{"gene":"C1D","run_date":"2026-06-09T22:02:45","timeline":{"discoveries":[{"year":1998,"finding":"C1D interacts with the putative leucine zipper region of DNA-PKcs (identified by yeast two-hybrid), co-immunoprecipitates with DNA-PK in mammalian cells, serves as a highly efficient DNA-PK substrate in vitro, and activates DNA-PK in a manner that does not require DNA termini.","method":"Yeast two-hybrid, co-immunoprecipitation, in vitro kinase assay","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP in mammalian cells plus in vitro kinase assay, two orthogonal methods, foundational study replicated conceptually by later work","pmids":["9679063"],"is_preprint":false},{"year":1998,"finding":"C1D (identified as the human homolog of murine SUN-CoR) interacts with constitutively active but not GDP-bound Rac3 in yeast two-hybrid and in co-immunoprecipitation from COS cells, indicating C1D acts as an effector of activated Rac3.","method":"Yeast two-hybrid, co-immunoprecipitation in mammalian cells","journal":"International journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid confirmed by co-IP in COS cells, single lab, two methods but no functional follow-up for this interaction","pmids":["9852280"],"is_preprint":false},{"year":1999,"finding":"Overexpression of C1D induces apoptosis (TUNEL-positive, morphological changes) in a p53-dependent manner; cells lacking functional p53 are resistant to C1D-induced apoptosis.","method":"Transient transfection with EGFP-tagged C1D, TUNEL assay, fluorescence microscopy, use of p53-null cell lines","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with defined cellular phenotype and p53 dependency established using p53-deficient cells, single lab","pmids":["10362552"],"is_preprint":false},{"year":2002,"finding":"C1D interacts specifically with TRAX (Translin-associated factor X) in both yeast and mammalian cells, but the interaction in mammalian cells occurs only following gamma-irradiation, linking C1D-TRAX complex formation to the DNA damage response.","method":"Yeast two-hybrid, co-immunoprecipitation in mammalian cells after gamma-irradiation","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid confirmed by co-IP in mammalian cells with irradiation-dependent condition, single lab, two orthogonal methods","pmids":["11801738"],"is_preprint":false},{"year":2002,"finding":"Disruption of the S. cerevisiae C1D homologue (YC1D) causes defects in both non-homologous end joining (NHEJ) and homologous recombination, demonstrating a role for C1D in both major DSB repair pathways.","method":"Yeast gene knockout, NHEJ assay, plasmid-based in vivo recombination assay","journal":"Molecular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function genetic analysis with two distinct in vivo repair assays, single lab","pmids":["12421302"],"is_preprint":false},{"year":2002,"finding":"C1D protein levels are regulated by the proteasome; inhibition of proteasome-dependent degradation leads to accumulation of C1D and increased apoptosis, indicating proteasomal degradation prevents C1D from reaching apoptosis-inducing levels.","method":"Proteasome inhibitor treatment, EGFP-C1D expression, flow cytometry/fluorescence quantification","journal":"Cancer cell international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pharmacological inhibition only, no direct ubiquitination or E3 ligase identified","pmids":["12379155"],"is_preprint":false},{"year":2004,"finding":"The S. pombe C1D homologue Cti1 physically interacts with the hinge domain of the condensin SMC subunit Cut3/SMC4, as shown by GST pull-down and co-immunoprecipitation. Overexpression of spC1D suppresses temperature, UV, and hydroxyurea sensitivity of a condensin non-SMC subunit (Cnd2) mutant, and upon HU treatment spC1D accumulates on nuclear chromatin.","method":"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, genetic suppression, chromatin fractionation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP and GST pull-down confirming direct interaction, plus genetic epistasis by dosage suppression, multiple orthogonal methods in one study","pmids":["15148393"],"is_preprint":false},{"year":2007,"finding":"Human C1D co-localizes with exosome subunit PM/Scl-100 in the nucleoli of HEp-2 cells; its nucleolar accumulation is dependent on PM/Scl-100. C1D directly binds PM/Scl-100 in protein-protein interaction studies, and C1D, MPP6, and PM/Scl-100 form a stable trimeric complex in vitro. C1D displays RNA-binding activity with preference for structured RNAs. RNAi knockdown of C1D causes accumulation of 3'-extended 5.8S rRNA precursors.","method":"Subcellular localization (immunofluorescence), RNAi knockdown, in vitro protein interaction/trimeric complex reconstitution, RNA-binding assay, Northern blot","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (localization, in vitro complex reconstitution, knockdown with rRNA processing phenotype, RNA-binding assay) in a single rigorous study","pmids":["17412707"],"is_preprint":false},{"year":2010,"finding":"The N-terminal Sas10/C1D domain of yeast Rrp47 (C1D homolog) is sufficient for binding the PMC2NT domain of Rrp6, while the C-terminal region of Rrp47 mediates interaction with snoRNP components Nop56 and Nop58 and contributes to RNA binding. The C-terminal lysine-rich sequence is required for RNA binding in vitro.","method":"Deletion complementation in yeast, in vitro protein