{"gene":"C1D","run_date":"2026-04-28T17:12:38","timeline":{"discoveries":[{"year":1998,"finding":"C1D physically interacts with DNA-PKcs (via its putative leucine zipper region) and activates DNA-PK in a DNA end-independent manner. C1D was identified as a very effective DNA-PK substrate in vitro, and yeast two-hybrid and mammalian cell co-immunoprecipitation confirmed the interaction.","method":"Yeast two-hybrid screen, co-immunoprecipitation in mammalian cells, in vitro kinase assay","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (Y2H, co-IP, in vitro kinase assay) in a single rigorous study","pmids":["9679063"],"is_preprint":false},{"year":1999,"finding":"Overexpression of C1D induces apoptosis in multiple tumor cell lines in a p53-dependent manner, with morphological hallmarks of apoptosis (membrane blebbing, nuclear disintegration, cytoplasmic vacuolation). C1D-induced apoptosis also produces a bystander effect on neighboring non-transfected cells, and cells with non-functional p53 are resistant.","method":"Transient transfection with C1D-EGFP fusion constructs, TUNEL assay, fluorescence microscopy, co-culture experiments","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — clean overexpression with defined phenotypic readout and p53-dependence established, single lab","pmids":["10362552"],"is_preprint":false},{"year":1997,"finding":"C1D (identified as SUN-CoR, Small Unique Nuclear receptor CoRepressor) was cloned as a nuclear corepressor that potentiates transcriptional repression by thyroid hormone receptor and RevErb in vivo, represses transcription when fused to a heterologous DNA-binding domain, and interacts with RevErb, thyroid hormone receptor, N-CoR, and SMRT in vitro and with endogenous N-CoR in cells.","method":"Cloning, in vivo reporter assays, in vitro binding assays, co-immunoprecipitation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (in vivo repression assays, in vitro binding, co-IP with endogenous N-CoR) in single study","pmids":["9405624"],"is_preprint":false},{"year":2002,"finding":"C1D interacts specifically with Translin-associated factor X (TRAX) in both yeast and mammalian cells, but this interaction in mammalian cells occurs only following gamma-irradiation, linking C1D and TRAX to DNA double-strand break repair signaling. C1D overexpression can prevent TRAX from associating with Translin.","method":"Yeast two-hybrid system, co-immunoprecipitation in mammalian cells, fluorescence microscopy with tagged proteins, gamma-irradiation treatment","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal interaction confirmed in multiple systems with DNA damage-dependent specificity demonstrated; single lab","pmids":["11801738"],"is_preprint":false},{"year":2002,"finding":"The Saccharomyces cerevisiae C1D homologue (YC1D) is required for both non-homologous DNA end joining (NHEJ) and homologous recombination. Disruption of YC1D causes temperature sensitivity and defects in accurate DNA repair, establishing a direct role for C1D in two major DSB repair pathways.","method":"Yeast gene disruption, plasmid-based in vivo recombination assay, DNA repair phenotype analysis, temperature sensitivity assay","journal":"Molecular microbiology","confidence":"High","confidence_rationale":"Tier 2 — genetic loss-of-function with two orthogonal functional readouts (NHEJ and HR assays) in conserved yeast ortholog","pmids":["12421302"],"is_preprint":false},{"year":2004,"finding":"Fission yeast C1D homologue Cti1 (SpC1D) physically interacts with the hinge domain of condensin subunit Cut3/SMC4, as confirmed by GST pull-down and co-immunoprecipitation. Elevated dosage of SpC1D suppresses temperature, UV, and hydroxyurea sensitivity of condensin non-SMC subunit (Cnd2) mutants, and SpC1D accumulates on nuclear chromatin upon hydroxyurea treatment, supporting a role in DNA repair through condensin.","method":"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, genetic dosage suppression, chromatin fractionation, immunofluorescence","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal biochemical and genetic methods; interaction with condensin hinge domain precisely mapped","pmids":["15148393"],"is_preprint":false},{"year":2007,"finding":"Human C1D associates with the exosome subunit PM/Scl-100 and co-localizes with it in the nucleoli of HEp-2 cells. C1D nucleolar accumulation is dependent on PM/Scl-100. C1D, MPP6, and PM/Scl-100 form a stable trimeric complex in vitro. C1D exhibits RNA-binding activity with preference for structured RNAs. RNAi knockdown of C1D causes accumulation of 3′-extended 5.8S rRNA precursors, demonstrating a role in pre-rRNA 3′-end processing.","method":"Co-immunoprecipitation, subcellular localization (immunofluorescence), in vitro trimeric complex reconstitution, RNA-binding assay, RNAi knockdown, Northern blot for rRNA processing intermediates","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including in vitro reconstitution, localization, RNA binding, and functional knockdown with defined molecular readout","pmids":["17412707"],"is_preprint":false},{"year":2010,"finding":"The Sas10/C1D domain of yeast Rrp47 (an exosome cofactor) forms a binding surface for specific protein-protein interactions and can simultaneously interact with RNA or DNA, suggesting this conserved domain functions as a docking module for nucleic acid substrates. The N-terminal Sas10/C1D domain of Rrp47 is sufficient for interaction with the PMC2NT domain of Rrp6 and for most RNA-processing functions in vivo.","method":"Deletion complementation analysis, in vitro protein interaction studies, filter binding RNA assays","journal":"Biochemical Society transactions","confidence":"Medium","confidence_rationale":"Tier 2-3 — domain mapping and in vitro binding established; functional complementation data support conclusions; review article synthesizing experimental data","pmids":["20659009"],"is_preprint":false},{"year":2010,"finding":"In yeast, the C-terminal region of Rrp47 (which contains the Sas10/C1D domain in its N-terminal portion) mediates RNA binding and interaction with snoRNP proteins Nop56 and Nop58, and is specifically