Affinage

WDR82

WD repeat-containing protein 82 · UniProt Q6UXN9

Length
313 aa
Mass
35.1 kDa
Annotated
2026-06-11
17 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

WDR82 is a WD40-repeat scaffold protein that couples histone H3K4 trimethylation and RNA polymerase II (RNAPII) regulation at transcription start sites (PMID:17998332, PMID:18838538). It is a specific subunit of the SETD1A/B-COMPASS complexes—but not the MLL1-4 complexes—binding the SETD1A RNA-recognition motif and a disordered region within SETD1A/B, and its loss reduces global H3K4me3 (PMID:18838538, PMID:37030068). WDR82 tethers COMPASS to chromatin by binding the Ser5-phosphorylated CTD of RNAPII and through H2B-ubiquitination-dependent chromatin association, with recruitment also directed by Nup98 at start sites (PMID:17998332, PMID:18838538, PMID:29269482). Beyond methyltransferase scaffolding, WDR82 forms a 'restrictor' complex with ZC3H4 and ARS2 that slows early RNAPII elongation at non-coding RNA loci, rendering polymerase susceptible to premature termination and thereby enforcing transcription directionality at divergent promoters [PMID:37329883, PMID:bio_10.1101_2025.01.08.631787]. This restrictor activity is mechanistically coupled to CTD dephosphorylation: WDR82 binds PNUTS-PP1 and, together with PNUTS-PP1, promotes Ser5 dephosphorylation and proteasomal degradation of chromatin-bound RNAPII, an activity that limits RNAPII residence time and prevents transcription-replication conflicts in a CDC73-dependent manner (PMID:33264625, PMID:37329883). WDR82 also participates in promoter-proximal termination with PCF11 to silence HIV-1 transcription in latency (PMID:38015843). At mitochondria, WDR82 acts in innate immunity, interacting with TRAF3 and promoting its K48-linked polyubiquitination and degradation to suppress RIG-I-like receptor signaling and type I IFN production (PMID:26519536). Loss of WDR82-dependent H3K4me3 disrupts developmental gene programs, including POU5F1 in early embryos (PMID:21123813).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2007 High

    Established how an H3K4 methyltransferase complex is targeted to active promoters, by showing WDR82 reads the Ser5-phosphorylated RNAPII CTD and binds SETD1A to tether COMPASS to transcription start sites.

    Evidence Co-IP, ChIP, and siRNA knockdown with H3K4me3/SETD1A occupancy readouts

    PMID:17998332

    Open questions at the time
    • Did not resolve the structural basis of CTD phosphospecificity
    • Did not distinguish SETD1A from SETD1B contributions
  2. 2008 High

    Defined WDR82's complex membership, demonstrating it is specific to Set1A/B-COMPASS but not MLL complexes and that chromatin association depends on H2B ubiquitination, linking it to a more robust H3K4 trimethylase.

    Evidence Affinity purification/MS, RNAi with H3K4me3 immunoblot, in vitro methyltransferase assay

    PMID:18838538

    Open questions at the time
    • Mechanism connecting H2B-ub to WDR82 recruitment not defined
    • Stoichiometry within COMPASS not established
  3. 2010 Medium

    Showed the developmental consequence of WDR82 loss, linking SETD1A/B dysfunction and loss of H3K4me3 at POU5F1 to embryonic apoptosis and arrested development.

    Evidence siRNA in mouse embryos with H3K4me3 ChIP, RT-PCR, and TUNEL

    PMID:21123813

    Open questions at the time
    • Single lab
    • Direct versus indirect effects on POU5F1 targets not separated
  4. 2015 Medium

    Revealed a non-COMPASS role at mitochondria, identifying WDR82 as a negative regulator of antiviral innate immunity that drives TRAF3 K48 ubiquitination and degradation.

    Evidence Fractionation/IF localization, TRAF3 co-IP, K48/K63 linkage-specific ubiquitination assay, IFN-beta reporter and viral replication assays

    PMID:26519536

    Open questions at the time
    • WDR82 is not a known E3 ligase—the responsible ligase activity is unidentified
    • Largely overexpression-based
    • Single lab
  5. 2015 Medium

    Established a conserved role in restraining elongation and promoting termination, with Drosophila Wdr82 acting with Su(s) to inhibit Pol II elongation and route transcripts to exosome degradation.

