Affinage

NRDE2

Nuclear exosome regulator NRDE2 · UniProt Q9H7Z3

Length
1164 aa
Mass
132.7 kDa
Annotated
2026-04-29
21 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NRDE2 is an evolutionarily conserved nuclear factor that operates at the interface of co-transcriptional gene silencing, RNA processing, and genome maintenance. In C. elegans, NRDE-2 associates with nuclear Argonaute/siRNA complexes on nascent transcripts to inhibit RNA Polymerase II (and Pol I) elongation, direct H3K9 methylation and chromatin compaction, and sustain transgenerational epigenetic silencing through a self-enforcing heterochromatin/small RNA amplification loop (PMID:20543824, PMID:22106253, PMID:34365510, PMID:37083324). In mammalian cells, NRDE2 forms a 1:1 complex with the RNA helicase MTR4 via a conserved MID domain, locking MTR4 in a closed conformation that inhibits nuclear exosome recruitment and thereby protects mRNAs for efficient nuclear export (PMID:30842217); independently, NRDE2 binds U1 snRNA directly and promotes recognition of weak 5′ splice sites in hundreds of pre-mRNAs, functioning as a non-canonical splicing factor (PMID:37137667, PMID:30538148). NRDE2 also facilitates homologous recombination repair by binding CK2 subunits, promoting CK2 holoenzyme assembly and MDC1 phosphorylation (PMID:38697125).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2010 High

    Identifying NRDE-2 as a nuclear factor that bridges Argonaute/siRNA complexes to transcription machinery resolved how cytoplasmic RNAi signals silence genes co-transcriptionally by inhibiting RNA Pol II elongation.

    Evidence Genetic screen, Co-IP of NRDE-2/NRDE-3, ChIP of Pol II occupancy, and pre-mRNA silencing assays in C. elegans

    PMID:20543824

    Open questions at the time
    • No structural basis for how NRDE-2 stalls Pol II
    • Mammalian co-transcriptional silencing role not yet tested
  2. 2011 High

    Demonstrating that NRDE-2 is required for heritable siRNA expression, H3K9 methylation in progeny, and NRDE-1 chromatin association established its position in a hierarchical pathway linking siRNAs to transgenerational epigenetic silencing.

    Evidence Small RNA-seq, ChIP for H3K9me, RIP, and genetic epistasis in C. elegans nrde mutants

    PMID:21901112 PMID:22106253

    Open questions at the time
    • Identity of H3K9 methyltransferase recruited by NRDE pathway unknown
    • Mechanism of heritable siRNA amplification involving NRDE-2 not defined
  3. 2018 High

    Discovery that human NRDE2 suppresses intron retention in GC-rich, weakly spliced introns and interacts with U5 snRNP and EJC components revealed a previously unknown mammalian splicing function distinct from the worm silencing role.

    Evidence RNA-seq for intron retention, Co-IP with spliceosome components, siRNA knockdown with DNA damage and mitotic phenotypes in human cells

    PMID:30538148

    Open questions at the time
    • Direct RNA-binding specificity determinants not mapped
    • Relative contribution of splicing vs. exosome regulation to genomic instability unclear
  4. 2018 Medium

    Showing that human NRDE2 forms a complex with MTR4 and that both proteins suppress DNA double-strand breaks linked the MTR4 partnership to genome integrity maintenance.

    Evidence Reciprocal Co-IP, mass spectrometry, γH2AX assays, and R-loop immunofluorescence in human cells

    PMID:29902117

    Open questions at the time
    • Mechanism by which NRDE2–MTR4 suppresses DSBs not resolved
    • R-loop contribution remains ambiguous
  5. 2019 High

    Structural and biochemical characterization of the NRDE2–MTR4 1:1 complex revealed how NRDE2's MID domain locks MTR4 in a closed conformation, blocking exosome, CBC, and ZFC3H1 interactions and thereby protecting mRNAs from degradation in nuclear speckles.

    Evidence Structural/biochemical analysis, mutagenesis, mRNA export assays, MID-deletion phenotype in mouse ES cells

    PMID:30842217

    Open questions at the time
    • Full atomic-resolution structure of NRDE2–MTR4 complex not reported
    • How NRDE2 selectivity for specific RNA targets is achieved remains unknown
  6. 2019 Medium

    Placing NRDE-2 in the pathway linking nuclear siRNAs to higher-order chromatin compaction in germ cells extended the silencing model from gene-level marks to large-scale chromatin organization.