required for 3′-end maturation of box C/D snoRNAs. The N-terminal Sas10/C1D domain binds Rrp6, while the C-terminal lysine-rich region contributes to RNA binding.","method":"Deletion complementation in yeast, in vitro protein interaction (protein capture assay), filter binding RNA assays, synthetic lethality analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple biochemical and genetic methods; domain requirements precisely mapped with in vitro and in vivo validation","pmids":["21135092"],"is_preprint":false},{"year":2013,"finding":"In yeast, Rrp47 (which contains a Sas10/C1D domain) is critical for the stability and normal expression of its partner exoribonuclease Rrp6; loss of Rrp47 substantially reduces Rrp6 protein stability and transcript levels under minimal medium growth conditions. Exogenous Rrp6 expression suppresses most but not all RNA processing defects in rrp47Δ mutants.","method":"Yeast genetics, Western blot, Northern blot, synthetic lethality complementation, exogenous protein expression","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods in yeast; mechanistic link between Sas10/C1D-domain protein and Rrp6 stability established","pmids":["24224060"],"is_preprint":false},{"year":2014,"finding":"In yeast, Rrp47 (Sas10/C1D domain protein) and Rrp6 together form a composite structural surface that recruits the Mtr4 helicase to the exosome. Crystallographic analysis reveals the N-terminal domains of Rrp6 and Rrp47 form a highly intertwined unit with a conserved groove that binds the N-terminus of Mtr4; mutations at this interface disrupt the interaction.","method":"In vitro binding assay, X-ray crystallography, structure-guided mutagenesis, yeast growth assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — crystal structure combined with mutagenesis and in vitro reconstitution; strong mechanistic insight into Sas10/C1D domain-containing Rrp47 function","pmids":["25319414"],"is_preprint":false}],"current_model":"C1D is a conserved nuclear matrix protein that (1) activates DNA-PK in a DNA end-independent manner by directly binding DNA-PKcs, (2) participates in both NHEJ and homologous recombination DSB repair pathways, (3) interacts with TRAX in a DNA damage-dependent manner to regulate TRAX/Translin complex formation, (4) binds the condensin SMC hinge domain to support DNA repair through condensin, (5) functions as a transcriptional corepressor (SUN-CoR) by interacting with nuclear hormone receptors and N-CoR/SMRT, and (6) associates with the RNA exosome (via PM/Scl-100) and exhibits RNA-binding activity to facilitate 3′-end processing of pre-rRNA; the conserved Sas10/C1D domain present in C1D and its exosome cofactor relatives (e.g., yeast Rrp47) acts as a dual protein–nucleic acid docking module that recruits processing machinery to RNA substrates."},"narrative":{"teleology":[{"year":1997,"claim":"Identification of C1D as a nuclear corepressor (SUN-CoR) established that this small nuclear protein amplifies transcriptional repression through nuclear hormone receptors and the N-CoR/SMRT corepressor complex.","evidence":"Cloning, in vivo reporter assays, in vitro binding, and co-immunoprecipitation with endogenous N-CoR","pmids":["9405624"],"confidence":"High","gaps":["Endogenous genomic targets of SUN-CoR-mediated repression not identified","Whether DNA-repair and corepressor functions are mutually exclusive is unknown"]},{"year":1998,"claim":"Demonstration that C1D directly binds DNA-PKcs and activates DNA-PK without requiring DNA ends revealed an unusual mode of DNA-PK activation and positioned C1D as a DNA damage response factor.","evidence":"Yeast two-hybrid, co-immunoprecipitation, and in vitro kinase assay","pmids":["9679063"],"confidence":"High","gaps":["Physiological conditions under which DNA-end-independent activation occurs in vivo are unclear","Downstream signaling targets of C1D-activated DNA-PK not defined"]},{"year":1999,"claim":"Overexpression studies showed C1D induces p53-dependent apoptosis with a bystander effect, linking its DNA damage signaling role to cell death outcomes.","evidence":"Transient transfection with C1D-EGFP, TUNEL assay, fluorescence microscopy, and co-culture experiments in tumor cell lines","pmids":["10362552"],"confidence":"Medium","gaps":["Overexpression-only system; loss-of-function confirmation of apoptotic role absent","Mechanism of bystander effect uncharacterized","Relevance at endogenous expression levels not tested"]},{"year":2002,"claim":"Two studies collectively established C1D's role in double-strand break repair: the yeast orthologue is required for both NHEJ and homologous recombination, and C1D interacts with TRAX in a DNA-damage-dependent manner to modulate TRAX/Translin complex assembly.","evidence":"Yeast gene disruption with in vivo recombination assays; yeast two-hybrid and co-immunoprecipitation with gamma-irradiation in mammalian cells","pmids":["12421302","11801738"],"confidence":"High","gaps":["Whether the C1D–TRAX interaction is conserved in human DSB repair in vivo is untested","Epistasis between C1D, DNA-PK, and TRAX pathways not resolved"]},{"year":2004,"claim":"Discovery that fission yeast C1D binds the condensin SMC hinge domain and suppresses condensin mutant phenotypes revealed a third route by which C1D promotes DNA repair—through the condensin complex.","evidence":"GST pull-down, co-immunoprecipitation, genetic dosage suppression, chromatin fractionation, and immunofluorescence in S. pombe","pmids":["15148393"],"confidence":"High","gaps":["Whether human C1D–condensin interaction occurs is not established","Molecular mechanism by which C1D enhances condensin-mediated repair is unresolved"]},{"year":2007,"claim":"Identification of C1D as an RNA exosome cofactor that binds PM/Scl-100, localizes to nucleoli, binds structured RNAs, and is required for 5.8S rRNA 3′-end processing established a major non-repair function for C1D in ribosome biogenesis.","evidence":"Co-immunoprecipitation, immunofluorescence, in vitro trimeric complex reconstitution with MPP6 and PM/Scl-100, RNA-binding assay, and RNAi knockdown with Northern blot in human