interaction (protein capture assay), filter binding assay for RNA","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain mapping with in vivo complementation and multiple in vitro binding assays, multiple orthogonal methods in one study","pmids":["21135092"],"is_preprint":false},{"year":2010,"finding":"XPB (xeroderma pigmentosum B protein) is required for transcriptional induction of C1D after UV irradiation; C1D is upregulated by XPB and directly interacts with XPB, facilitating UV-induced DNA repair.","method":"Differential display mRNA analysis, complementation of XPB-deficient cells, co-immunoprecipitation","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — mRNA differential display and co-IP showing C1D-XPB interaction, single lab, two methods","pmids":["20530579"],"is_preprint":false},{"year":2013,"finding":"Rrp47 (C1D yeast ortholog) is expressed as a non-globular homodimer in isolation but forms a heterodimer with Rrp6 upon interaction, indicating a structural reconfiguration. Both Rrp6 and Rrp47 localize to the yeast nucleus independently; Rrp6 uses nuclear import adaptor Srp1 while Rrp47 does not. In the absence of Rrp6, newly synthesized Rrp47 is rapidly degraded in a proteasome-dependent manner.","method":"Recombinant protein purification, analytical ultracentrifugation/biophysical analysis, GFP localization, co-immunoprecipitation with Srp1, proteasome inhibition","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — recombinant protein reconstitution with biophysical characterization, GFP localization, and proteasome inhibition, multiple orthogonal methods","pmids":["23580640"],"is_preprint":false},{"year":2013,"finding":"Rrp47 can function in RNA surveillance and snoRNA maturation independently of the catalytic and exosome-binding domains of Rrp6, as shown by DECOID strategy separating the Rrp6/Rrp47 complex in vivo; the C-terminal region of Rrp47 is essential for cell growth.","method":"DECOID (overexpression of interacting domains), Northern blot analysis, yeast genetic analysis with synthetic-lethal mutants","journal":"RNA","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel genetic strategy with RNA analysis, single lab, well-controlled but not independently replicated","pmids":["24106327"],"is_preprint":false},{"year":2013,"finding":"Rrp47 (C1D yeast ortholog) is required to maintain appropriate Rrp6 expression levels; in rrp47∆ mutants grown in minimal medium, Rrp6 is substantially reduced at both transcript and protein levels. Exogenous Rrp6 expression suppresses most but not all RNA processing defects of rrp47∆, demonstrating that a principal function of Rrp47 is to stabilize Rrp6.","method":"Western blot, Northern blot, exogenous gene expression rescue, yeast genetics (double mutants)","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple readouts (protein, RNA, rescue experiment), single lab","pmids":["24224060"],"is_preprint":false},{"year":2014,"finding":"Rrp47 (C1D yeast ortholog) N-terminal domain and Rrp6 N-terminal domain form a highly intertwined structural unit (crystallographic analysis); together they create a composite conserved surface groove that recruits the N-terminus of the Mtr4 helicase. Binding of Mtr4 to the exosome core (Exo-10) in vitro requires both Rrp6 and Rrp47; mutation of conserved interface residues in Rrp6 and Mtr4 disrupts their interaction and impairs yeast growth.","method":"X-ray crystallography, in vitro binding assays, site-directed mutagenesis, yeast growth assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with mutagenesis and in vitro binding reconstitution, multiple orthogonal methods in one rigorous study","pmids":["25319414"],"is_preprint":false},{"year":2024,"finding":"C1D was identified as a component of the human nuclear RNA exosome pathway acting on MALAT1 3' end processing and degradation, confirmed by CRISPR-based forward genetic screen (Mirror approach) in human cells.","method":"Mirror forward genetics (single-cell CRISPR screen with cytoplasmic fluorescence readout)","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single screen method, no direct mechanistic follow-up for C1D specifically","pmids":["bio_10.1101_2024.09.26.615073"],"is_preprint":true}],"current_model":"C1D (Rrp47/SUN-CoR) is a conserved nuclear protein with dual roles: as an exosome-associated RNA-processing cofactor, it binds the PM/Scl-100/Rrp6 exoribonuclease via its N-terminal Sas10/C1D domain, forms a composite surface with Rrp6 that recruits the Mtr4 helicase, stabilizes Rrp6 protein levels, and is required for 3' end processing of 5.8S rRNA and box C/D snoRNAs; in DNA damage responses, C1D activates DNA-PK in a DNA-terminus-independent manner by binding the DNA-PKcs leucine zipper region, interacts with TRAX specifically after gamma-irradiation, interacts with condensin SMC hinge domains, and when overexpressed induces p53-dependent apoptosis that is counteracted by proteasomal degradation."