    Evidence Fluorescence microscopy of chromatin compaction, genetic epistasis with nrde-2, nrde-3, hpl-2 in C. elegans

    PMID:31227740

    Open questions at the time
    • Mechanism connecting H3K9me to chromatin compaction via HP1 not biochemically resolved
    • Quantitative contribution of NRDE-2 vs. other factors unclear
  7. 2020 High

    Demonstrating that MTR-4 is recruited to pre-mRNAs undergoing nuclear RNAi in a NRDE-2-dependent manner unified the worm silencing and mammalian exosome-regulation functions through a conserved NRDE2–MTR4 interaction.

    Evidence IP-MS, Co-IP, genetic epistasis, immunofluorescence co-localization in C. elegans and human cells

    PMID:33055090

    Open questions at the time
    • Whether MTR4 exosome-recruitment inhibition is part of the worm silencing mechanism is untested
    • Structural basis of worm NRDE-2/MTR-4 interaction not determined
  8. 2021 Medium

    Showing that NRDE-2 accumulates in the nucleolus and inhibits RNA Pol I elongation via risiRNAs extended the co-transcriptional silencing paradigm beyond Pol II to ribosomal RNA transcription.

    Evidence Immunofluorescence of nucleolar NRDE-2, ChIP of Pol I occupancy, genetic loss-of-function in C. elegans

    PMID:34365510

    Open questions at the time
    • No biochemical reconstitution of Pol I stalling by NRDE-2
    • Relevance of Pol I silencing to mammalian NRDE2 unknown
  9. 2023 High

    Direct binding of NRDE2 to U1 snRNA (independent of canonical U1-specific proteins) and its requirement for weak 5′ splice site selection established the molecular basis for its non-canonical splicing function.

    Evidence BCLIP-seq, RNA-seq splicing analysis, genetic knockout, direct U1 snRNA binding assay in mouse ES cells

    PMID:37137667

    Open questions at the time
    • RNA-binding domain within NRDE2 responsible for U1 recognition not mapped
    • Whether U1 snRNA binding and MTR4 binding are mutually exclusive is unknown
  10. 2023 Medium

    Tethering NRDE-2 to chromatin suffices to trigger heterochromatin formation and de novo small RNA synthesis, establishing NRDE-2 as an upstream trigger of a self-enforcing silencing amplification loop.

    Evidence RNA tethering assay, small RNA-seq, immunofluorescence, genetic epistasis in C. elegans

    PMID:37083324

    Open questions at the time
    • Whether NRDE-2 has intrinsic chromatin-remodeling activity or solely scaffolds effectors is unresolved
    • Mammalian relevance of this amplification loop untested
  11. 2024 Medium

    Identifying NRDE2 as a CK2-binding protein that promotes CK2 holoenzyme assembly and MDC1 phosphorylation revealed a new mechanism through which NRDE2 facilitates homologous recombination repair.

    Evidence Co-IP of NRDE2 with CK2 subunits, CK2 kinase assay, MDC1 phosphorylation assay, HR repair assay, NRDE2-p.N377I variant analysis in human cells

    PMID:38697125

    Open questions at the time
    • Structural basis of NRDE2–CK2 interaction not determined
    • Relationship between CK2-mediated HR function and NRDE2's splicing/exosome roles unclear
    • Not independently replicated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NRDE2's multiple functions — co-transcriptional silencing, exosome inhibition via MTR4, U1-dependent splicing, and CK2-mediated HR repair — are coordinated or partitioned across cell types and contexts remains unresolved.
  • No unified structural model of full-length NRDE2 with its multiple partners
  • Relative physiological importance of each function in mammalian tissues unknown
  • Whether disease-associated variants selectively impair specific NRDE2 functions is largely unexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0003723 RNA binding 2
Localization
GO:0005634 nucleus 4 GO:0005654 nucleoplasm 2 GO:0005730 nucleolus 1
Pathway
R-HSA-4839726 Chromatin organization 4 R-HSA-73894 DNA Repair 2 R-HSA-8953854 Metabolism of RNA 2
Partners
CCDC174CSNK2A1CSNK2BMTR4NRDE-1NRDE-3
Complex memberships
NRDE2–MTR4 complex