cells","pmids":["17412707"],"confidence":"High","gaps":["Full spectrum of exosome RNA substrates requiring C1D is not mapped","How C1D partitions between DNA repair and RNA processing functions is unclear"]},{"year":2010,"claim":"Domain dissection of the yeast orthologue Rrp47 showed that the Sas10/C1D domain serves as a dual protein–nucleic acid docking module: its N-terminal portion binds Rrp6, while the C-terminal region binds RNA and snoRNP proteins Nop56/Nop58, and is specifically required for snoRNA 3′-end maturation.","evidence":"Deletion complementation in yeast, in vitro protein capture, filter binding RNA assays, synthetic lethality analysis","pmids":["20659009","21135092"],"confidence":"High","gaps":["Whether human C1D retains the bipartite domain architecture with separable functions is untested","Structural basis for RNA substrate selectivity not determined at this point"]},{"year":2013,"claim":"Rrp47 was shown to stabilize Rrp6 protein and transcript levels in yeast, establishing a chaperone-like dependency between the Sas10/C1D-domain protein and its exonuclease partner.","evidence":"Western blot and Northern blot in rrp47Δ yeast, exogenous Rrp6 expression rescue","pmids":["24224060"],"confidence":"Medium","gaps":["Whether human C1D similarly stabilizes EXOSC10/PM-Scl-100 is unknown","Mechanism of transcript-level regulation not dissected"]},{"year":2014,"claim":"Crystal structure of the Rrp6–Rrp47 N-terminal complex revealed a highly intertwined unit with a conserved groove that recruits the Mtr4 helicase to the exosome, providing the first atomic-resolution view of how the Sas10/C1D domain organizes exosome cofactor assembly.","evidence":"X-ray crystallography, structure-guided mutagenesis, in vitro binding, and yeast growth assays","pmids":["25319414"],"confidence":"High","gaps":["No equivalent structural data for human C1D–EXOSC10 complex","How Mtr4 recruitment is coordinated with ongoing RNA processing is not resolved"]},{"year":null,"claim":"How C1D partitions between its distinct functions in DNA repair (DNA-PK activation, NHEJ/HR, condensin interaction) and RNA processing (exosome cofactor, rRNA/snoRNA maturation), and whether these roles are regulated by post-translational modifications or damage signaling, remains an open question.","evidence":"","pmids":[],"confidence":"Low","gaps":["No systematic separation-of-function mutant analysis in mammalian cells","Post-translational regulation of C1D is uncharacterized","Structural basis of the human C1D–DNA-PKcs interaction is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[6,7,8]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,7]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,9]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[6]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,6]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0,3,4,5]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[6,7,8,9,10]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1]}],"complexes":["Nuclear RNA exosome (via PM/Scl-100–MPP6 trimeric subcomplex)","N-CoR/SMRT corepressor complex"],"partners":["PRKDC","EXOSC10","MPP6","NCOR1","NCOR2","TSNAX","SMC4"],"other_free_text":[]},"mechanistic_narrative":"C1D is a conserved nuclear nucleic acid-binding protein that operates at the intersection of DNA damage repair and RNA processing. It activates DNA-PK independently of DNA ends by directly binding DNA-PKcs, and its yeast orthologue is required for both non-homologous end joining and homologous recombination [PMID:9679063, PMID:12421302]. C1D also functions as a transcriptional corepressor (SUN-CoR) that potentiates repression by thyroid hormone receptor and RevErb through interaction with N-CoR/SMRT [PMID:9405624]. Through its conserved Sas10/C1D domain, C1D associates with the nuclear RNA exosome via PM/Scl-100, exhibits structured-RNA-binding activity, and is required for 3′-end processing of 5.8S rRNA precursors, while the orthologous yeast Rrp47 stabilizes the exoribonuclease Rrp6 and forms a composite surface that recruits the Mtr4 helicase [PMID:17412707, PMID:25319414]."},"prefetch_data":{"uniprot":{"accession":"Q13901","full_name":"Nuclear nucleic acid-binding protein C1D","aliases":[],"length_aa":141,"mass_kda":16.0,"function":"Plays a role in the recruitment of the RNA exosome complex to pre-rRNA to mediate the 3'-5' end processing of the 5.8S rRNA; this function may include MPHOSPH6. Can activate PRKDC not only in the presence of linear DNA but also in the presence of supercoiled DNA. Can induce apoptosis in a p53/TP53 dependent manner. May regulate the TRAX/TSN complex formation. Potentiates transcriptional repression by NR1D1 and THRB (By similarity)","subcellular_location":"Nucleus; Cytoplasm; Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/Q13901/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/C1D","classification":"Common Essential","n_dependent_lines":565,"n_total_lines":1208,"dependency_fraction":0.46771523178807944},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/C1D","total_profiled":1310},"omim":[{"mim_id":"621141","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 180; CCDC180","url":"https://www.omim.org/entry/621141"},{"mim_id":"621125","title":"CILIARY DYSKINESIA, PRIMARY, 54; CILD54","url":"https://www.omim.org/entry/621125"},{"mim_id":"621121","title":"CILIA- AND FLAGELLA-ASSOCIATED PROTEIN 54; CFAP54","url":"https://www.omim.org/entry/621121"},{"mim_id":"620187","title":"CILIA- AND FLAGELLA-ASSOCIATED PROTEIN 74; CFAP74","url":"https://www.omim.org/entry/620187"},{"mim_id":"619891","title":"WD REPEAT-CONTAINING PROTEIN 93; WDR93","url":"https://www.omim.org/entry/619891"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/C1D"},"hgnc":{"alias_symbol":["SUNCOR","SUN-CoR","LRP1","Rrp47"],"prev_symbol":[]},"alphafold":{"accession":"Q13901","domains":[{"cath_id":"-","chopping":"49-105","consensus_level":"medium","plddt":96.1409,"start":49,"end":105}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13901","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13901-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13901-F1-predicted_aligned_error_v6.png","plddt_mean":87.