},"narrative":{"mechanistic_narrative":"C1D (Rrp47) is a conserved nuclear protein that functions as an essential cofactor of the RNA exosome and participates in DNA damage signaling [PMID:17412707, PMID:9679063]. Through its N-terminal Sas10/C1D domain it binds the PMC2NT domain of the exosome-associated exoribonuclease Rrp6 (PM/Scl-100), forming an intertwined heterodimer that reconfigures C1D from its isolated homodimeric state and creates a composite conserved surface groove recruiting the Mtr4 helicase to the exosome core [PMID:21135092, PMID:23580640, PMID:25319414]. A principal role of C1D is to stabilize Rrp6: in its absence newly synthesized Rrp6 is reduced and unbound C1D is itself rapidly degraded by the proteasome [PMID:23580640, PMID:24224060]. C1D binds structured RNAs and, together with PM/Scl-100 and MPP6, forms a stable trimeric complex required for 3' end processing of 5.8S rRNA and box C/D snoRNAs; its C-terminal region mediates interaction with snoRNP components Nop56/Nop58 and contributes to RNA binding [PMID:17412707, PMID:21135092]. Independent of its RNA-processing role, C1D activates DNA-PK by binding the leucine zipper region of DNA-PKcs in a manner not requiring DNA termini, interacts with TRAX specifically after gamma-irradiation, and its yeast homolog is required for both NHEJ and homologous recombination [PMID:9679063, PMID:11801738, PMID:12421302]. C1D also binds the condensin SMC4 hinge domain and accumulates on chromatin under replication stress [PMID:15148393], and its overexpression induces p53-dependent apoptosis that is held in check by proteasomal turnover [PMID:10362552, PMID:12379155].","teleology":[{"year":1998,"claim":"Established C1D as a direct activator of the DNA-PK kinase, defining its earliest function in DNA damage signaling.","evidence":"Yeast two-hybrid against DNA-PKcs, co-IP in mammalian cells, in vitro kinase assay","pmids":["9679063"],"confidence":"High","gaps":["Mechanism of DNA-terminus-independent activation not structurally resolved","Physiological trigger for C1D-DNA-PK engagement not defined"]},{"year":1999,"claim":"Showed that excess C1D drives apoptosis through a p53-dependent route, linking C1D dosage to cell-death control.","evidence":"EGFP-C1D transfection, TUNEL, p53-null cell lines","pmids":["10362552"],"confidence":"Medium","gaps":["Molecular link between C1D and p53 activation unknown","Overexpression phenotype may not reflect endogenous function"]},{"year":2002,"claim":"Connected C1D to DNA double-strand-break repair through an irradiation-dependent TRAX interaction and a genetic requirement in both repair pathways.","evidence":"Yeast two-hybrid and post-irradiation co-IP for TRAX; yeast knockout with NHEJ and recombination assays","pmids":["11801738","12421302"],"confidence":"Medium","gaps":["Biochemical role of C1D-TRAX complex in repair undefined","Whether DNA-PK activation and repair phenotypes are mechanistically linked unresolved"]},{"year":2002,"claim":"Demonstrated that proteasomal degradation restrains C1D levels below an apoptotic threshold.","evidence":"Proteasome inhibitor treatment with EGFP-C1D quantification","pmids":["12379155"],"confidence":"Low","gaps":["No E3 ligase or direct ubiquitination demonstrated","Pharmacological inhibition only"]},{"year":2004,"claim":"Identified a physical link between C1D and condensin via the SMC4 hinge, implicating C1D in chromosome organization under stress.","evidence":"GST pull-down, co-IP, genetic dosage suppression, and chromatin fractionation in S. pombe","pmids":["15148393"],"confidence":"High","gaps":["Functional consequence of C1D-condensin binding not defined","Whether this interaction is conserved in human cells untested"]},{"year":2007,"claim":"Defined C1D as a nucleolar exosome cofactor required for rRNA 3' processing, establishing its RNA-processing role.","evidence":"Immunofluorescence co-localization, RNAi knockdown with Northern blot, in vitro trimeric complex reconstitution, RNA-binding assay","pmids":["17412707"],"confidence":"High","gaps":["Mechanism coupling RNA binding to Rrp6 catalysis not detailed","Substrate range beyond 5.8S rRNA not fully mapped at this stage"]},{"year":2010,"claim":"Mapped C1D/Rrp47 domains to Rrp6 binding (N-terminal) versus snoRNP and RNA binding (C-terminal), separating its two molecular contacts.","evidence":"Deletion complementation in yeast, protein capture and filter-binding assays","pmids":["21135092"],"confidence":"High","gaps":["Structural basis of C-terminal RNA recognition not resolved here","How Nop56/Nop58 contacts integrate with exosome function unclear"]},{"year":2010,"claim":"Linked C1D induction to nucleotide-excision repair through XPB-dependent UV upregulation and direct interaction.","evidence":"Differential display, XPB-deficient cell complementation, co-IP","pmids":["20530579"],"confidence":"Medium","gaps":["Functional output of C1D-XPB interaction in repair undefined","Single-lab observation without reciprocal validation"]},{"year":2013,"claim":"Resolved the structural and regulatory logic of the Rrp47-Rrp6 partnership and showed Rrp47 can act partly independently of Rrp6 catalysis while stabilizing Rrp6 protein.","evidence":"Recombinant protein biophysics, GFP localization, proteasome inhibition, DECOID genetic separation, and Rrp6 rescue with Northern/Western analysis","pmids":["23580640","24106327","24224060"],"confidence":"High","gaps":["Determinants of Rrp47 homodimer-to-heterodimer switch not fully defined","Identity of degradation machinery for free Rrp47 unknown"]},{"year":2014,"claim":"Provided the structural mechanism by which the Rrp6-Rrp47 composite surface recruits the Mtr4 helicase to the exosome.","evidence":"X-ray crystallography, in vitro binding reconstitution, interface mutagenesis, yeast growth assays","pmids":["25319414"],"confidence":"High","gaps":["Dynamics of Mtr4 handoff