Affinage

WDR76

WD repeat-containing protein 76 · UniProt Q9H967

Length
626 aa
Mass
69.8 kDa
Annotated
2026-06-11
24 papers in source corpus 12 papers cited in narrative 13 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

WDR76 is a WD40-repeat protein with dual roles in genotoxic stress response and in the destabilization of RAS GTPases, linking nuclear quality control to suppression of RAS/MAPK signaling (PMID:25817432, PMID:30655611). As an E3 linker protein, WDR76 couples with the CUL1 E3 ligase to drive polyubiquitination-dependent proteasomal degradation of both wild-type and mutant HRAS and KRAS, thereby restraining RAS signaling and tumorigenesis across hepatocellular, colorectal, and pancreatic cancers (PMID:30655611, PMID:40889735). This activity has physiological consequences beyond cancer: loss of WDR76 elevates HRas and confers resistance to high-fat-diet-induced obesity, while WDR76-driven RAS degradation also limits cancer stem cell activation (PMID:31362761, PMID:31873167). WDR76 itself is degraded by APC/C-CDH1 acting with the E2 enzyme UBE2C through a KEN-box motif, and its loss permits KRAS accumulation and MAPK pathway activation (PMID:40889735). In parallel, WDR76 and its yeast ortholog Cmr1 are rapidly recruited to sites of DNA damage and concentrate within an intranuclear quality control compartment (INQ) that sequesters misfolded, ubiquitylated and sumoylated proteins, in association with the CCT chaperonin complex (PMID:25817432, PMID:27248496). WDR76 engages chromatin through multiple interactions: it binds core histones, the DNA damage proteins PARP1 and DNA-PK/KU, and heterochromatin proteins CBX1/3/5, and bridges to H3K4me3-marked nucleosomes via the histone reader SPIN1 (PMID:27248496, PMID:31353912, PMID:39116123).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2012 Medium

    Establishing whether the ortholog had intrinsic chromatin activity, in vitro work showed Cmr1 binds DNA with preference for UV-damaged substrates and accumulates on chromatin after UV, framing it as a damage-responsive chromatin-associated protein.

    Evidence In vitro DNA-binding assays with UV-damaged substrates and chromatin fractionation in S. cerevisiae

    PMID:22367945

    Open questions at the time
    • Does not identify the functional consequence of damaged-DNA binding
    • Yeast ortholog only; human WDR76 DNA-binding not tested
  2. 2015 High

    Connecting WDR76 to a cellular stress structure, Cmr1/WDR76 was shown to localize to a novel intranuclear quality control compartment (INQ) under genotoxic stress and to associate with the CCT chaperonin, defining a conserved role in protein quality control.

    Evidence Fluorescence microscopy, proteomics and genetic screens in yeast with reciprocal Co-IP and imaging in human cells

    PMID:25817432

    Open questions at the time
    • Mechanism by which WDR76 promotes sequestration of misfolded proteins unresolved
    • Whether INQ recruitment depends on the WD40 domain not defined
  3. 2016 Medium

    To map WDR76's chromatin context, proteomic and imaging work identified its associations with core histones, PARP1/XRCC5 and heterochromatin CBX proteins and confirmed rapid recruitment to laser-induced damage, situating it within the DNA damage response.

    Evidence Quantitative AP-MS, reciprocal Co-IP, and live-cell laser micro-irradiation imaging in human cells

    PMID:27248496

    Open questions at the time
    • Direct versus indirect nature of histone and CBX interactions not all resolved
    • Functional role in repair pathway choice undefined
  4. 2016 Medium

    Addressing whether chromatin association reflected transcription, genome-wide profiling showed Cmr1 occupies actively transcribed coding regions in a transcription-dependent manner and facilitates Pol II occupancy, broadening its chromatin function beyond damage.

    Evidence ChIP-seq and genetic epistasis (Kin28, Rpd3, Hos2) in S. cerevisiae

    PMID:26848854

    Open questions at the time
    • Mechanism linking Cmr1 to Pol II occupancy unknown
    • Conservation of transcriptional role in human WDR76 untested
  5. 2019 High

    Defining a distinct molecular function, WDR76 was shown to act as an E3 linker driving polyubiquitination and proteasomal degradation of HRAS/KRAS, suppressing RAS signaling and tumorigenesis in vivo.

