Affinage

NRDE2

Nuclear exosome regulator NRDE2 · UniProt Q9H7Z3

Length
1164 aa
Mass
132.7 kDa
Annotated
2026-06-10
21 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NRDE2 is an evolutionarily conserved nuclear RNA-associated factor that couples small-RNA-directed silencing, control of nuclear RNA degradation, and pre-mRNA splicing fidelity (PMID:20543824, PMID:30842217, PMID:37137667). In C. elegans it was first defined as a component of the nuclear RNAi machinery: recruited by the nuclear Argonaute NRDE-3 to siRNA-targeted nascent transcripts, it inhibits RNA polymerase II during transcriptional elongation, promotes heritable H3K9 methylation and chromatin compaction, and is required for the association of NRDE-1 with pre-mRNA and chromatin, establishing a self-enforcing transgenerational silencing loop (PMID:20543824, PMID:22106253, PMID:21901112, PMID:31227740, PMID:37083324). This silencing activity extends to RNA polymerase I, where ribosomal-antisense siRNAs drive nucleolar accumulation of NRDE-2 and NRDE-2-dependent inhibition of Pol I elongation (PMID:34365510). A second, conserved function is the negative regulation of nuclear RNA degradation: human NRDE2 forms a 1:1 complex with the RNA helicase MTR4 through a conserved MTR4-interacting domain (MID), localizing predominantly to nuclear speckles where it locks MTR4 in a closed conformation, blocks its engagement with the exosome, CBC and ZFC3H1, and thereby promotes efficient mRNA nuclear export; MID deletion abolishes mouse embryonic stem cell self-renewal (PMID:30842217, PMID:33055090). NRDE2 also directly binds U1 snRNA independently of canonical U1 snRNP proteins and, interacting with the U5 snRNP and exon junction complex, promotes selection and processing of weak 5' splice sites and suppresses intron retention in GC-rich introns; loss of NRDE2 impairs splicing of CEP131, reducing CEP131 protein and causing centrosome maturation defects, mitotic errors and genomic instability (PMID:30538148, PMID:37137667). Finally, NRDE2 promotes homologous-recombination repair by binding CK2 subunits to facilitate CK2 holoenzyme assembly and MDC1 phosphorylation, and it maintains low double-strand-break levels in complex with MTR4 (PMID:29902117, PMID:38697125).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2010 High

    Established NRDE-2 as a core effector of nuclear RNAi by showing it is recruited by an Argonaute/siRNA complex to nascent transcripts to inhibit RNA Pol II elongation, answering how nuclear small RNAs enforce co-transcriptional silencing.

    Evidence Genetic screen, co-IP and RNAP II ChIP with genetic epistasis in C. elegans

    PMID:20543824

    Open questions at the time
    • Did not define the biochemical mechanism by which NRDE-2 stalls Pol II elongation
    • Mammalian relevance of the Pol II-silencing role not established
  2. 2011 High

    Linked NRDE-2 to heritable, transgenerational silencing by showing the Nrde pathway maintains siRNA expression and H3K9 methylation across generations and is required for NRDE-1 association with chromatin and pre-mRNA.

    Evidence Genetic epistasis, small RNA-seq and H3K9me ChIP, reciprocal co-IP in C. elegans

    PMID:21901112 PMID:22106253

    Open questions at the time
    • Did not resolve how H3K9 methyltransferases are recruited downstream of NRDE-2
    • Direct NRDE-2 binding to chromatin versus indirect tethering not distinguished
  3. 2018 High

    Defined a splicing function for human NRDE2, showing it associates with U5 snRNP, the EJC and the exosome and suppresses intron retention, mechanistically connecting NRDE2 loss to CEP131 mis-splicing, centrosome defects and genomic instability.