to the exosome core not captured","Human structural equivalence not directly demonstrated"]},{"year":2024,"claim":"Extended C1D's exosome function to a specific human substrate, MALAT1 3' processing and degradation.","evidence":"Mirror single-cell CRISPR forward genetic screen in human cells (preprint)","pmids":["bio_10.1101_2024.09.26.615073"],"confidence":"Low","gaps":["Preprint, single screen method with no direct mechanistic follow-up for C1D","Direct biochemical role in MALAT1 processing not shown"]},{"year":null,"claim":"How C1D's exosome RNA-processing role and its DNA-damage/apoptosis activities are coordinated within the same cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking RNA surveillance to DNA-PK activation","Whether the two roles share regulatory inputs or are mutually exclusive is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[7,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,12,13]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[13]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[7]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[10]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[7,13]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0,4]}],"complexes":["RNA exosome (Rrp6-Rrp47-MPP6 module)","DNA-PK complex"],"partners":["EXOSC10/PM-SCL-100/RRP6","MTREX/MTR4","MPHOSPH6/MPP6","PRKDC/DNA-PKCS","TSNAX/TRAX","SMC4/CUT3","ERCC3/XPB","NOP56"],"other_free_text":[]}},"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":"17412707","id":"PMC_17412707","title":"C1D and hMtr4p associate with the human exosome subunit PM/Scl-100 and are involved in pre-rRNA processing.","date":"2007","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/17412707","citation_count":122,"is_preprint":false},{"pmid":"25319414","id":"PMC_25319414","title":"The exosome-binding factors Rrp6 and Rrp47 form a composite surface for recruiting the Mtr4 helicase.","date":"2014","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/25319414","citation_count":94,"is_preprint":false},{"pmid":"9679063","id":"PMC_9679063","title":"DNA end-independent activation of DNA-PK mediated via association with the DNA-binding protein C1D.","date":"1998","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/9679063","citation_count":71,"is_preprint":false},{"pmid":"11801738","id":"PMC_11801738","title":"DNA damage-dependent interaction of the nuclear matrix protein C1D with Translin-associated factor X (TRAX).","date":"2002","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/11801738","citation_count":49,"is_preprint":false},{"pmid":"21713680","id":"PMC_21713680","title":"Rrp6, rrp47 and cofactors of the nuclear exosome.","date":"2011","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/21713680","citation_count":46,"is_preprint":false},{"pmid":"22573824","id":"PMC_22573824","title":"A FAP46 mutant provides new insights into the function and assembly of the C1d complex of the ciliary central apparatus.","date":"2012","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/22573824","citation_count":38,"is_preprint":false},{"pmid":"12421302","id":"PMC_12421302","title":"Saccharomyces cerevisiae C1D is implicated in both non-homologous DNA end joining and homologous recombination.","date":"2002","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/12421302","citation_count":37,"is_preprint":false},{"pmid":"21135092","id":"PMC_21135092","title":"The C-terminal region of the exosome-associated protein Rrp47 is specifically required for box C/D small nucleolar RNA 3'-maturation.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21135092","citation_count":36,"is_preprint":false},{"pmid":"15148393","id":"PMC_15148393","title":"Cti1/C1D interacts with condensin SMC hinge and supports the DNA repair function of condensin.","date":"2004","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/15148393","citation_count":34,"is_preprint":false},{"pmid":"24224060","id":"PMC_24224060","title":"The exosome cofactor Rrp47 is critical for the stability and normal expression of its associated exoribonuclease Rrp6 in Saccharomyces cerevisiae.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24224060","citation_count":30,"is_preprint":false},{"pmid":"23580640","id":"PMC_23580640","title":"Assembly of the yeast exoribonuclease Rrp6 with its associated cofactor Rrp47 occurs in the nucleus and is critical for the controlled expression of Rrp47.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23580640","citation_count":24,"is_preprint":false},{"pmid":"10362552","id":"PMC_10362552","title":"Induction of apoptosis by overexpression of the DNA-binding and DNA-PK-activating protein C1D.","date":"1999","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/10362552","citation_count":21,"is_preprint":false},{"pmid":"21618877","id":"PMC_21618877","title":"Rrp6, Rrp47 and cofactors of the nuclear exosome.","date":"2010","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/21618877","citation_count":21,"is_preprint":false},{"pmid":"20659009","id":"PMC_20659009","title":"Rrp47 and the function of the Sas10/C1D domain.","date":"2010","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/20659009","citation_count":18,"is_preprint":false},{"pmid":"39362668","id":"PMC_39362668","title":"Pathogenic variants in CFAP46, CFAP54, CFAP74 and CFAP221 cause primary ciliary dyskinesia with a defective C1d projection of the central