Affinage

C1D

Nuclear nucleic acid-binding protein C1D · UniProt Q13901

Length
141 aa
Mass
16.0 kDa
Annotated
2026-06-09
25 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1998 High

    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

    PMID:9679063

    Open questions at the time
    • Mechanism of DNA-terminus-independent activation not structurally resolved
    • Physiological trigger for C1D-DNA-PK engagement not defined
  2. 1999 Medium

    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

    PMID:10362552

    Open questions at the time
    • Molecular link between C1D and p53 activation unknown
    • Overexpression phenotype may not reflect endogenous function
  3. 2002 Medium

    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

    PMID:11801738 PMID:12421302

    Open questions at the time
    • Biochemical role of C1D-TRAX complex in repair undefined
    • Whether DNA-PK activation and repair phenotypes are mechanistically linked unresolved
  4. 2002 Low

    Demonstrated that proteasomal degradation restrains C1D levels below an apoptotic threshold.

    Evidence Proteasome inhibitor treatment with EGFP-C1D quantification

    PMID:12379155

    Open questions at the time
    • No E3 ligase or direct ubiquitination demonstrated
    • Pharmacological inhibition only
  5. 2004 High

    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

    PMID:15148393

    Open questions at the time
    • Functional consequence of C1D-condensin binding not defined
    • Whether this interaction is conserved in human cells untested
  6. 2007 High

    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

    PMID:17412707

    Open questions at the time
    • Mechanism coupling RNA binding to Rrp6 catalysis not detailed
    • Substrate range beyond 5.8S rRNA not fully mapped at this stage
  7. 2010 High

    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

    PMID:21135092

    Open questions at the time
    • Structural basis of C-terminal RNA recognition not resolved here
    • How Nop56/Nop58 contacts integrate with exosome function unclear
  8. 2010 Medium

    Linked C1D induction to nucleotide-excision repair through XPB-dependent UV upregulation and direct interaction.

    Evidence Differential display, XPB-deficient cell complementation, co-IP

    PMID:20530579

    Open questions at the time
    • Functional output of C1D-XPB interaction in repair undefined
    • Single-lab observation without reciprocal validation
  9. 2013 High

    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

    PMID:23580640 PMID:24106327 PMID:24224060

    Open questions at the time
    • Determinants of Rrp47 homodimer-to-heterodimer switch not fully defined
    • Identity of degradation machinery for free Rrp47 unknown
  10. 2014 High

    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

    PMID:25319414

    Open questions at the time
    • Dynamics of Mtr4 handoff to the exosome core not captured
    • Human structural equivalence not directly demonstrated
  11. 2024 Low

    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)

    PMID:bio_10.1101_2024.09.26.615073

    Open questions at the time
    • Preprint, single screen method with no direct mechanistic follow-up for C1D
    • Direct biochemical role in MALAT1 processing not shown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How C1D's exosome RNA-processing role and its DNA-damage/apoptosis activities are coordinated within the same cell remains unresolved.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0003723 RNA binding 2 GO:0060090 molecular adaptor activity 1
Localization
GO:0005634 nucleus 1 GO:0005694 chromosome 1 GO:0005730 nucleolus 1
Pathway
R-HSA-73894 DNA Repair 2 R-HSA-8953854 Metabolism of RNA 2
Partners
ERCC3/XPBEXOSC10/PM-SCL-100/RRP6MPHOSPH6/MPP6MTREX/MTR4NOP56PRKDC/DNA-PKCSSMC4/CUT3TSNAX/TRAX
Complex memberships
DNA-PK complexRNA exosome (Rrp6-Rrp47-MPP6 module)

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 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. Yeast two-hybrid, co-immunoprecipitation, in vitro kinase assay Genes & development High 9679063
1998 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. Yeast two-hybrid, co-immunoprecipitation in mammalian cells International journal of molecular medicine Medium 9852280
1999 Overexpression of C1D induces apoptosis (TUNEL-positive, morphological changes) in a p53-dependent manner; cells lacking functional p53 are resistant to C1D-induced apoptosis. Transient transfection with EGFP-tagged C1D, TUNEL assay, fluorescence microscopy, use of p53-null cell lines Journal of cell science Medium 10362552
2002 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. Yeast two-hybrid, co-immunoprecipitation in mammalian cells after gamma-irradiation Journal of cell science Medium 11801738
2002 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. Yeast gene knockout, NHEJ assay, plasmid-based in vivo recombination assay Molecular microbiology Medium 12421302
2002 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. Proteasome inhibitor treatment, EGFP-C1D expression, flow cytometry/fluorescence quantification Cancer cell international Low 12379155
2004 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. Yeast two-hybrid, GST pull-down, co-immunoprecipitation, genetic suppression, chromatin fractionation Proceedings of the National Academy of Sciences of the United States of America High 15148393
2007 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. Subcellular localization (immunofluorescence), RNAi knockdown, in vitro protein interaction/trimeric complex reconstitution, RNA-binding assay, Northern blot Nucleic acids research High 17412707
2010 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. Deletion complementation in yeast, in vitro protein interaction (protein capture assay), filter binding assay for RNA The Journal of biological chemistry High 21135092
2010 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. Differential display mRNA analysis, complementation of XPB-deficient cells, co-immunoprecipitation Molecular cancer research Medium 20530579
2013 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. Recombinant protein purification, analytical ultracentrifugation/biophysical analysis, GFP localization, co-immunoprecipitation with Srp1, proteasome inhibition The Journal of biological chemistry High 23580640
2013 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. DECOID (overexpression of interacting domains), Northern blot analysis, yeast genetic analysis with synthetic-lethal mutants RNA Medium 24106327
2013 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. Western blot, Northern blot, exogenous gene expression rescue, yeast genetics (double mutants) PloS one Medium 24224060
2014 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. X-ray crystallography, in vitro binding assays, site-directed mutagenesis, yeast growth assays The EMBO journal High 25319414
2024 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. Mirror forward genetics (single-cell CRISPR screen with cytoplasmic fluorescence readout) bioRxivpreprint Low bio_10.1101_2024.09.26.615073