    Evidence RNA-seq intron-retention analysis, co-IP, knockdown phenotyping and centrosomal immunofluorescence in human cells

    PMID:30538148

    Open questions at the time
    • Whether NRDE2 acts directly in spliceosome assembly or recruits the machinery was not resolved here
    • The breadth of physiological splicing targets beyond the tested subset unknown
  4. 2018 Medium

    Implicated NRDE2 and MTR4 in genome maintenance by showing the complex keeps double-strand-break levels low, raising the question of how an RNA-degradation regulator protects DNA integrity.

    Evidence Co-IP and DSB quantification with R-loop immunofluorescence in human cells

    PMID:29902117

    Open questions at the time
    • Mechanism linking NRDE2/MTR4 to DSB suppression not defined (R-loop-independent)
    • Single-lab functional assays without orthogonal in vivo confirmation
  5. 2019 High

    Determined the structural and functional basis of NRDE2's negative regulation of nuclear RNA decay, showing a 1:1 MID-mediated complex that locks MTR4 closed, blocks exosome/CBC/ZFC3H1 engagement, ensures mRNA export, and is essential for ESC self-renewal.

    Evidence Co-IP, structural analysis, biochemical reconstitution, deletion mutagenesis, mRNA export and mouse ESC self-renewal assays

    PMID:30842217

    Open questions at the time
    • How NRDE2 chooses which transcripts to protect from MTR4/exosome not defined
    • Reconciliation of MTR4 sequestration with NRDE2's silencing role in worms left open
  6. 2019 Medium

    Extended NRDE-2's nuclear silencing role to higher-order chromatin by showing nuclear small RNAs drive germline chromatin compaction requiring NRDE-3, NRDE-2 and HPL-2.

    Evidence Genetic epistasis, FISH chromatin-compaction assay, exogenous small RNA delivery in C. elegans

    PMID:31227740

    Open questions at the time
    • Direct molecular link between NRDE-2 and HP1-like HPL-2 not established
    • Single-lab study
  7. 2020 High

    Identified MTR-4 as the major NRDE-2 partner in worms and showed its siRNA/Argonaute-dependent recruitment to pre-mRNAs is required for nuclear RNAi, unifying the silencing and RNA-helicase functions across species.

    Evidence IP-mass spectrometry, co-IP, colocalization and genetic epistasis in C. elegans, with confirmation of the human interaction

    PMID:33055090

    Open questions at the time
    • How MTR-4 helicase activity contributes mechanistically to Pol II silencing not resolved
    • Whether the silencing and mRNA-protective roles of the NRDE2/MTR4 complex are separable left open
  8. 2020 Low

    Suggested NRDE2 can be co-opted to protect viral transcripts from nuclear RNA decay by sequestering decay factors during KSHV infection.

    Evidence NRDE2 knockdown in KSHV-infected cells with viral transcript and decay-pathway quantification

    PMID:32376621

    Open questions at the time
    • Single knockdown experiment without biochemical reconstitution of the protective mechanism
    • Direct NRDE2 binding to viral transcripts or decay factors not demonstrated
  9. 2021 Medium

    Showed NRDE-2's silencing activity is not restricted to Pol II, demonstrating risiRNA-directed nucleolar recruitment and NRDE-2-dependent inhibition of RNA Pol I elongation.

    Evidence Forward genetic screen, RNAP I ChIP, immunofluorescence and genetic epistasis in C. elegans

    PMID:34365510

    Open questions at the time
    • Mechanism of NRDE-2 relocalization between nucleoplasm and nucleolus unknown
    • Single-lab study
  10. 2023 High

    Established NRDE2 as a direct splicing factor, showing it binds U1 snRNA independently of canonical U1 proteins and is required for processing of weak 5' splice sites genome-wide.

    Evidence BCLIP-seq, RNA-seq splicing analysis and protein-RNA binding assays in mouse ES cells

    PMID:37137667

    Open questions at the time
    • Structural basis of NRDE2-U1 snRNA recognition not defined
    • How U1 binding integrates with the U5/EJC interactions reported in human cells unresolved
  11. 2023 Medium

    Demonstrated that NRDE-2 tethering is sufficient to nucleate heterochromatin and trigger de novo guide-RNA synthesis, defining a self-enforcing silencing amplification loop.