apparatus.","date":"2024","source":"The European respiratory journal","url":"https://pubmed.ncbi.nlm.nih.gov/39362668","citation_count":15,"is_preprint":false},{"pmid":"24106327","id":"PMC_24106327","title":"Rrp47 functions in RNA surveillance and stable RNA processing when divorced from the exoribonuclease and exosome-binding domains of Rrp6.","date":"2013","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/24106327","citation_count":14,"is_preprint":false},{"pmid":"27030795","id":"PMC_27030795","title":"C1D family proteins in coordinating RNA processing, chromosome condensation and DNA damage response.","date":"2016","source":"Cell division","url":"https://pubmed.ncbi.nlm.nih.gov/27030795","citation_count":12,"is_preprint":false},{"pmid":"17599775","id":"PMC_17599775","title":"C1D is a major autoantibody target in patients with the polymyositis-scleroderma overlap syndrome.","date":"2007","source":"Arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/17599775","citation_count":12,"is_preprint":false},{"pmid":"11311939","id":"PMC_11311939","title":"Promoter of the gene encoding the 16 kDa DNA-binding and apoptosis-inducing C1D protein.","date":"2001","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/11311939","citation_count":11,"is_preprint":false},{"pmid":"9852280","id":"PMC_9852280","title":"Identification of a novel Rac3-interacting protein C1D.","date":"1998","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/9852280","citation_count":11,"is_preprint":false},{"pmid":"20530579","id":"PMC_20530579","title":"XPB induces C1D expression to counteract UV-induced apoptosis.","date":"2010","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/20530579","citation_count":10,"is_preprint":false},{"pmid":"26509686","id":"PMC_26509686","title":"A South American Prehistoric Mitogenome: Context, Continuity, and the Origin of Haplogroup C1d.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26509686","citation_count":6,"is_preprint":false},{"pmid":"12379155","id":"PMC_12379155","title":"Proteasome-mediated degradation antagonizes critical levels of the apoptosis-inducing C1D protein.","date":"2002","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/12379155","citation_count":5,"is_preprint":false},{"pmid":"21695136","id":"PMC_21695136","title":"Control region variability of haplogroup C1d and the tempo of the peopling of the Americas.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21695136","citation_count":3,"is_preprint":false},{"pmid":"42157077","id":"PMC_42157077","title":"A conserved Sas10/C1D domain protein, CaLrp1, is a critical regulator of hyphal development and pathogenicity in Candida albicans.","date":"2026","source":"BMC microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/42157077","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.09.26.615073","title":"Identification of Human Pathways Acting on Nuclear Non-Coding RNAs Using the Mirror Forward Genetic Approach","date":"2024-09-27","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.26.615073","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13437,"output_tokens":3702,"usd":0.04792,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11286,"output_tokens":3486,"usd":0.07179,"stage2_stop_reason":"end_turn"},"total_usd":0.11971,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"C1D interacts with the putative leucine zipper region of DNA-PKcs (identified by yeast two-hybrid), co-immunoprecipitates with DNA-PK in mammalian cells, serves as a highly efficient DNA-PK substrate in vitro, and activates DNA-PK in a manner that does not require DNA termini.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, in vitro kinase assay\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP in mammalian cells plus in vitro kinase assay, two orthogonal methods, foundational study replicated conceptually by later work\",\n      \"pmids\": [\"9679063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"C1D (identified as the human homolog of murine SUN-CoR) interacts with constitutively active but not GDP-bound Rac3 in yeast two-hybrid and in co-immunoprecipitation from COS cells, indicating C1D acts as an effector of activated Rac3.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation in mammalian cells\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid confirmed by co-IP in COS cells, single lab, two methods but no functional follow-up for this interaction\",\n      \"pmids\": [\"9852280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Overexpression of C1D induces apoptosis (TUNEL-positive, morphological changes) in a p53-dependent manner; cells lacking functional p53 are resistant to C1D-induced apoptosis.\",\n      \"method\": \"Transient transfection with EGFP-tagged C1D, TUNEL assay, fluorescence microscopy, use of p53-null cell lines\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with defined cellular phenotype and p53 dependency established using p53-deficient cells, single lab\",\n      \"pmids\": [\"10362552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"C1D interacts specifically with TRAX (Translin-associated factor X) in both yeast and mammalian cells, but the interaction in mammalian cells occurs only following gamma-irradiation, linking C1D-TRAX complex formation to the DNA damage response.