPC and enhancing PRKN-mediated K48-linked ubiquitination, leading to proteasomal degradation. Loss of OTUD1 (via promoter methylation) stabilizes RAD23B-XPC and confers cisplatin resistance in NSCLC.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitin linkage-specific analysis, overexpression/knockdown, in vitro and in vivo cisplatin sensitivity assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with ubiquitin linkage analysis and functional cisplatin resistance readout, single lab\",\n      \"pmids\": [\"41286308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Rad23b directly interacts with mutant ataxin-3 (mATXN3), promotes its ubiquitination, and facilitates delivery to the proteasome; however, Rad23b paradoxically disrupts proteasome catalytic activity, preventing mATXN3 degradation and exacerbating aggregate formation. Rad23b knockdown/knockout reduces mATXN3 aggregates and neuronal cell death.\",\n      \"method\": \"Overexpression and knockdown/knockout functional assays, ubiquitination assay, co-immunoprecipitation, proteasome activity assay, immunohistochemistry in SCA3 transgenic mice\",\n      \"journal\": \"Neurotherapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays with transgenic mouse validation, single lab\",\n      \"pmids\": [\"42172862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The EF-hand insertion domain of MINDY3 deubiquitinase specifically binds the UbL domain of RAD23B (and RAD23A), but not other UBL-domain proteins. This interaction mediates MINDY3 recruitment to DNA damage sites. MINDY3 can form a ternary complex with RAD23A/B and polyubiquitin, and may deubiquitylate RAD23A/B-bound clients.\",\n      \"method\": \"Crystal structure of MINDY3 EF-hand:RAD23A UbL complex, Co-IP in cells, biochemical binding assays, DNA damage localization assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with cell-based and biochemical validation, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.07.16.665128\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RAD23B is necessary for the formation of transient aggregate-associated proteasome condensates (TAADs) that co-localize with cytosolic alpha-synuclein aggregates to facilitate their clearance via the ubiquitin-proteasome system.\",\n      \"method\": \"Quantitative live-cell imaging, siRNA knockdown, proteasome activity assay, proteomics\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, functional imaging assay without detailed mechanistic dissection of RAD23B's specific role\",\n      \"pmids\": [\"bio_10.1101_2025.09.15.676044\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Rad23B inhibits Ataxin-3 droplet maturation (liquid-to-solid phase transition) through heterotypic interactions but does not inhibit amyloid formation under dilute conditions, suggesting aggregation via misfolding is distinct from condensation pathway.\",\n      \"method\": \"In vitro LLPS assay, Thioflavin-T binding, co-incubation of purified proteins\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — in vitro LLPS assay with purified proteins, single lab, single method, limited mechanistic detail in abstract\",\n      \"pmids\": [\"40684934\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RAD23B functions as a multidomain adaptor protein that (1) stabilizes XPC and stimulates damage recognition in global genome nucleotide excision repair by forming a tight complex with XPC, recruiting TFIIH to damaged DNA via XPC–XPB/p62 contacts, and enabling high-affinity, specificity-driven DNA lesion binding through hopping-based 1D diffusion; (2) serves as a ubiquitin-proteasome shuttling factor by presenting ubiquitinated substrates to the 26S proteasome via its N-terminal UbL domain interacting with S5a/PSMD4, while its UBA domains bind and inhibit polyubiquitin assembly; (3) is itself regulated by post-translational modifications including PARP1-mediated PARylation (reducing DNA binding), PSMD7-mediated deubiquitination (stabilization), and OTUD1-dependent ubiquitin chain editing (promoting degradation); and (4) its subcellular localization (nuclear vs. cytoplasmic/Golgi) is spatially controlled by interactors such as PAQR3 and HDAC6, which modulate XPC stability, proteasome activity, and cellular responses to genotoxic and HDAC inhibitor treatments.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RAD23B is a multidomain adaptor that bridges global-genome nucleotide excision repair (NER) and the ubiquitin-proteasome system [#0, #20]. In NER, it forms a tight complex with XPC, stimulating XPC-dependent damage recognition through a 56-residue amphipathic XPC-binding domain that is necessary and sufficient for both binding and repair stimulation [#1, #9]. The XPC-RAD23B complex binds diverse bulky and helix-distorting lesions with nanomolar affinity and high specificity over undamaged DNA, with damage discrimination driven primarily by DNA structural distortion rather than adduct chemistry [#5, #12, #15]; within the complex XPC makes the direct DNA contacts while RAD23B interacts with DNA largely indirectly [#16]. Recognition proceeds through hopping-based one-dimensional diffusion that allows lesion search and interrogation [#26], with dissociation kinetics being rate-limiting for repair of certain lesions [#23], and the complex recruits TFIIH to damaged DNA via XPC contacts with XPB/p62 to nucleate downstream repair assembly [#3]. In its second role, RAD23B acts as a proteasome shuttle factor: its N-terminal ubiquitin-like (UbL) domain mimics ubiquitin to bind the