    Evidence Tethering assay with small RNA-seq and genetic epistasis in C. elegans

    PMID:37083324

    Open questions at the time
    • Molecular link from NRDE-2 tethering to small RNA biogenesis machinery not defined
    • Single-lab study
  12. 2024 Medium

    Revealed a direct role for human NRDE2 in DNA repair, showing it binds CK2 subunits to promote holoenzyme assembly and MDC1 phosphorylation enabling homologous recombination, with a point variant abolishing the function.

    Evidence Co-IP, CK2 kinase and MDC1 phosphorylation assays, HR repair assays and variant functional analysis in human cells

    PMID:38697125

    Open questions at the time
    • Relationship between the CK2/HR role and the NRDE2/MTR4 DSB-suppression role not integrated
    • Single-lab functional study

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NRDE2's distinct activities — small-RNA-directed Pol I/II silencing, MTR4/exosome inhibition, U1-dependent splicing, and CK2-mediated DNA repair — are coordinated within a single protein, and which are mediated by shared versus separable domains, remains unresolved.
  • No unified structural model assigning each function to defined NRDE2 regions
  • Whether transcript/chromatin targeting is direct or relies on partner complexes is unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 1 GO:0098772 molecular function regulator activity 1 GO:0140313 molecular sequestering activity 1
Localization
GO:0005634 nucleus 2 GO:0005654 nucleoplasm 1 GO:0005730 nucleolus 1
Pathway
R-HSA-4839726 Chromatin organization 3 R-HSA-8953854 Metabolism of RNA 3 R-HSA-73894 DNA Repair 2
Partners
CK2HPL-2HRDE-1MTR4NRDE-1NRDE-3U1 SNRNA
Complex memberships
NRDE2-MTR4 complexnuclear RNAi (NRDE) pathway