    Evidence HCC proteomics, Co-IP, ubiquitination assays, WDR76 knockout and liver-specific transgenic mouse models

    PMID:30655611

    Open questions at the time
    • Identity of the partner E3 ligase not yet defined in this study
    • Relationship between RAS degradation and the nuclear INQ role unclear
  6. 2019 Medium

    Extending the RAS-degradation axis to physiology, mouse genetics showed WDR76 loss elevates RAS/HRas to accelerate intestinal tumorigenesis and cancer stem cell activation and to alter adipocyte differentiation and diet-induced obesity.

    Evidence Wdr76-/- mice, ApcMin/+ crosses, HFD models, 3T3-L1 differentiation and spheroid assays

    PMID:31362761 PMID:31873167

    Open questions at the time
    • Tissue-specific determinants of which RAS isoform is targeted unresolved
    • Direct ubiquitination not re-demonstrated in adipocyte context
  7. 2019 Medium

    Dissecting WDR76's interaction architecture, AP-MS with size-exclusion chromatography resolved distinct complexes, mapping CCT binding to the WD40 domain and DNA-PK/KU, PARP1, GAN, SIRT1 and histone contacts outside it.

    Evidence AP-MS coupled to size-exclusion chromatography with reciprocal Co-IP validation

    PMID:31353912

    Open questions at the time
    • Functional output of GAN and SIRT1 interactions undefined
    • Whether complexes are mutually exclusive in vivo unknown
  8. 2024 Medium

    Resolving how WDR76 reads chromatin marks, integrative structural modeling showed WDR76 forms a complex with the H3K4me3 reader SPIN1 that copurifies with H3K4me3-marked histones, providing a bridge to active chromatin in the damage response.

    Evidence Serial capture affinity purification, cross-linking MS and Bayesian integrative structural modeling with microscopy

    PMID:39116123

    Open questions at the time
    • Structural model is computational with experimental constraints, not an experimental structure
    • Functional contribution of the SPIN1 bridge to repair untested
  9. 2025 Medium

    Identifying the E3 partner and the regulation of WDR76 itself, work showed WDR76 couples with CUL1 (not CUL4) to degrade wild-type and mutant KRAS, while APC/C-CDH1 with UBE2C degrades WDR76 via a KEN-box, completing a regulatory loop controlling MAPK activation.

    Evidence Co-IP, ubiquitination assays, AAV knockdown and KrasG12D-driven pancreatic mouse models

    PMID:40889735

    Open questions at the time
    • Signals that engage APC/C-CDH1 toward WDR76 unknown
    • Single lab; CUL1 coupling mechanism not structurally defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How WDR76's nuclear quality-control/chromatin functions mechanistically connect to its cytoplasmic role as a CUL1-coupled RAS-degradation factor remains unresolved.
  • No unified model linking INQ/DNA-damage recruitment to RAS ubiquitination
  • Determinants of WDR76 subcellular partitioning unknown
  • Whether human WDR76 retains the yeast transcription-elongation role untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0042393 histone binding 2 GO:0060090 molecular adaptor activity 2 GO:0140096 catalytic activity, acting on a protein 2 GO:0003677 DNA binding 1
Localization
GO:0005634 nucleus 3 GO:0000228 nuclear chromosome 2
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-392499 Metabolism of proteins 2 R-HSA-73894 DNA Repair 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
CBX5CUL1HRASKRASPARP1SIRT1SPIN1UBE2C
Complex memberships
CCT chaperonin (associated)INQ (intranuclear quality control compartment)WDR76-SPIN1 complex