    Evidence Genetic co-depletion in Drosophila with nascent RNA and polyadenylation-site sequencing

    PMID:26577379

    Open questions at the time
    • Human orthology of the Su(s) interaction not addressed
    • Single model system
  6. 2017 High

    Identified the recruitment determinant for COMPASS, showing Nup98 binds start sites and is required for WDR82-Set1A chromatin loading and adjacent H3K4me3.

    Evidence ChIP-seq for Nup98/WDR82/Set1A and siRNA depletion with H3K4me3 ChIP-seq

    PMID:29269482

    Open questions at the time
    • Direct physical contact between Nup98 and WDR82 not mapped
    • Restricted to hematopoietic context
  7. 2020 High

    Connected WDR82 to genome stability, showing it works with PNUTS-PP1 to dephosphorylate the CTD and degrade chromatin-bound RNAPII, preventing transcription-replication conflicts.

    Evidence siRNA with EdU, DNA fiber assay, FRAP, proteasome inhibition, and CDC73 epistasis

    PMID:33264625

    Open questions at the time
    • E3 ligase mediating RNAPII degradation not identified
    • Genomic sites of conflict resolution not mapped
  8. 2022 Medium

    Demonstrated redox regulation of WDR82 function, with ROS-induced carbonylation inactivating the H3K4 methyltransferase complex and reducing H3K4me3 at glucose-metabolic genes.

    Evidence Carbonylation detection, WDR82 overexpression rescue with H3K4me3 ChIP, SOD3 manipulation

    PMID:35290440

    Open questions at the time
    • Carbonylated residues not mapped
    • Single lab
  9. 2023 High

    Provided the structural and biophysical basis for the SETD1A/B-WDR82 interaction, showing a disordered region in SETD1A/B binds WDR82 adjacent to a canonical RRM fold.

    Evidence X-ray crystallography of SETD1A/B RRM domains and ITC binding assay

    PMID:37030068

    Open questions at the time
    • No structure of the bound WDR82-IDR complex
    • RRM-RNA contact not experimentally confirmed
  10. 2023 High

    Defined the restrictor complex architecture, establishing ZC3H4-WDR82-ARS2 as a co-transcriptional ncRNA restriction module functionally linked to PNUTS-mediated termination and shielded at mRNAs by U1 snRNA.

    Evidence ZC3H4 domain mutagenesis, co-IP, nascent RNA-seq, and U1 snRNA depletion epistasis

    PMID:37329883

    Open questions at the time
    • Direct WDR82 contribution versus ZC3H4 scaffold not fully separated
    • Mechanism of U1-mediated shielding not resolved
  11. 2023 Medium

    Extended WDR82-dependent H3K4me3 to disease, showing its loss in pediatric high-grade glioma reduces H3K4me3 at stemness/proliferation genes and sensitizes cells to chemotherapy.

    Evidence siRNA knockdown, H3K4me3 ChIP-seq, expression analysis, chemotherapy sensitivity assay

    PMID:37444539

    Open questions at the time
    • Single tumor model
    • Causal driver versus correlative role not established
  12. 2023 Medium

    Showed WDR82 contributes to HIV-1 latency, partnering with PCF11 to drive promoter-proximal termination and silence proviral transcription.

    Evidence PCF11-WDR82 co-IP, ChIP at the HIV-1 promoter-proximal region, and individual/combined knockdown with reactivation assays

    PMID:38015843

    Open questions at the time
    • Relationship of PCF11 pathway to ZC3H4 restrictor not delineated
    • Single lab
  13. 2024 Medium

    Proposed the quaternary PPWZ assembly mechanistically coupling restrictor to CTD dephosphorylation, with PNUTS binding WDR82 directly and a substrate-trap PP1 fusion blocking antisense termination and Ser5 dephosphorylation.

    Evidence Co-purification/MS, AlphaFold modeling, and dominant-negative PP1(H66K)-PNUTS substrate trap with termination and CTD readouts (preprint)

    PMID:bio_10.1101_2024.07.12.603302

    Open questions at the time
    • Preprint, not peer-reviewed
    • Quaternary complex predicted by AlphaFold, not experimentally resolved
  14. 2025 Medium

    Refined the restrictor mechanism, showing it slows early elongation to make RNAPII susceptible to other termination machineries and acts as a determinant of transcriptional directionality, blocked at mRNAs by 5' splice sites.