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 C. elegans NRDE-2 (ortholog of human NRDE2) associates with the Argonaute protein NRDE-3 within nuclei and is recruited by NRDE-3/siRNA complexes to nascent transcripts targeted by RNAi. NRDE-2 is required for siRNA-mediated silencing of pre-mRNAs 3' to sites of RNAi, for accumulation of RNA Polymerase II at RNAi-targeted genomic loci, and for decreases in RNAP II occupancy and transcriptional activity 3' to RNAi target sites, establishing that NRDE-2 inhibits RNAP II during the elongation phase of transcription. Genetic screen, co-immunoprecipitation (NRDE-2/NRDE-3 association), ChIP (RNAP II occupancy), genetic loss-of-function with pre-mRNA silencing and RNAP II elongation readouts Nature High 20543824
2011 The nuclear RNAi (Nrde) pathway, including NRDE-2, maintains heritable RNAi silencing in C. elegans. The Argonaute NRDE-3 associates with heritable siRNAs and, together with NRDE-1, NRDE-2, and NRDE-4, promotes siRNA expression and H3K9 methylation in progeny of dsRNA-exposed animals, demonstrating that NRDE-2 is required for transgenerational epigenetic silencing. Genetic epistasis, small RNA sequencing, chromatin immunoprecipitation (H3K9me), loss-of-function mutant analysis Proceedings of the National Academy of Sciences of the United States of America High 22106253
2011 C. elegans NRDE-2 is required for the association of NRDE-1 with pre-mRNA and chromatin of RNAi-targeted genes, and for siRNA-directed H3K9 methylation at those loci. NRDE-3 and NRDE-2 act upstream of NRDE-1 in the nuclear RNAi pathway linking endogenous siRNAs to chromatin modification. RNA immunoprecipitation, chromatin immunoprecipitation, genetic epistasis with nrde mutants PLoS genetics High 21901112
2019 Human NRDE2 forms a 1:1 complex with MTR4 (nuclear exosome cofactor) via a conserved MTR4-interacting domain (MID). NRDE2 localizes predominantly in nuclear speckles, where it inhibits MTR4 recruitment and RNA degradation, and thereby ensures efficient mRNA nuclear export. Structurally, NRDE2 interacts with MTR4's key residues and locks MTR4 in a closed conformation, inhibiting MTR4 interaction with the exosome and with CBC and ZFC3H1. MID deletion causes loss of self-renewal of mouse embryonic stem cells. Co-immunoprecipitation, structural analysis (biochemical), in vitro binding assays, localization (immunofluorescence), loss-of-function (MID deletion) with mRNA export and stem cell phenotype readouts Genes & development High 30842217
2018 Human NRDE2 is an essential RNA splicing factor that suppresses intron retention in a subset of pre-mRNAs containing short, GC-rich introns with weak 5' and 3' splice sites. NRDE2 preferentially interacts with U5 snRNP components, the exon junction complex, and the RNA exosome. NRDE2 depletion causes genomic instability, DNA damage, centrosome maturation defects, and mitotic progression defects. NRDE2 directly binds and promotes splicing of CEP131 pre-mRNA, and loss of NRDE2 reduces CEP131 protein, impairing recruitment of γ-tubulin and Aurora Kinase A to spindle poles. RNA-seq (intron retention), co-immunoprecipitation (U5 snRNP, EJC, exosome), siRNA knockdown, immunofluorescence, flow cytometry (DNA damage), direct RNA binding (CEP131 pre-mRNA) RNA (New York, N.Y.) High 30538148
2018 Human NRDE-2 forms a complex with MTR4 and both proteins maintain low DNA double-strand break levels. The NRDE-2/MTR4 complex functions in the DNA damage response independently of R-loop formation, though NRDE-2 and MTR4 can affect R-loop signals at a subset of genes. Co-immunoprecipitation, mass spectrometry, DNA damage assays (γH2AX), R-loop immunofluorescence (S9.6 antibody), siRNA knockdown RNA biology Medium 29902117
2020 C. elegans NRDE-2 physically interacts with the RNA helicase MTR-4, and MTR-4 is recruited to pre-mRNAs undergoing nuclear RNAi in a manner requiring nuclear siRNAs, the nuclear Argonaute HRDE-1, and NRDE-2. MTR-4 is required for nuclear RNAi and co-localizes with NRDE-2 in nuclei. The NRDE-2/MTR-4 interaction is evolutionarily conserved (confirmed in human cells). Immunoprecipitation-mass spectrometry, co-immunoprecipitation, genetic epistasis, immunofluorescence co-localization Genetics High 33055090