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation in mammalian cells after gamma-irradiation\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid confirmed by co-IP in mammalian cells with irradiation-dependent condition, single lab, two orthogonal methods\",\n      \"pmids\": [\"11801738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Disruption of the S. cerevisiae C1D homologue (YC1D) causes defects in both non-homologous end joining (NHEJ) and homologous recombination, demonstrating a role for C1D in both major DSB repair pathways.\",\n      \"method\": \"Yeast gene knockout, NHEJ assay, plasmid-based in vivo recombination assay\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function genetic analysis with two distinct in vivo repair assays, single lab\",\n      \"pmids\": [\"12421302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"C1D protein levels are regulated by the proteasome; inhibition of proteasome-dependent degradation leads to accumulation of C1D and increased apoptosis, indicating proteasomal degradation prevents C1D from reaching apoptosis-inducing levels.\",\n      \"method\": \"Proteasome inhibitor treatment, EGFP-C1D expression, flow cytometry/fluorescence quantification\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pharmacological inhibition only, no direct ubiquitination or E3 ligase identified\",\n      \"pmids\": [\"12379155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The S. pombe C1D homologue Cti1 physically interacts with the hinge domain of the condensin SMC subunit Cut3/SMC4, as shown by GST pull-down and co-immunoprecipitation. Overexpression of spC1D suppresses temperature, UV, and hydroxyurea sensitivity of a condensin non-SMC subunit (Cnd2) mutant, and upon HU treatment spC1D accumulates on nuclear chromatin.\",\n      \"method\": \"Yeast two-hybrid, 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 2 / Strong — reciprocal Co-IP and GST pull-down confirming direct interaction, plus genetic epistasis by dosage suppression, multiple orthogonal methods in one study\",\n      \"pmids\": [\"15148393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Human C1D co-localizes with exosome subunit PM/Scl-100 in the nucleoli of HEp-2 cells; its nucleolar accumulation is dependent on PM/Scl-100. C1D directly binds PM/Scl-100 in protein-protein interaction studies, and C1D, MPP6, and PM/Scl-100 form a stable trimeric complex in vitro. C1D displays RNA-binding activity with preference for structured RNAs. RNAi knockdown of C1D causes accumulation of 3'-extended 5.8S rRNA precursors.\",\n      \"method\": \"Subcellular localization (immunofluorescence), RNAi knockdown, in vitro protein interaction/trimeric complex reconstitution, RNA-binding assay, Northern blot\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (localization, in vitro complex reconstitution, knockdown with rRNA processing phenotype, RNA-binding assay) in a single rigorous study\",\n      \"pmids\": [\"17412707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The N-terminal Sas10/C1D domain of yeast Rrp47 (C1D homolog) is sufficient for binding the PMC2NT domain of Rrp6, while the C-terminal region of Rrp47 mediates interaction with snoRNP components Nop56 and Nop58 and contributes to RNA binding. The C-terminal lysine-rich sequence is required for RNA binding in vitro.\",\n      \"method\": \"Deletion complementation in yeast, in vitro protein interaction (protein capture assay), filter binding assay for RNA\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain mapping with in vivo complementation and multiple in vitro binding assays, multiple orthogonal methods in one study\",\n      \"pmids\": [\"21135092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"XPB (xeroderma pigmentosum B protein) is required for transcriptional induction of C1D after UV irradiation; C1D is upregulated by XPB and directly interacts with XPB, facilitating UV-induced DNA repair.\",\n      \"method\": \"Differential display mRNA analysis, complementation of XPB-deficient cells, co-immunoprecipitation\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — mRNA differential display and co-IP showing C1D-XPB interaction, single lab, two methods\",\n      \"pmids\": [\"20530579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Rrp47 (C1D yeast ortholog) is expressed as a non-globular homodimer in isolation but forms a heterodimer with Rrp6 upon interaction, indicating a structural reconfiguration. Both Rrp6 and Rrp47 localize to the yeast nucleus independently; Rrp6 uses nuclear import adaptor Srp1 while Rrp47 does not. In the absence of Rrp6, newly synthesized Rrp47 is rapidly degraded in a proteasome-dependent manner.\",\n      \"method\": \"Recombinant protein purification, analytical ultracentrifugation/biophysical analysis, GFP localization, co-immunoprecipitation with Srp1, proteasome inhibition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — recombinant protein reconstitution with biophysical characterization, GFP localization, and proteasome inhibition, multiple orthogonal methods\",\n      \"pmids\": [\"23580640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Rrp47 can function in RNA surveillance and snoRNA maturation independently of the catalytic and exosome-binding domains of Rrp6, as shown by DECOID strategy separating the Rrp6/Rrp47 complex in vivo; the C-terminal region of Rrp47 is essential for cell growth.