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 Yeast Cmr1 (ortholog of human WDR76) localizes to a novel intranuclear quality control compartment (INQ) in response to genotoxic stress, co-localizing with Mrc1/Claspin, Pph3, and the CCT chaperonin complex along with 25 other proteins; this compartment sequesters misfolded, ubiquitylated, and sumoylated proteins. Fluorescence microscopy, proteomic analysis, genetic interaction screens in S. cerevisiae Nature communications High 25817432
2015 Human WDR76 relocalized to nuclear foci and physically associated with the CCT chaperonin complex in response to proteasome inhibition and DNA damage, indicating an evolutionarily conserved function of the Cmr1/WDR76 axis in genotoxic stress response. Co-immunoprecipitation, fluorescence microscopy in human cells Nature communications Medium 25817432
2019 WDR76 functions as an E3 linker protein mediating polyubiquitination-dependent proteasomal degradation of RAS (HRAS, KRAS), thereby suppressing RAS signaling and tumorigenesis in hepatocellular carcinoma. Proteomic analysis of HCC tissue, co-immunoprecipitation, ubiquitination assays, WDR76 knockout mice, liver-specific WDR76 transgenic mice, cell proliferation/invasion assays Nature communications High 30655611
2019 WDR76-mediated RAS degradation suppresses cancer stem cell (CSC) activation and tumorigenesis in colorectal cancer; Wdr76-/- mice crossed with ApcMin/+ mice developed more and larger tumors with elevated RAS and β-catenin levels, and WDR76 modulated CRC spheroid formation. Wdr76-/- mouse genetics, ApcMin/+ crosses, histology, immunohistochemistry, immunoblotting, CRC spheroid culture with WDR76 overexpression/knockdown Cell communication and signaling : CCS Medium 31362761
2019 WDR76 controls adipocyte differentiation and HFD-induced obesity via HRas destabilization; Wdr76-/- mice are resistant to HFD-induced obesity with elevated HRas, while liver-specific WDR76 transgenic mice show increased obesity with reduced HRas. Wdr76-/- mice, liver-specific Wdr76 transgenic mice, HFD model, western blotting, 3T3-L1 adipocyte differentiation assays Scientific reports Medium 31873167
2016 WDR76 associates with histones H2A, H2B, and H4, and with DNA damage response proteins PARP1 and XRCC5, and with heterochromatin proteins CBX1, CBX3, and CBX5; WDR76 is rapidly recruited to sites of laser-induced DNA damage. Quantitative affinity purification-mass spectrometry (AP-MS), co-immunoprecipitation, quantitative live-cell imaging of laser-induced DNA damage PloS one Medium 27248496
2019 WDR76 interacts with the CCT complex via its WD40 repeat domain, and interacts with DNA-PK-KU, PARP1, GAN, SIRT1, and histones outside of the WD40 domain; AP-MS coupled to size-exclusion chromatography resolved distinct WDR76-based protein complexes. Affinity purification coupled to mass spectrometry (AP-MS), size-exclusion chromatography, reciprocal Co-IP validation Journal of proteome research Medium 31353912
2024 WDR76 forms a complex with SPIN1, a histone reader that recognizes H3K4me3; the WDR76:SPIN1 complex copurifies with core histones bearing the H3K4me3 mark, and structural modeling places SPIN1 recognizing H3K4me3 while interacting with WDR76; the complex is implicated in the DNA damage response. Serial capture affinity purification (SCAP), cross-linking mass spectrometry, Bayesian integrative structural modeling (IMP), microscopy Proceedings of the National Academy of Sciences of the United States of America Medium 39116123
2012 S. cerevisiae Cmr1/YDL156W binds DNA in vitro and exhibits preferential affinity for UV-damaged DNA substrates; chromatin fractionation showed Cmr1 enrichment in the chromatin fraction upon UV irradiation. DNA-cellulose column purification, in vitro DNA binding assays with UV-damaged DNA substrates, chromatin fractionation, mass spectrometry Journal of microbiology (Seoul, Korea) Medium 22367945
2016 S. cerevisiae Cmr1 is recruited to coding regions of actively transcribed genes genome-wide in a transcription-dependent manner; its occupancy correlates with RNA Pol II occupancy and is stimulated by Pol II CTD kinase Kin28 and histone deacetylases Rpd3 and Hos2; Cmr1 facilitates Pol II occupancy at coding sequences but is dispensable for co-transcriptional histone occupancy and modification. ChIP-seq, genome-wide occupancy analysis, genetic deletion of Kin28, Rpd3, Hos2, Pol II ChIP in cmr1Δ cells PloS one Medium 26848854
2022 The natural compound kurarinone induces G0/G1 cell cycle arrest in colorectal cancer cells by promoting WDR76-dependent proteasomal degradation of K-RAS, leading to downregulation of cyclin D1/D3 and CDK4/6. Western blotting, cell viability assays, flow cytometry cell cycle analysis, proteasome inhibitor rescue experiments European journal of pharmacology Low 35381263
2025 WDR76 couples with CUL1 E3 ligase (not CUL4) to promote degradation of both wild-type and mutant KRAS; UBE2C cooperates with APC/C-CDH1 to degrade WDR76 via a KEN-box motif, leading to KRAS accumulation and MAPK pathway activation in pancreatic cancer. Co-immunoprecipitation, ubiquitination assays, AAV-mediated WDR76 knockdown in mouse pancreas, KrasG12D-driven mouse models, western blotting Cancer letters Medium 40889735
2023 WDR76-mediated degradation of HRAS underlies 5-fluorouracil sensitivity in colon cancer; WDR76 overexpression sensitized resistant cells to 5-FU, while knockdown enhanced resistance that was reversed by HRAS inhibitor Kobe006. Western blotting, qRT-PCR, cell viability assay, colony formation assay, flow cytometry, xenograft mouse model Discover oncology Low 37081180