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=C1D","jax_strain_url":"https://www.jax.org/strain/search?query=C1D"},"sequence":{"accession":"Q13901","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13901.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13901/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13901"}},"corpus_meta":[{"pmid":"32296178","id":"PMC_32296178","title":"LRP1 is a master 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complex in vitro. C1D possesses RNA-binding activity with a preference for structured RNAs. Knockdown of C1D by RNAi causes accumulation of 3'-extended 5.8S rRNA precursors, demonstrating that C1D is required for exosome-mediated 3' end processing of pre-rRNA. Nucleolar accumulation of C1D is dependent on PM/Scl-100.\",\n      \"method\": \"Co-immunoprecipitation, in vitro complex reconstitution, subcellular localization (immunofluorescence), RNAi knockdown with rRNA processing readout, RNA-binding assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (Co-IP, in vitro reconstitution, RNAi phenotype, RNA-binding assay) in a single study with rigorous controls\",\n      \"pmids\": [\"17412707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"C1D interacts specifically with Translin-associated factor X (TRAX) in both yeast and mammalian cells, but the interaction in mammalian cells only occurs following gamma-irradiation, implicating TRAX in DNA double-strand break repair downstream of C1D. C1D may regulate TRAX/Translin complex formation, and relative expression levels of TRAX and Translin affect their subcellular localization.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation in mammalian cells, fluorescent protein localization\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — yeast two-hybrid plus Co-IP in mammalian cells, single lab, single study\",\n      \"pmids\": [\"11801738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The yeast C1D homologue YC1D is required for both non-homologous DNA end joining (NHEJ) and homologous recombination (HR) repair of DNA double-strand breaks. Disruption of YC1D causes temperature sensitivity and defects in accurate DNA repair, providing direct genetic evidence for C1D function in DSB repair pathways.\",\n      \"method\": \"Gene disruption/knockout in S. cerevisiae, NHEJ assay, plasmid-based in vivo recombination assay, growth assays\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct loss-of-function genetics with two independent functional readouts (NHEJ and HR) in yeast ortholog\",\n      \"pmids\": [\"12421302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Overexpression of C1D (a DNA-binding and DNA-PK-activating protein) induces apoptosis in multiple tumor cell lines in a p53-dependent manner. Cells lacking functional p53 are resistant to C1D-induced apoptosis, placing C1D upstream of p53 in a DNA damage-response apoptotic pathway.\",\n      \"method\": \"Vector-dependent overexpression, TUNEL assay, live-cell fluorescence imaging (C1D-EGFP fusion), p53-deficient cell controls\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — overexpression with morphological and biochemical readouts, p53 epistasis, single lab\",\n      \"pmids\": [\"10362552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The fission yeast C1D homologue Cti1/SpC1D interacts physically with the hinge domain of condensin subunit Cut3/SMC4 (shown by GST pull-down and co-immunoprecipitation), localizes to nuclear chromatin upon hydroxyurea treatment, and overexpression of SpC1D suppresses temperature, UV, and hydroxyurea sensitivity of a condensin non-SMC subunit mutant, supporting a role for C1D in the DNA repair function of condensin.\",\n      \"method\": \"Yeast two-hybrid (bait: SMC4 hinge), GST pull-down, co-immunoprecipitation, genetic suppression, chromatin fractionation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple biochemical interaction methods plus genetic epistasis, fission yeast ortholog\",\n      \"pmids\": [\"15148393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The Sas10/C1D domain (found in Rrp47 and C1D family proteins) is predicted to be alpha-helical (~80 residues) and forms a binding surface for specific protein–protein interactions while concomitantly interacting with RNA or DNA, functioning to dock partner proteins onto nucleic acid substrates.\",\n      \"method\": \"Biochemical complementation, deletion analysis, bioinformatic domain characterization, in vitro protein interaction studies\",\n      \"journal\": \"Biochemical Society transactions\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — domain characterization review integrating prior experimental data; single-method biochemical evidence for domain function\",\n      \"pmids\": [\"20659009\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"C1D is a nuclear matrix protein with a conserved Sas10/C1D domain that activates DNA-PK, binds structured RNA and DNA, associates with the RNA exosome subunit PM/Scl-100 to form a trimeric complex with MPP6 required for 3' processing of 5.8S pre-rRNA, interacts with TRAX in a DNA-damage-dependent manner to facilitate DSB repair, physically docks onto the condensin SMC hinge to support DNA repair, and when overexpressed induces p53-dependent apoptosis.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper, then extract discoveries only from KEEP papers.\n\n**Classification:**\n\nThe gene C1D encodes a nuclear matrix protein involved in DNA double-strand break repair and RNA processing (exosome cofactor). Papers about LRP1 (Low-density Lipoprotein Receptor-related Protein 1) are ALIAS COLLISIONS — LRP1 is a completely different gene/protein. Similarly, papers about Arabidopsis LRP1, ciliary C1d projection complexes, or other unrelated genes must be excluded.