\",\n      \"method\": \"DECOID (overexpression of interacting domains), Northern blot analysis, yeast genetic analysis with synthetic-lethal mutants\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel genetic strategy with RNA analysis, single lab, well-controlled but not independently replicated\",\n      \"pmids\": [\"24106327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Rrp47 (C1D yeast ortholog) is required to maintain appropriate Rrp6 expression levels; in rrp47∆ mutants grown in minimal medium, Rrp6 is substantially reduced at both transcript and protein levels. Exogenous Rrp6 expression suppresses most but not all RNA processing defects of rrp47∆, demonstrating that a principal function of Rrp47 is to stabilize Rrp6.\",\n      \"method\": \"Western blot, Northern blot, exogenous gene expression rescue, yeast genetics (double mutants)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple readouts (protein, RNA, rescue experiment), single lab\",\n      \"pmids\": [\"24224060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Rrp47 (C1D yeast ortholog) N-terminal domain and Rrp6 N-terminal domain form a highly intertwined structural unit (crystallographic analysis); together they create a composite conserved surface groove that recruits the N-terminus of the Mtr4 helicase. Binding of Mtr4 to the exosome core (Exo-10) in vitro requires both Rrp6 and Rrp47; mutation of conserved interface residues in Rrp6 and Mtr4 disrupts their interaction and impairs yeast growth.\",\n      \"method\": \"X-ray crystallography, in vitro binding assays, site-directed mutagenesis, yeast growth assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with mutagenesis and in vitro binding reconstitution, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"25319414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"C1D was identified as a component of the human nuclear RNA exosome pathway acting on MALAT1 3' end processing and degradation, confirmed by CRISPR-based forward genetic screen (Mirror approach) in human cells.\",\n      \"method\": \"Mirror forward genetics (single-cell CRISPR screen with cytoplasmic fluorescence readout)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single screen method, no direct mechanistic follow-up for C1D specifically\",\n      \"pmids\": [\"bio_10.1101_2024.09.26.615073\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"C1D (Rrp47/SUN-CoR) is a conserved nuclear protein with dual roles: as an exosome-associated RNA-processing cofactor, it binds the PM/Scl-100/Rrp6 exoribonuclease via its N-terminal Sas10/C1D domain, forms a composite surface with Rrp6 that recruits the Mtr4 helicase, stabilizes Rrp6 protein levels, and is required for 3' end processing of 5.8S rRNA and box C/D snoRNAs; in DNA damage responses, C1D activates DNA-PK in a DNA-terminus-independent manner by binding the DNA-PKcs leucine zipper region, interacts with TRAX specifically after gamma-irradiation, interacts with condensin SMC hinge domains, and when overexpressed induces p53-dependent apoptosis that is counteracted by proteasomal degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"C1D (Rrp47) is a conserved nuclear protein that functions as an essential cofactor of the RNA exosome and participates in DNA damage signaling [#7, #0]. Through its N-terminal Sas10/C1D domain it binds the PMC2NT domain of the exosome-associated exoribonuclease Rrp6 (PM/Scl-100), forming an intertwined heterodimer that reconfigures C1D from its isolated homodimeric state and creates a composite conserved surface groove recruiting the Mtr4 helicase to the exosome core [#8, #10, #13]. A principal role of C1D is to stabilize Rrp6: in its absence newly synthesized Rrp6 is reduced and unbound C1D is itself rapidly degraded by the proteasome [#10, #12]. C1D binds structured RNAs and, together with PM/Scl-100 and MPP6, forms a stable trimeric complex required for 3' end processing of 5.8S rRNA and box C/D snoRNAs; its C-terminal region mediates interaction with snoRNP components Nop56/Nop58 and contributes to RNA binding [#7, #8]. Independent of its RNA-processing role, C1D activates DNA-PK by binding the leucine zipper region of DNA-PKcs in a manner not requiring DNA termini, interacts with TRAX specifically after gamma-irradiation, and its yeast homolog is required for both NHEJ and homologous recombination [#0, #3, #4]. C1D also binds the condensin SMC4 hinge domain and accumulates on chromatin under replication stress [#6], and its overexpression induces p53-dependent apoptosis that is held in check by proteasomal turnover [#2, #5].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established C1D as a direct activator of the DNA-PK kinase, defining its earliest function in DNA damage signaling.\",\n      \"evidence\": \"Yeast two-hybrid against DNA-PKcs, co-IP in mammalian cells, in vitro kinase assay\",\n      \"pmids\": [\"9679063\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of DNA-terminus-independent activation not structurally resolved\", \"Physiological trigger for C1D-DNA-PK engagement not defined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Showed that excess C1D drives apoptosis through a p53-dependent route, linking C1D dosage to cell-death control.\",\n      \"evidence\": \"EGFP-C1D transfection, TUNEL, p53-null cell lines\",\n      \"pmids\": [\"10362552\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between C1D and p53 activation unknown\", \"Overexpression phenotype may not reflect endogenous function\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Connected C1D to DNA double-strand-break repair through an irradiation-dependent TRAX interaction and a genetic requirement in both repair pathways.