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 C1D and hMtr4p associate with the human exosome subunit PM/Scl-100 and are involved in pre-rRNA processing. Nucleic acids research 122 17412707
2014 The exosome-binding factors Rrp6 and Rrp47 form a composite surface for recruiting the Mtr4 helicase. The EMBO journal 94 25319414
1998 DNA end-independent activation of DNA-PK mediated via association with the DNA-binding protein C1D. Genes & development 71 9679063
2002 DNA damage-dependent interaction of the nuclear matrix protein C1D with Translin-associated factor X (TRAX). Journal of cell science 49 11801738
2011 Rrp6, rrp47 and cofactors of the nuclear exosome. Advances in experimental medicine and biology 46 21713680
2012 A FAP46 mutant provides new insights into the function and assembly of the C1d complex of the ciliary central apparatus. Journal of cell science 38 22573824
2002 Saccharomyces cerevisiae C1D is implicated in both non-homologous DNA end joining and homologous recombination. Molecular microbiology 37 12421302
2010 The C-terminal region of the exosome-associated protein Rrp47 is specifically required for box C/D small nucleolar RNA 3'-maturation. The Journal of biological chemistry 36 21135092
2004 Cti1/C1D interacts with condensin SMC hinge and supports the DNA repair function of condensin. Proceedings of the National Academy of Sciences of the United States of America 34 15148393
2013 The exosome cofactor Rrp47 is critical for the stability and normal expression of its associated exoribonuclease Rrp6 in Saccharomyces cerevisiae. PloS one 30 24224060
2013 Assembly of the yeast exoribonuclease Rrp6 with its associated cofactor Rrp47 occurs in the nucleus and is critical for the controlled expression of Rrp47. The Journal of biological chemistry 24 23580640
2010 Rrp6, Rrp47 and cofactors of the nuclear exosome. Advances in experimental medicine and biology 21 21618877
1999 Induction of apoptosis by overexpression of the DNA-binding and DNA-PK-activating protein C1D. Journal of cell science 21 10362552
2010 Rrp47 and the function of the Sas10/C1D domain. Biochemical Society transactions 18 20659009
2024 Pathogenic variants in CFAP46, CFAP54, CFAP74 and CFAP221 cause primary ciliary dyskinesia with a defective C1d projection of the central apparatus. The European respiratory journal 15 39362668
2013 Rrp47 functions in RNA surveillance and stable RNA processing when divorced from the exoribonuclease and exosome-binding domains of Rrp6. RNA (New York, N.Y.) 14 24106327
2016 C1D family proteins in coordinating RNA processing, chromosome condensation and DNA damage response. Cell division 12 27030795
2007 C1D is a major autoantibody target in patients with the polymyositis-scleroderma overlap syndrome. Arthritis and rheumatism 12 17599775
2001 Promoter of the gene encoding the 16 kDa DNA-binding and apoptosis-inducing C1D protein. Biochimica et biophysica acta 11 11311939
1998 Identification of a novel Rac3-interacting protein C1D. International journal of molecular medicine 11 9852280
2010 XPB induces C1D expression to counteract UV-induced apoptosis. Molecular cancer research : MCR 10 20530579
2015 A South American Prehistoric Mitogenome: Context, Continuity, and the Origin of Haplogroup C1d. PloS one 6 26509686
2002 Proteasome-mediated degradation antagonizes critical levels of the apoptosis-inducing C1D protein. Cancer cell international 5 12379155
2011 Control region variability of haplogroup C1d and the tempo of the peopling of the Americas. PloS one 3 21695136
2026 A conserved Sas10/C1D domain protein, CaLrp1, is a critical regulator of hyphal development and pathogenicity in Candida albicans. BMC microbiology 0 42157077

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