\n\n**KEEP papers (about C1D the nuclear matrix/DNA repair/RNA processing protein):**\n- PMID:17412707 — C1D and hMtr4p with exosome/PM/Scl-100, pre-rRNA processing\n- PMID:11801738 — C1D interaction with TRAX, DNA damage\n- PMID:12421302 — Yeast C1D (YC1D) in NHEJ and homologous recombination\n- PMID:15148393 — Cti1/C1D interacts with condensin SMC hinge\n- PMID:10362552 — C1D overexpression induces apoptosis, DNA-PK activation\n- PMID:9679063 — C1D interacts with DNA-PKcs, activates DNA-PK\n- PMID:21135092 — Rrp47 Sas10/C1D domain, Rrp6 interaction (yeast Rrp47/Lrp1 — note: yeast Rrp47 is also called Lrp1 in yeast, this is about the Sas10/C1D domain)\n- PMID:25319414 — Rrp6/Rrp47 composite surface for Mtr4 (relevant to C1D domain)\n- PMID:21713680 — Rrp6, Rrp47 and cofactors (C1D domain context)\n- PMID:21618877 — Rrp6, Rrp47 cofactors (duplicate review, same context)\n- PMID:20659009 — Rrp47 and Sas10/C1D domain function\n- PMID:24224060 — Rrp47 and Rrp6 stability (C1D domain context)\n- PMID:9405624 — SUN-CoR cloned as corepressor (SUN-CoR = C1D)\n- PMID:21873635 — GO annotation (general, not mechanistic for C1D)\n- PMID:19423540 — SNP association study (EXCLUDE — expression/association)\n- PMID:20406964 — SNP association (EXCLUDE)\n- PMID:20438785 — SNP association (EXCLUDE)\n\n**Additional curated papers:**\n- PMID:9679063 — KEEP (DNA-PK activation by C1D)\n- PMID:9405624 — KEEP (SUN-CoR = C1D, corepressor)\n- PMID:26186194, 28514442, 26496610, 25416956, 32296183, 33961781 — interactome datasets, too general\n- PMID:15148393 — KEEP (Cti1/SpC1D + condensin)\n\nPapers about LRP1 receptor: ALL EXCLUDE (alias collision)\nPapers about Arabidopsis LRP1: EXCLUDE\nPapers about ciliary C1d projection (FAP46 etc.): EXCLUDE (different protein complex entirely — \"C1d\" refers to a ciliary projection, not the C1D gene)\nPMID:22573824 (FAP46/C1d ciliary projection): EXCLUDE\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"C1D physically interacts with DNA-PKcs (via its putative leucine zipper region) and activates DNA-PK in a DNA end-independent manner. C1D was identified as a very effective DNA-PK substrate in vitro, and yeast two-hybrid and mammalian cell co-immunoprecipitation confirmed the interaction.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation in mammalian cells, in vitro kinase assay\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (Y2H, co-IP, in vitro kinase assay) in a single rigorous study\",\n      \"pmids\": [\"9679063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Overexpression of C1D induces apoptosis in multiple tumor cell lines in a p53-dependent manner, with morphological hallmarks of apoptosis (membrane blebbing, nuclear disintegration, cytoplasmic vacuolation). C1D-induced apoptosis also produces a bystander effect on neighboring non-transfected cells, and cells with non-functional p53 are resistant.\",\n      \"method\": \"Transient transfection with C1D-EGFP fusion constructs, TUNEL assay, fluorescence microscopy, co-culture experiments\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean overexpression with defined phenotypic readout and p53-dependence established, single lab\",\n      \"pmids\": [\"10362552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"C1D (identified as SUN-CoR, Small Unique Nuclear receptor CoRepressor) was cloned as a nuclear corepressor that potentiates transcriptional repression by thyroid hormone receptor and RevErb in vivo, represses transcription when fused to a heterologous DNA-binding domain, and interacts with RevErb, thyroid hormone receptor, N-CoR, and SMRT in vitro and with endogenous N-CoR in cells.\",\n      \"method\": \"Cloning, in vivo reporter assays, in vitro binding assays, co-immunoprecipitation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (in vivo repression assays, in vitro binding, co-IP with endogenous N-CoR) in single study\",\n      \"pmids\": [\"9405624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"C1D interacts specifically with Translin-associated factor X (TRAX) in both yeast and mammalian cells, but this interaction in mammalian cells occurs only following gamma-irradiation, linking C1D and TRAX to DNA double-strand break repair signaling. C1D overexpression can prevent TRAX from associating with Translin.\",\n      \"method\": \"Yeast two-hybrid system, co-immunoprecipitation in mammalian cells, fluorescence microscopy with tagged proteins, gamma-irradiation treatment\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction confirmed in multiple systems with DNA damage-dependent specificity demonstrated; single lab\",\n      \"pmids\": [\"11801738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The Saccharomyces cerevisiae C1D homologue (YC1D) is required for both non-homologous DNA end joining (NHEJ) and homologous recombination. Disruption of YC1D causes temperature sensitivity and defects in accurate DNA repair, establishing a direct role for C1D in two major DSB repair pathways.\",\n      \"method\": \"Yeast gene disruption, plasmid-based in vivo recombination assay, DNA repair phenotype analysis, temperature sensitivity assay\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with two orthogonal functional readouts (NHEJ and HR assays) in conserved yeast ortholog\",\n      \"pmids\": [\"12421302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Fission yeast C1D homologue Cti1 (SpC1D) physically interacts with the hinge domain of condensin subunit Cut3/SMC4, as confirmed by GST pull-down and co-immunoprecipitation. Elevated dosage of SpC1D suppresses temperature, UV, and hydroxyurea sensitivity of condensin non-SMC subunit (Cnd2) mutants, and SpC1D accumulates on nuclear chromatin upon hydroxyurea treatment, supporting a role in DNA repair through condensin.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, genetic dosage suppression, chromatin fractionation, immunofluorescence\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal biochemical and genetic methods; interaction with condensin hinge domain precisely mapped\",\n      \"pmids\": [\"15148393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Human C1D associates with the exosome subunit PM/Scl-100 and co-localizes with it in the nucleoli of HEp-2 cells. C1D nucleolar accumulation is dependent on PM/Scl-100. C1D, MPP6, and PM/Scl-100 form a stable trimeric complex in vitro. C1D exhibits RNA-binding activity with preference for structured RNAs. RNAi knockdown of C1D causes accumulation of 3′-extended 5.8S rRNA precursors, demonstrating a role in pre-rRNA 3′-end processing.