proteasome subunit S5a, while its UBA domains engage K48-linked polyubiquitin and inhibit chain extension, with an intramolecular UbL-UBA interaction modulating these contacts [#7, #8]. Consistent with this, the majority of RAD23B interactors are ubiquitin-proteasome components, and loss of Rad23b in mice impairs erythropoiesis through a proteasome-dependent mechanism while NER remains intact owing to redundancy with Rad23a [#20]. RAD23B levels and activity are tuned by post-translational and spatial control: PARP1 PARylates the complex to reduce DNA binding [#21], PSMD7 stabilizes RAD23B by preventing its degradation [#29], OTUD1 directs RAD23B-XPC for proteasomal degradation through ubiquitin-chain editing [#35], and the localization regulators PAQR3 and HDAC6 sequester RAD23B at the Golgi or cytoplasm to limit XPC stabilization and proteasome cargo shuttling [#24, #19, #31]. RAD23B also engages polyglutamine disease proteins, binding ataxin-3 via its UbL domain and being sequestered into polyQ inclusions through its UBA domains, linking it to substrate handling in neurodegeneration [#4, #25]. Beyond these core roles, individual studies implicate RAD23B in p53 stabilization after genotoxic stress, cancer-cell invasion via CORO1C, and a vertebrate-derived copper-binding metalloadaptor function [#14, #30, #34].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that RAD23B is a functional cofactor of XPC rather than an isolated repair factor, defining its primary role in stimulating global-genome NER.\",\n      \"evidence\": \"Reconstituted in vitro NER assay with recombinant proteins in fractionated XP-C extracts across multiple lesion types\",\n      \"pmids\": [\"8756644\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map the interaction interface\", \"In vitro stimulation did not address in vivo requirement given Rad23a redundancy\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Mapped the molecular basis of the XPC interaction, showing a discrete amphipathic helical domain is necessary and sufficient for XPC binding and NER stimulation.\",\n      \"evidence\": \"Deletion mutagenesis, His-tagged pulldowns, in vitro NER stimulation, and yeast two-hybrid domain mapping\",\n      \"pmids\": [\"9372923\", \"9164480\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Two-hybrid functional correlation was indirect\", \"Did not resolve how the domain stabilizes XPC\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Connected the XPC-RAD23B complex to downstream repair assembly by showing it recruits TFIIH to damaged DNA, and identified UbL binding to disease protein ataxin-3.\",\n      \"evidence\": \"Reciprocal Co-IP and cell-free reconstitution showing TFIIH recruitment defect; yeast two-hybrid plus immunofluorescence for ataxin-3\",\n      \"pmids\": [\"10734143\", \"10915768\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TFIIH contact attributed to XPC, not RAD23B directly\", \"Ataxin-3 interaction functional consequence not established at this stage\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Quantified the affinity and specificity of damage recognition, demonstrating lesion preference and strong discrimination against undamaged DNA.\",\n      \"evidence\": \"Fluorescence anisotropy equilibrium binding and competition with defined damaged substrates\",\n      \"pmids\": [\"12022861\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether specificity arises from chemistry or DNA distortion\", \"Kinetic basis of discrimination not addressed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined the structural and proteasome-targeting roles of the UbL/UBA domains, showing UbL mimics ubiquitin to bind S5a while UBA inhibits chain assembly.\",\n      \"evidence\": \"NMR structures of UbL and UIM:UbL complexes with chemical-shift and mutagenesis mapping; SFM of DNA bending\",\n      \"pmids\": [\"12832454\", \"14585839\", \"12547395\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect proteasome shuttling to specific in vivo substrates\", \"DNA bending role inferred, not functionally tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Resolved damage discrimination kinetics and began distinguishing paralog-specific proteasome behavior and a role in damage-induced p53 stabilization.\",\n      \"evidence\": \"Stopped-flow pre-steady-state kinetics; paralog mutagenesis and co-purification; siRNA, ChIP and ubiquitin-mutant analysis of p53\",\n      \"pmids\": [\"16460043\", \"16712842\", \"16924240\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"p53 role from single lab without reciprocal validation\", \"Mechanism linking RAD23B to p53 ubiquitin accumulation unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that lesion stereochemistry and helix-opening govern XPC-RAD23B binding and NER efficiency, and showed XPC is the direct DNA-contacting subunit.\",\n      \"evidence\": \"Permanganate footprinting with reconstituted NER; site-specific photocrosslinking with denaturing IP\",\n      \"pmids\": [\"17525733\", \"17320292\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RAD23B's contribution to DNA contact remained indirect/unclear\", \"Orientation specificity mechanism not structurally resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated an in vivo proteasome-shuttling role distinct from NER, with the Rad23b interactome dominated by UPS components and erythropoiesis defects upon loss.