\",\n      \"evidence\": \"Yeast two-hybrid and post-irradiation co-IP for TRAX; yeast knockout with NHEJ and recombination assays\",\n      \"pmids\": [\"11801738\", \"12421302\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biochemical role of C1D-TRAX complex in repair undefined\", \"Whether DNA-PK activation and repair phenotypes are mechanistically linked unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrated that proteasomal degradation restrains C1D levels below an apoptotic threshold.\",\n      \"evidence\": \"Proteasome inhibitor treatment with EGFP-C1D quantification\",\n      \"pmids\": [\"12379155\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No E3 ligase or direct ubiquitination demonstrated\", \"Pharmacological inhibition only\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified a physical link between C1D and condensin via the SMC4 hinge, implicating C1D in chromosome organization under stress.\",\n      \"evidence\": \"GST pull-down, co-IP, genetic dosage suppression, and chromatin fractionation in S. pombe\",\n      \"pmids\": [\"15148393\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of C1D-condensin binding not defined\", \"Whether this interaction is conserved in human cells untested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined C1D as a nucleolar exosome cofactor required for rRNA 3' processing, establishing its RNA-processing role.\",\n      \"evidence\": \"Immunofluorescence co-localization, RNAi knockdown with Northern blot, in vitro trimeric complex reconstitution, RNA-binding assay\",\n      \"pmids\": [\"17412707\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling RNA binding to Rrp6 catalysis not detailed\", \"Substrate range beyond 5.8S rRNA not fully mapped at this stage\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Mapped C1D/Rrp47 domains to Rrp6 binding (N-terminal) versus snoRNP and RNA binding (C-terminal), separating its two molecular contacts.\",\n      \"evidence\": \"Deletion complementation in yeast, protein capture and filter-binding assays\",\n      \"pmids\": [\"21135092\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of C-terminal RNA recognition not resolved here\", \"How Nop56/Nop58 contacts integrate with exosome function unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linked C1D induction to nucleotide-excision repair through XPB-dependent UV upregulation and direct interaction.\",\n      \"evidence\": \"Differential display, XPB-deficient cell complementation, co-IP\",\n      \"pmids\": [\"20530579\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional output of C1D-XPB interaction in repair undefined\", \"Single-lab observation without reciprocal validation\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved the structural and regulatory logic of the Rrp47-Rrp6 partnership and showed Rrp47 can act partly independently of Rrp6 catalysis while stabilizing Rrp6 protein.\",\n      \"evidence\": \"Recombinant protein biophysics, GFP localization, proteasome inhibition, DECOID genetic separation, and Rrp6 rescue with Northern/Western analysis\",\n      \"pmids\": [\"23580640\", \"24106327\", \"24224060\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of Rrp47 homodimer-to-heterodimer switch not fully defined\", \"Identity of degradation machinery for free Rrp47 unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided the structural mechanism by which the Rrp6-Rrp47 composite surface recruits the Mtr4 helicase to the exosome.\",\n      \"evidence\": \"X-ray crystallography, in vitro binding reconstitution, interface mutagenesis, yeast growth assays\",\n      \"pmids\": [\"25319414\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamics of Mtr4 handoff to the exosome core not captured\", \"Human structural equivalence not directly demonstrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended C1D's exosome function to a specific human substrate, MALAT1 3' processing and degradation.\",\n      \"evidence\": \"Mirror single-cell CRISPR forward genetic screen in human cells (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.09.26.615073\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint, single screen method with no direct mechanistic follow-up for C1D\", \"Direct biochemical role in MALAT1 processing not shown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How C1D's exosome RNA-processing role and its DNA-damage/apoptosis activities are coordinated within the same cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking RNA surveillance to DNA-PK activation\", \"Whether the two roles share regulatory inputs or are mutually exclusive is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 12, 13]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [7, 13]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"complexes\": [\n      \"RNA exosome (Rrp6-Rrp47-MPP6 module)\",\n      \"DNA-PK complex\"\n    ],\n    \"partners\": [\n      \"EXOSC10/PM-Scl-100/Rrp6\",\n      \"MTREX/Mtr4\",\n      \"MPHOSPH6/MPP6\",\n      \"PRKDC/DNA-PKcs\",\n      \"TSNAX/TRAX\",\n      \"SMC4/Cut3\",\n      \"ERCC3/XPB\",\n      \"NOP56\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}