2021 In C. elegans, risiRNA-directed NRDE-2 accumulates in the nucleolus and co-localizes with RNA Polymerase I. risiRNAs direct NRDE proteins to associate with pre-rRNAs and silence pre-rRNA expression. NRDE-2 is required for risiRNA-mediated inhibition of RNA Polymerase I elongation, evidenced by decreased RNAP I occupancy downstream of RNAi-targeted sites. Immunofluorescence (NRDE-2 nucleolar localization), ChIP (RNAP I occupancy), genetic loss-of-function, forward genetic screen Nucleic acids research Medium 34365510
2019 In C. elegans, small RNA-directed chromatin compaction in germ cells requires NRDE-2 (pre-mRNA associated factor), the Argonaute NRDE-3, and the HP1-like protein HPL-2, placing NRDE-2 in the pathway linking nuclear siRNAs to higher-order chromatin organization. Fluorescence microscopy (chromatin compaction), genetic epistasis with nrde-2, nrde-3, and hpl-2 mutants Scientific reports Medium 31227740
2023 Mouse NRDE2 (and CCDC174) bind directly to U1 snRNA independently of canonical U1 snRNP-specific proteins and are required for the selection and efficient 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 (splicing analysis), genetic knockout, direct U1 snRNA binding assay RNA (New York, N.Y.) High 37137667
2023 Tethering NRDE-2 in C. elegans induces heterochromatin formation and subsequently causes de novo synthesis of HRDE-1 guide RNAs, which then amplify small RNAs that load on downstream Argonautes, establishing NRDE-2 as an upstream trigger of a self-enforcing heterochromatin/small RNA amplification loop. RNA tethering assay, small RNA sequencing, immunofluorescence, genetic epistasis 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 and thereby facilitates HR repair. The NRDE2-p.N377I variant abolishes these functions. Co-immunoprecipitation (NRDE2-CK2 subunits), kinase activity assay (CK2 holoenzyme), phosphorylation assay (MDC1), HR repair assay, variant functional analysis Cell genomics Medium 38697125
2020 Human NRDE2 protects KSHV late viral transcripts from PABPN1- and poly(A) polymerase-mediated RNA decay (PPD) at the proper time of late gene expression, enabling time-dependent evasion of PPD. This places NRDE2 as a factor that can sequester decay factors (MTR4/exosome pathway) to protect specific RNAs from nuclear degradation. siRNA knockdown of NRDE2, RNA-seq of viral transcripts, functional decay assays in KSHV-infected cells 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 235 20543824
2011 Nuclear RNAi maintains heritable gene silencing in Caenorhabditis elegans. Proceedings of the National Academy of Sciences of the United States of America 153 22106253
2011 A pre-mRNA-associating factor links endogenous siRNAs to chromatin regulation. PLoS genetics 116 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 20 31227740
2023 Genome-wide association and environmental suppression of the mortal germline phenotype of wild C. elegans. EMBO reports 16 37983674
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
2020 A Conserved NRDE-2/MTR-4 Complex Mediates Nuclear RNAi in Caenorhabditis elegans. Genetics 12 33055090
2007 A functional homing endonuclease in the Bacillus anthracis nrdE group I intron. Journal of bacteriology 12 17496101
2019 Identification of proteins associated with splicing factors Ntr1, Ntr2, Brr2 and Gpl1 in the fission yeast Schizosaccharomyces pombe. Cell cycle (Georgetown, Tex.) 11 31219728
2024 NRDE2 deficiency impairs homologous recombination repair and sensitizes hepatocellular carcinoma to PARP inhibitors. Cell genomics 10 38697125
2023 The nuclear Argonaute HRDE-1 directs target gene re-localization and shuttles to nuage to promote small RNA-mediated inherited silencing. Cell reports 8 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.) 3 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