    Evidence Auxin-inducible degron depletion of ZC3H4/WDR82 with nascent RNA-seq and unbiased sequence screens (preprint)

    PMID:bio_10.1101_2025.01.08.631787

    Open questions at the time
    • Preprint, not peer-reviewed
    • Identity of the downstream terminating machinery not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single scaffold partitions between COMPASS-mediated H3K4me3 activation, restrictor-mediated termination, and mitochondrial TRAF3 regulation—and what determines its allocation among these complexes—remains unresolved.
  • No mechanism explaining mutually exclusive complex assembly
  • E3 ligase activities for TRAF3 and RNAPII degradation unidentified
  • No integrated structure of restrictor with PNUTS-PP1

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0008092 cytoskeletal protein binding 1 GO:0042393 histone binding 1
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 3 GO:0005739 mitochondrion 1
Pathway
R-HSA-74160 Gene expression (Transcription) 3 R-HSA-8953854 Metabolism of RNA 3 R-HSA-4839726 Chromatin organization 2 R-HSA-168256 Immune System 1 R-HSA-69306 DNA Replication 1
Partners
ARS2PCF11PNUTSRNAPIISETD1ASETD1BTRAF3ZC3H4
Complex memberships
PPWZ (PNUTS-PP1-WDR82-ZC3H4)Restrictor (ZC3H4-WDR82-ARS2)SETD1A/B-COMPASS