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 C. elegans NRDE-2 associates with the Argonaute protein NRDE-3 within nuclei and is recruited by NRDE-3/siRNA complexes to nascent transcripts targeted by RNAi. Nuclear-localized siRNAs direct NRDE-2-dependent silencing of pre-mRNAs 3' to sites of RNAi, NRDE-2-dependent accumulation of RNA polymerase II at genomic loci targeted by RNAi, and NRDE-2-dependent decreases in RNAP II occupancy and transcriptional activity 3' to sites of RNAi, establishing NRDE-2 as a component of the nuclear RNAi machinery that inhibits RNAP II during the elongation phase of transcription. Genetic screen, co-immunoprecipitation, ChIP (RNAP II occupancy), genetic epistasis in C. elegans Nature High 20543824
2011 In C. elegans, the nuclear RNAi (Nrde) pathway including NRDE-2 maintains heritable RNAi silencing across generations. NRDE-3 associates with heritable siRNAs and, acting with NRDE-1, NRDE-2, and NRDE-4, promotes siRNA expression in inheriting progeny and facilitates heritable deposition of H3K9 methylation marks. Genetic epistasis, small RNA sequencing, ChIP for H3K9me in C. elegans Proceedings of the National Academy of Sciences of the United States of America High 22106253
2011 In C. elegans, NRDE-3 and NRDE-2 are required for the association of NRDE-1 with pre-mRNA and chromatin. Endogenous siRNA-driven H3K9 methylation requires NRDE-2 as part of the nuclear RNAi pathway, linking small RNAs to chromatin modification. Co-immunoprecipitation, ChIP for H3K9me, genetic epistasis in C. elegans PLoS genetics High 21901112
2019 Human NRDE2 forms a 1:1 complex with MTR4 via a conserved MTR4-interacting domain (MID). NRDE2 mainly localizes in nuclear speckles where it inhibits MTR4 recruitment and RNA degradation, ensuring efficient mRNA nuclear export. Structurally, NRDE2 interacts with MTR4's key residues, locks MTR4 in a closed conformation, and inhibits MTR4 interaction with the exosome and with CBC and ZFC3H1. MID deletion results in loss of self-renewal of mouse embryonic stem cells. Co-immunoprecipitation, structural analysis, biochemical assays, deletion mutagenesis, mRNA nuclear export assays, mouse ESC self-renewal assay Genes & development High 30842217
2018 Human NRDE2 is required for suppressing intron retention in a subset of pre-mRNAs containing short, GC-rich introns with weak splice sites. NRDE2 preferentially interacts with components of the U5 snRNP, the exon junction complex, and the RNA exosome. NRDE2 depletion causes increased genomic instability, DNA damage, defects in centrosome maturation and mitotic progression. NRDE2 specifically binds to and promotes efficient splicing of CEP131 pre-mRNA; loss of NRDE2 reduces CEP131 protein and impairs recruitment of γ-tubulin and Aurora Kinase A to spindle poles. RNA-seq (intron retention), co-immunoprecipitation (U5 snRNP, EJC, exosome), NRDE2 knockdown with phenotypic readouts, immunofluorescence for centrosomal proteins RNA (New York, N.Y.) High 30538148
2018 Human NRDE-2 forms a complex with MTR4 and both proteins play a role in the DNA damage response by maintaining low DNA double-strand break levels. The DNA damage function does not depend on R-loop formation, though NRDE-2 and MTR4 can affect R-loop signals at a subset of genes. Co-immunoprecipitation, DNA damage assays (DSB quantification), R-loop immunofluorescence RNA biology Medium 29902117
2019 In C. elegans, nuclear small RNAs direct chromatin compaction in germ cells, and this compaction requires the small RNA-binding Argonaute NRDE-3, the pre-mRNA associated factor NRDE-2, and the HP1-like protein HPL-2, as shown by experimentally providing small RNAs and genetic loss-of-function. Genetic epistasis, FISH-based chromatin compaction assay, exogenous small RNA delivery in C. elegans Scientific reports Medium 31227740
2020 In C. elegans, the major NRDE-2 interacting protein is the RNA helicase MTR-4. MTR-4 colocalizes with NRDE-2 in nuclei and is required for nuclear RNAi. MTR-4 is recruited to pre-mRNAs undergoing nuclear RNAi via a process requiring nuclear siRNAs, the nuclear Argonaute HRDE-1, and NRDE-2. The NRDE-2/MTR-4 interaction is evolutionarily conserved (confirmed also for human NRDE2 and MTR4). Immunoprecipitation-mass spectrometry, co-immunoprecipitation, colocalization imaging, genetic epistasis for nuclear RNAi in C. elegans Genetics High 33055090
2021 In C. elegans, risiRNAs (antisense ribosomal siRNAs) direct the association of NRDE proteins with pre-rRNAs. In the presence of risiRNAs, NRDE-2 accumulates in the nucleolus and colocalizes with RNA polymerase I. risiRNAs inhibit transcription elongation of RNA Pol I by decreasing RNAP I occupancy downstream of the RNAi-targeted site, in an NRDE-2-dependent manner. Forward genetic screen, ChIP for RNAP I occupancy, immunofluorescence localization, genetic epistasis in C. elegans Nucleic acids research Medium 34365510
2023 Mouse NRDE2 binds directly to U1 snRNA independently of canonical U1 snRNP-specific proteins and associates with 5' splice sites. NRDE2 is required for the selection and effective processing of weak 5' splice sites in hundreds of genes in mouse ES cells. BCLIP-seq (cross-linking immunoprecipitation coupled to high-throughput sequencing), RNA-seq for splicing analysis, protein-RNA binding assays in mouse ES cells RNA (New York, N.Y.) High 37137667
2023 Tethering the C. elegans heterochromatin-silencing factor NRDE-2 to target RNA induces heterochromatin formation, which subsequently causes de novo synthesis of HRDE-1 guide RNAs, which then further amplify small RNAs on downstream Argonautes, establishing a self-enforcing silencing loop. Tethering assay, small RNA sequencing, genetic epistasis in C. elegans Cell reports Medium 37083324
2024 Human NRDE2 promotes homologous recombination (HR) repair by binding to subunits of casein kinase 2 (CK2) and facilitating assembly and activity of the CK2 holoenzyme, which increases phosphorylation of MDC1 to facilitate HR repair. The NRDE2-p.N377I variant abolishes these functions. Co-immunoprecipitation (NRDE2–CK2 interaction), kinase activity assays, MDC1 phosphorylation assays, HR repair assays, variant functional analysis Cell genomics Medium 38697125
2020 Human NRDE2 protects KSHV late viral transcripts from PPD (PABPN1- and PAPα/γ-mediated RNA decay) at the proper time of their expression, by sequestering decay factors, thereby enabling evasion of nuclear RNA decay. NRDE2 knockdown in KSHV-infected cells, viral transcript quantification, RNA decay pathway analysis Journal of virology Low 32376621