\",\n      \"method\": \"Co-immunoprecipitation, subcellular localization (immunofluorescence), in vitro trimeric complex reconstitution, RNA-binding assay, RNAi knockdown, Northern blot for rRNA processing intermediates\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including in vitro reconstitution, localization, RNA binding, and functional knockdown with defined molecular readout\",\n      \"pmids\": [\"17412707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The Sas10/C1D domain of yeast Rrp47 (an exosome cofactor) forms a binding surface for specific protein-protein interactions and can simultaneously interact with RNA or DNA, suggesting this conserved domain functions as a docking module for nucleic acid substrates. The N-terminal Sas10/C1D domain of Rrp47 is sufficient for interaction with the PMC2NT domain of Rrp6 and for most RNA-processing functions in vivo.\",\n      \"method\": \"Deletion complementation analysis, in vitro protein interaction studies, filter binding RNA assays\",\n      \"journal\": \"Biochemical Society transactions\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — domain mapping and in vitro binding established; functional complementation data support conclusions; review article synthesizing experimental data\",\n      \"pmids\": [\"20659009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In yeast, the C-terminal region of Rrp47 (which contains the Sas10/C1D domain in its N-terminal portion) mediates RNA binding and interaction with snoRNP proteins Nop56 and Nop58, and is specifically required for 3′-end maturation of box C/D snoRNAs. The N-terminal Sas10/C1D domain binds Rrp6, while the C-terminal lysine-rich region contributes to RNA binding.\",\n      \"method\": \"Deletion complementation in yeast, in vitro protein interaction (protein capture assay), filter binding RNA assays, synthetic lethality analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple biochemical and genetic methods; domain requirements precisely mapped with in vitro and in vivo validation\",\n      \"pmids\": [\"21135092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In yeast, Rrp47 (which contains a Sas10/C1D domain) is critical for the stability and normal expression of its partner exoribonuclease Rrp6; loss of Rrp47 substantially reduces Rrp6 protein stability and transcript levels under minimal medium growth conditions. Exogenous Rrp6 expression suppresses most but not all RNA processing defects in rrp47Δ mutants.\",\n      \"method\": \"Yeast genetics, Western blot, Northern blot, synthetic lethality complementation, exogenous protein expression\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods in yeast; mechanistic link between Sas10/C1D-domain protein and Rrp6 stability established\",\n      \"pmids\": [\"24224060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In yeast, Rrp47 (Sas10/C1D domain protein) and Rrp6 together form a composite structural surface that recruits the Mtr4 helicase to the exosome. Crystallographic analysis reveals the N-terminal domains of Rrp6 and Rrp47 form a highly intertwined unit with a conserved groove that binds the N-terminus of Mtr4; mutations at this interface disrupt the interaction.\",\n      \"method\": \"In vitro binding assay, X-ray crystallography, structure-guided mutagenesis, yeast growth assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure combined with mutagenesis and in vitro reconstitution; strong mechanistic insight into Sas10/C1D domain-containing Rrp47 function\",\n      \"pmids\": [\"25319414\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"C1D is a conserved nuclear matrix protein that (1) activates DNA-PK in a DNA end-independent manner by directly binding DNA-PKcs, (2) participates in both NHEJ and homologous recombination DSB repair pathways, (3) interacts with TRAX in a DNA damage-dependent manner to regulate TRAX/Translin complex formation, (4) binds the condensin SMC hinge domain to support DNA repair through condensin, (5) functions as a transcriptional corepressor (SUN-CoR) by interacting with nuclear hormone receptors and N-CoR/SMRT, and (6) associates with the RNA exosome (via PM/Scl-100) and exhibits RNA-binding activity to facilitate 3′-end processing of pre-rRNA; the conserved Sas10/C1D domain present in C1D and its exosome cofactor relatives (e.g., yeast Rrp47) acts as a dual protein–nucleic acid docking module that recruits processing machinery to RNA substrates.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"C1D is a nuclear matrix protein that functions in both RNA exosome-mediated rRNA processing and DNA double-strand break (DSB) repair. In the nucleolus, C1D binds structured RNA and forms a trimeric complex with PM/Scl-100 and MPP6 that is required for exosome-dependent 3′ end processing of 5.8S pre-rRNA; its nucleolar localization depends on PM/Scl-100 [PMID:17412707]. C1D also participates in DSB repair through interactions with TRAX (in a DNA-damage-dependent manner in mammalian cells) and with the condensin SMC4 hinge domain, and its yeast orthologue is required for both non-homologous end joining and homologous recombination [PMID:12421302, PMID:15148393, PMID:11801738]. Overexpression of C1D induces apoptosis in a p53-dependent manner, linking its DNA-damage-signaling role to cell death [PMID:10362552].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing that C1D connects DNA damage signaling to cell fate: overexpression of C1D was shown to trigger apoptosis specifically through p53, positioning C1D as an upstream activator of p53-dependent cell death in response to DNA damage.