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 WDR82 binds directly to the Ser5-phosphorylated C-terminal domain (CTD) of RNA polymerase II large subunit, but does not bind to unphosphorylated or Ser2-phosphorylated CTD. WDR82 also interacts with the RNA recognition motif (RRM) of SETD1A, thereby tethering the SETD1A/COMPASS complex to transcription start sites of expressed genes. Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), siRNA knockdown with functional readout of H3K4me3 and SETD1A occupancy Molecular and cellular biology High 17998332
2008 WDR82 is a specific component of the Set1A/B COMPASS complexes but not of MLL1-4 COMPASS-like complexes. WDR82 associates with chromatin in a histone H2B ubiquitination-dependent manner. RNAi-mediated knockdown of WDR82 reduces global H3K4me3 levels. In vitro enzymatic assays demonstrated that the Set1 complex is a more robust H3K4 trimethylase than MLL complexes. Affinity purification/mass spectrometry, RNAi knockdown with H3K4me3 immunoblot, in vitro methyltransferase activity assay Molecular and cellular biology High 18838538
2010 In mouse early embryos, WDR82 deficiency causes dysfunction of SETD1A/SETD1B, loss of H3K4me3 at the transcription start region of POU5F1, down-regulation of POU5F1 and its downstream factors STAT3/BIRC5, and extremely high apoptotic rates in blastocysts, resulting in blocked embryonic development. siRNA knockdown in mouse embryos, ChIP for H3K4me3 at POU5F1 promoter, RT-PCR for gene expression, TUNEL assay for apoptosis Biology of reproduction Medium 21123813
2015 In Drosophila, Wdr82 acts with Suppressor of sable [Su(s)] to inhibit RNA Pol II elongation through repetitive elements at Hsp70 loci and promotes transcription termination with polyadenylation at heterogeneous sites lacking canonical polyadenylation signals, resulting in exosome-mediated RNA degradation. Genetic co-depletion in Drosophila, nascent RNA analysis, identification of polyadenylation sites by sequencing RNA (New York, N.Y.) Medium 26577379
2015 WDR82 localizes to mitochondria via its N-terminal WD40 domain and interacts with TRAF3 at mitochondria. WDR82 overexpression promotes K48-linked (but not K63-linked) polyubiquitination of TRAF3, leading to its degradation and consequent suppression of RIG-I-like receptor signaling and type I IFN production. Subcellular fractionation and immunofluorescence for localization, co-immunoprecipitation for TRAF3 interaction, ubiquitination assay with K48/K63 linkage-specific antibodies, overexpression/knockdown with IFN-β reporter and viral replication assays Journal of immunology Medium 26519536
2017 Nup98 (nucleoporin 98) binds to transcription start sites in hematopoietic cells and recruits the WDR82-Set1A/COMPASS complex; depletion of Nup98 or WDR82 abolishes Set1A chromatin recruitment and ablates H3K4me3 at adjacent promoters. ChIP-seq for Nup98, WDR82, Set1A occupancy; siRNA depletion of Nup98 or WDR82 with H3K4me3 ChIP-seq as readout Genes & development High 29269482
2020 WDR82 binds PNUTS and together with PNUTS-PP1 promotes dephosphorylation of the RNA Pol II CTD and proteasomal degradation of RNAPII on chromatin. Depletion of WDR82 increases RNAPII chromatin residence time, slows replication fork rates, and causes S-phase accumulation, indicating prevention of transcription-replication conflicts. Reduced replication after WDR82 depletion is dependent on transcription and the phospho-CTD binding protein CDC73. siRNA knockdown with EdU incorporation, replication fork rate (DNA fiber assay), RNAPII residence time (FRAP), proteasome inhibitor experiments, epistasis with CDC73 knockdown Cell reports High 33264625
2022 WDR82 carbonylation (oxidative modification) induced by reactive oxygen species leads to inactivation of the histone H3K4 methyltransferase complex and decreased H3K4me3 at promoters of glucose metabolic genes. WDR82 overexpression in hepatoblasts is sufficient to restore H3K4me3 levels, and placental SOD3 from exercising dams prevents WDR82 carbonylation. Protein carbonylation detection, WDR82 overexpression in hepatoblasts with H3K4me3 ChIP, genetic/pharmacological manipulation of SOD3 Diabetes Medium 35290440
2023 The crystal structures of the RRM domains of SETD1A and SETD1B were solved; an intrinsically disordered region (IDR) in SETD1A/B binds WDR82, as measured by isothermal titration calorimetry (ITC). The human RRM domains adopt a canonical fold but differ structurally from the yeast Set1 RRM, and positively charged regions within them may contact RNA. X-ray crystallography of SETD1A/B RRM domains, ITC binding assay for IDR-WDR82 interaction Biochemical and biophysical research communications High 37030068
2023 ZC3H4 forms a functional 'restrictor' complex with WDR82 and ARS2. The domains of ZC3H4 that contact ARS2 and WDR82 are both required for ncRNA transcriptional restriction. ZC3H4-WDR82-ARS2 co-transcriptionally control an overlapping population of ncRNAs. PNUTS is proximal to restrictor (ZC3H4-WDR82) and is required for termination of all major RNAPII transcript classes; U1 snRNA shields protein-coding transcripts from restrictor/PNUTS-mediated termination. Domain deletion mutagenesis of ZC3H4, co-immunoprecipitation, nascent RNA-seq (TT-seq/GRO-seq), U1 snRNA depletion epistasis Molecular cell High 37329883
2023 WDR82 downregulation in pediatric high-grade glioma cells reduces H3K4me3 promoter occupancy at genes associated with stem cell features, cell proliferation, cell cycle, and DNA damage repair, and increases sensitivity to chemotherapy. WDR82 siRNA knockdown, ChIP-seq for H3K4me3, gene expression analysis, chemotherapy sensitivity assay Cancers Medium 37444539
2023 PCF11 interacts with WDR82, and both are recruited interdependently to the promoter-proximal region of the HIV-1 provirus to mediate premature transcription termination and silence HIV-1 expression in latently infected cells. Co-depletion of PCF11 and WDR82 showed they act in the same pathway. Co-immunoprecipitation (PCF11-WDR82 interaction), ChIP for recruitment at HIV-1 promoter-proximal region, siRNA knockdown (individual and combined) with HIV-1 reactivation assay Proceedings of the National Academy of Sciences of the United States of America Medium 38015843
2024 WDR82 (as part of restrictor ZC3H4/WDR82) co-purifies with PP1 phosphatase and PNUTS. AlphaFold predicts a quaternary PPWZ complex where PP1-associated PNUTS and ZC3H4 both contact WDR82. PNUTS binds directly to WDR82. A substrate-trap inactive PP1(H66K)-PNUTS fusion acts as a dominant-negative inhibitor of antisense termination and CTD Ser5 dephosphorylation; both activities require the PNUTS-WDR82 binding domain. CTD Ser5 hyperphosphorylation is associated with higher processivity and reduced pausing. Co-purification/mass spectrometry, AlphaFold structural modeling, dominant-negative PP1(H66K)-PNUTS substrate trap with nascent RNA termination assay and CTD phosphorylation readout bioRxivpreprint Medium bio_10.1101_2024.07.12.603302
2025 The Restrictor complex (ZC3H4/WDR82) reduces the rate of early transcription elongation by RNAPII at ncRNA loci, rendering RNAPII susceptible to termination by other machineries rather than directly terminating RNAPII itself. This activity is blocked at most mRNAs by the presence of a 5' splice site, making Restrictor a critical determinant of transcription directionality at divergent promoters. Rapid protein degradation (auxin-inducible degron) of ZC3H4/WDR82 followed by nascent RNA sequencing; unbiased sequence screens for Restrictor targeting determinants bioRxivpreprint Medium bio_10.1101_2025.01.08.631787