\",\n      \"evidence\": \"Rad23b-null mouse with unbiased interactor proteomics, erythroid differentiation flow cytometry, and proteasome inhibition; HDAC6 Co-IP and interactome\",\n      \"pmids\": [\"23897431\", \"23703321\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific ubiquitinated cargoes in erythropoiesis not identified\", \"HDAC6 regulation deacetylase-independent mechanism only partly defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified PARylation as a post-translational regulator of DNA binding, with PAR competing with DNA for the complex.\",\n      \"evidence\": \"32P-NAD+ incorporation, immunoblotting, and competitive binding assays\",\n      \"pmids\": [\"26170451\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of PARylation not established\", \"Single-lab biochemistry without structural mapping of modified sites\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed that subcellular compartmentation controls function: Golgi tethering by PAQR3 sequesters RAD23B and destabilizes XPC, reducing NER capacity.\",\n      \"evidence\": \"Co-IP, subcellular fractionation, ubiquitination and γ-H2AX assays with knockdown/overexpression\",\n      \"pmids\": [\"28473198\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Physiological trigger for PAQR3-mediated sequestration unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the search mechanism of XPC-RAD23B at single-molecule resolution, showing hopping-based 1D diffusion and biphasic lesion interrogation.\",\n      \"evidence\": \"High-throughput DNA curtain single-molecule imaging with diffusion analysis\",\n      \"pmids\": [\"31372632\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RAD23B-specific contribution to diffusion not isolated\", \"Did not address handoff to downstream factors\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Refined lesion-recognition rules by demonstrating competition with base-excision repair and a lesion-avoidance effect for stably stacked adducts.\",\n      \"evidence\": \"Competition binding with NEIL1 and single-turnover kinetics; fluorescence KD measurement with structural modeling; SPR koff analysis\",\n      \"pmids\": [\"32302101\", \"33035795\", \"27327897\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo pathway competition with BER not tested\", \"Structural models not experimentally validated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established RAD23B as a regulated node in cancer through stabilization by PSMD7 and as an adaptor in invasion signaling via CORO1C.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, knockdown, and xenografts in gastric and colorectal cancer models\",\n      \"pmids\": [\"34512150\", \"34062216\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct deubiquitination of RAD23B by PSMD7 not biochemically reconstituted\", \"CORO1C axis mechanism is correlative\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the HDAC6 axis and adaptor function, showing HDAC6-inhibitor-released RAD23B shuttles cargo affecting antigen presentation, and RAD23B serves as the ubiquitin adaptor for Twist1.\",\n      \"evidence\": \"Pharmacologic HDAC6 domain inhibition with proteasome, antigen-presentation and T-cell assays; Co-IP and ubiquitination assays for Twist1\",\n      \"pmids\": [\"38747592\", \"39582466\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct cargo identity in immune context incompletely defined\", \"Twist1 adaptor role from single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Diversified the functional landscape with new partners (UV-DDB handoff, MINDY3, OTUD1), a copper-binding metalloadaptor function, and roles in aggregate clearance and phase separation.\",\n      \"evidence\": \"Single-molecule and biochemical UX-complex assays; crystal structure of MINDY3 UbL complex (preprint); ubiquitin-linkage analysis for OTUD1; structural/biochemical copper-binding and evolutionary analysis; live-cell imaging and LLPS assays\",\n      \"pmids\": [\"40530698\", \"bio_10.1101_2025.07.16.665128\", \"41286308\", \"40972527\", \"42172862\", \"bio_10.1101_2025.09.15.676044\", \"40684934\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Copper metalloadaptor function is a single novel study requiring replication\", \"Phase-separation and condensate roles are preprint/low-confidence\", \"Integration of new partners into a unified regulatory model incomplete\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RAD23B's two functions — NER damage recognition and proteasomal substrate shuttling — are coordinated within a cell, and which determinants partition it between these roles, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking spatial regulation, PTMs, and substrate choice\", \"RAD23B-specific in vivo proteasome substrates largely unidentified\", \"Physiological relevance of copper-binding and phase-separation functions in humans untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 3, 7, 8, 20]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [5, 12, 16, 26]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 8, 29]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [11, 14, 24]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [11, 19, 30]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [24]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0, 1, 3, 5, 15, 26]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [7, 8, 20, 29, 35]}\n    ],\n    \"complexes\": [\"XPC-RAD23B complex\", \"UV-DDB/XPC-RAD23B (UX) complex\"],\n    \"partners\": [\"XPC\", \"TFIIH\", \"PSMD4\", \"PAQR3\", \"HDAC6\", \"PSMD7\", \"OTUD1\", \"ATXN3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}