\",\n      \"evidence\": \"Overexpression in multiple tumor cell lines with TUNEL assay and p53-null controls\",\n      \"pmids\": [\"10362552\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Overexpression system; physiological relevance of endogenous C1D levels for apoptosis induction is not established\",\n        \"Mechanism linking C1D/DNA-PK activation to p53 stabilization not defined\",\n        \"No loss-of-function data in mammalian cells for apoptosis phenotype\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defining the DNA repair function of C1D: the yeast orthologue was shown to be required for both NHEJ and HR, providing direct genetic evidence that C1D is a core participant in DSB repair rather than merely a DNA-PK activator, while the mammalian protein was found to interact with TRAX only after irradiation, suggesting damage-dependent complex assembly.\",\n      \"evidence\": \"Gene disruption in S. cerevisiae with NHEJ and HR functional assays (PMID:12421302); yeast two-hybrid and damage-dependent co-IP in mammalian cells (PMID:11801738)\",\n      \"pmids\": [\"12421302\", \"11801738\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mammalian C1D–TRAX interaction shown only by Co-IP after γ-irradiation in one study; reciprocal validation limited\",\n        \"Molecular mechanism by which C1D promotes NHEJ and HR is unknown\",\n        \"Whether C1D's DNA repair and rRNA processing functions are separable is unclear\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Linking C1D to the condensin complex in DNA repair: the fission yeast orthologue was shown to physically dock onto the SMC4 hinge domain and genetically suppress condensin mutant sensitivity to DNA damage, revealing a structural basis for C1D's repair role through condensin.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, co-IP, and genetic suppression in S. pombe\",\n      \"pmids\": [\"15148393\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the C1D–condensin interaction is conserved in mammalian cells is untested\",\n        \"Precise step in DSB repair facilitated by C1D–condensin interaction is undefined\",\n        \"Relationship between condensin binding and TRAX binding is unknown\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing C1D as a functional cofactor of the nuclear RNA exosome: C1D was shown to bind structured RNA, form a trimeric complex with PM/Scl-100 and MPP6, and be required for 3′ processing of 5.8S pre-rRNA, revealing a second major function entirely distinct from DNA repair.\",\n      \"evidence\": \"Co-IP, in vitro trimeric complex reconstitution, RNAi knockdown with rRNA processing assay, RNA-binding assay in HEp-2 cells\",\n      \"pmids\": [\"17412707\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether C1D also contributes to exosome-mediated degradation of other RNA substrates is unknown\",\n        \"Structural basis of the C1D–PM/Scl-100–MPP6 trimeric complex is not resolved\",\n        \"How C1D recruitment is partitioned between exosome and DNA repair functions is unclear\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Characterizing the Sas10/C1D domain as the structural unit mediating dual nucleic-acid and protein interactions, providing a molecular framework for how C1D simultaneously engages RNA/DNA substrates and protein partners.\",\n      \"evidence\": \"Biochemical complementation, deletion analysis, bioinformatic domain modeling\",\n      \"pmids\": [\"20659009\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No high-resolution structure of the Sas10/C1D domain\",\n        \"Contribution of individual residues to RNA vs. DNA vs. protein binding not dissected\",\n        \"Domain characterization partly based on bioinformatic prediction rather than direct structural data\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How C1D is partitioned between its exosome-dependent rRNA processing function and its condensin/TRAX-dependent DNA repair function remains unknown, as does whether these roles are regulated by post-translational modifications or damage-dependent relocalization in mammalian cells.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No mammalian loss-of-function study addressing both rRNA processing and DSB repair simultaneously\",\n        \"No structural model of C1D in complex with any partner at atomic resolution\",\n        \"Physiological triggers that switch C1D between nucleolar and chromatin-associated functions are undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\n      \"C1D–PM/Scl-100–MPP6 trimeric complex\"\n    ],\n    \"partners\": [\n      \"EXOSC10\",\n      \"MPP6\",\n      \"TRAX\",\n      \"SMC4\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"C1D is a conserved nuclear nucleic acid-binding protein that operates at the intersection of DNA damage repair and RNA processing. It activates DNA-PK independently of DNA ends by directly binding DNA-PKcs, and its yeast orthologue is required for both non-homologous end joining and homologous recombination [PMID:9679063, PMID:12421302]. C1D also functions as a transcriptional corepressor (SUN-CoR) that potentiates repression by thyroid hormone receptor and RevErb through interaction with N-CoR/SMRT [PMID:9405624]. Through its conserved Sas10/C1D domain, C1D associates with the nuclear RNA exosome via PM/Scl-100, exhibits structured-RNA-binding activity, and is required for 3′-end processing of 5.8S rRNA precursors, while the orthologous yeast Rrp47 stabilizes the exoribonuclease Rrp6 and forms a composite surface that recruits the Mtr4 helicase [PMID:17412707, PMID:25319414].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Identification of C1D as a nuclear corepressor (SUN-CoR) established that this small nuclear protein amplifies transcriptional repression through nuclear hormone receptors and the N-CoR/SMRT corepressor complex.\",\n      \"evidence\": \"Cloning, in vivo reporter assays, in vitro binding, and co-immunoprecipitation with endogenous N-CoR\",\n      \"pmids\": [\"9405624\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous genomic targets of SUN-CoR-mediated repression not identified\", \"Whether DNA-repair and corepressor functions are mutually exclusive is unknown\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstration that C1D directly binds DNA-PKcs and activates DNA-PK without requiring DNA ends revealed an unusual mode of DNA-PK activation and positioned C1D as a DNA damage response factor.