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Molecular regulation of H3K4 trimethylation by Wdr82, a component of human Set1/COMPASS. Molecular and cellular biology 258 18838538
2007 Wdr82 is a C-terminal domain-binding protein that recruits the Setd1A Histone H3-Lys4 methyltransferase complex to transcription start sites of transcribed human genes. Molecular and cellular biology 176 17998332
2017 Nup98 recruits the Wdr82-Set1A/COMPASS complex to promoters to regulate H3K4 trimethylation in hematopoietic progenitor cells. Genes & development 73 29269482
2020 WDR82/PNUTS-PP1 Prevents Transcription-Replication Conflicts by Promoting RNA Polymerase II Degradation on Chromatin. Cell reports 50 33264625
2023 A restrictor complex of ZC3H4, WDR82, and ARS2 integrates with PNUTS to control unproductive transcription. Molecular cell 39 37329883
2022 Maternal Exercise-Induced SOD3 Reverses the Deleterious Effects of Maternal High-Fat Diet on Offspring Metabolism Through Stabilization of H3K4me3 and Protection Against WDR82 Carbonylation. Diabetes 27 35290440
2010 WDR82, a key epigenetics-related factor, plays a crucial role in normal early embryonic development in mice. Biology of reproduction 24 21123813
2020 BATF3 promotes malignant phenotype of colorectal cancer through the S1PR1/p-STAT3/miR-155-3p/WDR82 axis. Cancer gene therapy 20 33057139
2015 Suppressor of sable [Su(s)] and Wdr82 down-regulate RNA from heat-shock-inducible repetitive elements by a mechanism that involves transcription termination. RNA (New York, N.Y.) 20 26577379
2022 microRNA-155-3p delivered by M2 macrophages-derived exosomes enhances the progression of medulloblastoma through regulation of WDR82. Journal of translational medicine 18 34983581
2022 Elevated H3K4me3 Through MLL2-WDR82 upon Hyperglycemia Causes Jagged Ligand Dependent Notch Activation to Interplay with Differentiation State of Endothelial Cells. Frontiers in cell and developmental biology 18 35392173
2015 WDR82 Negatively Regulates Cellular Antiviral Response by Mediating TRAF3 Polyubiquitination in Multiple Cell Lines. Journal of immunology (Baltimore, Md. : 1950) 15 26519536
2022 WDR82-binding long noncoding RNA lncEry controls mouse erythroid differentiation and maturation. The Journal of experimental medicine 10 35315911
2023 Premature transcription termination complex proteins PCF11 and WDR82 silence HIV-1 expression in latently infected cells. Proceedings of the National Academy of Sciences of the United States of America 8 38015843
2023 WD repeat domain 82 (Wdr82) facilitates mouse iPSCs generation by interfering mitochondrial oxidative phosphorylation and glycolysis. Cellular and molecular life sciences : CMLS 6 37470863
2023 WDR82-Mediated H3K4me3 Is Associated with Tumor Proliferation and Therapeutic Efficacy in Pediatric High-Grade Gliomas. Cancers 5 37444539
2023 Molecular insight into the SETD1A/B N-terminal region and its interaction with WDR82. Biochemical and biophysical research communications 2 37030068

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