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Small regulatory RNAs inhibit RNA polymerase II during the elongation phase of transcription. Nature 237 20543824
2011 Nuclear RNAi maintains heritable gene silencing in Caenorhabditis elegans. Proceedings of the National Academy of Sciences of the United States of America 154 22106253
2011 A pre-mRNA-associating factor links endogenous siRNAs to chromatin regulation. PLoS genetics 117 21901112
2019 NRDE2 negatively regulates exosome functions by inhibiting MTR4 recruitment and exosome interaction. Genes & development 44 30842217
2014 Caenorhabditis elegans RSD-2 and RSD-6 promote germ cell immortality by maintaining small interfering RNA populations. Proceedings of the National Academy of Sciences of the United States of America 34 25258416
2021 Antisense ribosomal siRNAs inhibit RNA polymerase I-directed transcription in C. elegans. Nucleic acids research 25 34365510
2019 Chromatin Compaction by Small RNAs and the Nuclear RNAi Machinery in C. elegans. Scientific reports 21 31227740
2023 Genome-wide association and environmental suppression of the mortal germline phenotype of wild C. elegans. EMBO reports 17 37983674
2020 A Conserved NRDE-2/MTR-4 Complex Mediates Nuclear RNAi in Caenorhabditis elegans. Genetics 14 33055090
2018 NRDE-2, the human homolog of fission yeast Nrl1, prevents DNA damage accumulation in human cells. RNA biology 14 29902117
2018 Human nuclear RNAi-defective 2 (NRDE2) is an essential RNA splicing factor. RNA (New York, N.Y.) 14 30538148
2024 NRDE2 deficiency impairs homologous recombination repair and sensitizes hepatocellular carcinoma to PARP inhibitors. Cell genomics 12 38697125
2019 Identification of proteins associated with splicing factors Ntr1, Ntr2, Brr2 and Gpl1 in the fission yeast Schizosaccharomyces pombe. Cell cycle (Georgetown, Tex.) 12 31219728
2007 A functional homing endonuclease in the Bacillus anthracis nrdE group I intron. Journal of bacteriology 12 17496101
2023 The nuclear Argonaute HRDE-1 directs target gene re-localization and shuttles to nuage to promote small RNA-mediated inherited silencing. Cell reports 9 37083324
2010 Gene silencing: small RNAs control RNA polymerase II elongation. Current biology : CB 7 20833310
2020 Kaposi's Sarcoma-Associated Herpesvirus Fine-Tunes the Temporal Expression of Late Genes by Manipulating a Host RNA Quality Control Pathway. Journal of virology 6 32376621
2023 Mouse nuclear RNAi-defective 2 promotes splicing of weak 5' splice sites. RNA (New York, N.Y.) 4 37137667
2018 lin-4 and the NRDE pathway are required to activate a transgenic lin-4 reporter but not the endogenous lin-4 locus in C. elegans. PloS one 3 29324872
2024 Rare-variant association study unveils the Achilles' heel for HCC. Cell genomics 0 38723605
2023 A germline-targeted genetic screen for xrn-2 suppressors identifies a novel gene C34C12.2 in Caenorhabditis elegans. Genetics and molecular biology 0 37216322

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