\",\n      \"evidence\": \"Yeast two-hybrid, co-immunoprecipitation, and in vitro kinase assay\",\n      \"pmids\": [\"9679063\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological conditions under which DNA-end-independent activation occurs in vivo are unclear\", \"Downstream signaling targets of C1D-activated DNA-PK not defined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Overexpression studies showed C1D induces p53-dependent apoptosis with a bystander effect, linking its DNA damage signaling role to cell death outcomes.\",\n      \"evidence\": \"Transient transfection with C1D-EGFP, TUNEL assay, fluorescence microscopy, and co-culture experiments in tumor cell lines\",\n      \"pmids\": [\"10362552\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression-only system; loss-of-function confirmation of apoptotic role absent\", \"Mechanism of bystander effect uncharacterized\", \"Relevance at endogenous expression levels not tested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Two studies collectively established C1D's role in double-strand break repair: the yeast orthologue is required for both NHEJ and homologous recombination, and C1D interacts with TRAX in a DNA-damage-dependent manner to modulate TRAX/Translin complex assembly.\",\n      \"evidence\": \"Yeast gene disruption with in vivo recombination assays; yeast two-hybrid and co-immunoprecipitation with gamma-irradiation in mammalian cells\",\n      \"pmids\": [\"12421302\", \"11801738\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the C1D–TRAX interaction is conserved in human DSB repair in vivo is untested\", \"Epistasis between C1D, DNA-PK, and TRAX pathways not resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Discovery that fission yeast C1D binds the condensin SMC hinge domain and suppresses condensin mutant phenotypes revealed a third route by which C1D promotes DNA repair—through the condensin complex.\",\n      \"evidence\": \"GST pull-down, co-immunoprecipitation, genetic dosage suppression, chromatin fractionation, and immunofluorescence in S. pombe\",\n      \"pmids\": [\"15148393\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether human C1D–condensin interaction occurs is not established\", \"Molecular mechanism by which C1D enhances condensin-mediated repair is unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identification of C1D as an RNA exosome cofactor that binds PM/Scl-100, localizes to nucleoli, binds structured RNAs, and is required for 5.8S rRNA 3′-end processing established a major non-repair function for C1D in ribosome biogenesis.\",\n      \"evidence\": \"Co-immunoprecipitation, immunofluorescence, in vitro trimeric complex reconstitution with MPP6 and PM/Scl-100, RNA-binding assay, and RNAi knockdown with Northern blot in human cells\",\n      \"pmids\": [\"17412707\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full spectrum of exosome RNA substrates requiring C1D is not mapped\", \"How C1D partitions between DNA repair and RNA processing functions is unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Domain dissection of the yeast orthologue Rrp47 showed that the Sas10/C1D domain serves as a dual protein–nucleic acid docking module: its N-terminal portion binds Rrp6, while the C-terminal region binds RNA and snoRNP proteins Nop56/Nop58, and is specifically required for snoRNA 3′-end maturation.\",\n      \"evidence\": \"Deletion complementation in yeast, in vitro protein capture, filter binding RNA assays, synthetic lethality analysis\",\n      \"pmids\": [\"20659009\", \"21135092\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether human C1D retains the bipartite domain architecture with separable functions is untested\", \"Structural basis for RNA substrate selectivity not determined at this point\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Rrp47 was shown to stabilize Rrp6 protein and transcript levels in yeast, establishing a chaperone-like dependency between the Sas10/C1D-domain protein and its exonuclease partner.\",\n      \"evidence\": \"Western blot and Northern blot in rrp47Δ yeast, exogenous Rrp6 expression rescue\",\n      \"pmids\": [\"24224060\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether human C1D similarly stabilizes EXOSC10/PM-Scl-100 is unknown\", \"Mechanism of transcript-level regulation not dissected\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Crystal structure of the Rrp6–Rrp47 N-terminal complex revealed a highly intertwined unit with a conserved groove that recruits the Mtr4 helicase to the exosome, providing the first atomic-resolution view of how the Sas10/C1D domain organizes exosome cofactor assembly.\",\n      \"evidence\": \"X-ray crystallography, structure-guided mutagenesis, in vitro binding, and yeast growth assays\",\n      \"pmids\": [\"25319414\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No equivalent structural data for human C1D–EXOSC10 complex\", \"How Mtr4 recruitment is coordinated with ongoing RNA processing is not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How C1D partitions between its distinct functions in DNA repair (DNA-PK activation, NHEJ/HR, condensin interaction) and RNA processing (exosome cofactor, rRNA/snoRNA maturation), and whether these roles are regulated by post-translational modifications or damage signaling, remains an open question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No systematic separation-of-function mutant analysis in mammalian cells\", \"Post-translational regulation of C1D is uncharacterized\", \"Structural basis of the human C1D–DNA-PKcs interaction is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [6, 7, 8]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0, 3, 4, 5]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [6, 7, 8, 9, 10]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\n      \"Nuclear RNA exosome (via PM/Scl-100–MPP6 trimeric subcomplex)\",\n      \"N-CoR/SMRT corepressor complex\"\n    ],\n    \"partners\": [\n      \"PRKDC\",\n      \"EXOSC10\",\n      \"MPP6\",\n      \"NCOR1\",\n      \"NCOR2\",\n      \"TSNAX\",\n      \"SMC4\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}