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Melanin biosynthesis in the maize pathogen Cochliobolus heterostrophus depends on two mitogen-activated protein kinases, Chk1 and Mps1, and the transcription factor Cmr1. Eukaryotic cell 109 17237364
2015 Cmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality control. Nature communications 80 25817432
2019 WDR76 is a RAS binding protein that functions as a tumor suppressor via RAS degradation. Nature communications 41 30655611
2019 WDR76 degrades RAS and suppresses cancer stem cell activation in colorectal cancer. Cell communication and signaling : CCS 25 31362761
2019 Melanin biosynthesis in the desert-derived Aureobasidium melanogenum XJ5-1 is controlled mainly by the CWI signal pathway via a transcriptional activator Cmr1. Current genetics 23 31263942
2016 WDR76 Co-Localizes with Heterochromatin Related Proteins and Rapidly Responds to DNA Damage. PloS one 23 27248496
2012 Helicase domain encoded by Cucumber mosaic virus RNA1 determines systemic infection of Cmr1 in pepper. PloS one 23 22905216
2017 Cmr1 enables efficient RNA and DNA interference of a III-B CRISPR-Cas system by binding to target RNA and crRNA. Nucleic acids research 20 28977458
2022 Kurarinone induced p53-independent G0/G1 cell cycle arrest by degradation of K-RAS via WDR76 in human colorectal cancer cells. European journal of pharmacology 16 35381263
2019 Biochemical Reduction of the Topology of the Diverse WDR76 Protein Interactome. Journal of proteome research 14 31353912
2019 WDR76 mediates obesity and hepatic steatosis via HRas destabilization. Scientific reports 14 31873167
2012 Saccharomyces cerevisiae Cmr1 protein preferentially binds to UV-damaged DNA in vitro. Journal of microbiology (Seoul, Korea) 14 22367945
2013 Yeast gene CMR1/YDL156W is consistently co-expressed with genes participating in DNA-metabolic processes in a variety of stringent clustering experiments. Journal of the Royal Society, Interface 12 23349438
2014 Crystal structure and CRISPR RNA-binding site of the Cmr1 subunit of the Cmr interference complex. Acta crystallographica. Section D, Biological crystallography 10 24531487
2024 An integrated structural model of the DNA damage-responsive H3K4me3 binding WDR76:SPIN1 complex with the nucleosome. Proceedings of the National Academy of Sciences of the United States of America 8 39116123
2023 Influence of Cmr1 in the Regulation of Antioxidant Function Melanin Biosynthesis in Aureobasidium pullulans. Foods (Basel, Switzerland) 8 37297380
2021 The role of WDR76 protein in human diseases. Bosnian journal of basic medical sciences 8 33714259
2016 Recruitment of Saccharomyces cerevisiae Cmr1/Ydl156w to Coding Regions Promotes Transcription Genome Wide. PloS one 7 26848854
2021 The correlation of WDR76 expression with survival outcomes and immune infiltrates in lung adenocarcinoma. PeerJ 6 34707943
2003 Mutations in the candidate tumour suppressor gene FLJ12973 on chromosome 15q15 are rare in colorectal cancer. Cancer letters 3 12860291
2025 UBE2C promotes pancreatic tumorigenesis by KRAS stabilization via APC/CCDH1-mediated WDR76 degradation. Cancer letters 2 40889735
2024 Positive selection and functional diversification of transcription factor Cmr1 homologs in Alternaria. Applied microbiology and biotechnology 2 38229332
2023 WDR76 regulates 5-fluorouracil sensitivity in colon cancer via HRAS. Discover oncology 2 37081180
2023 Serial Capture Affinity Purification and Integrated Structural Modeling of the H3K4me3 Binding and DNA Damage Related WDR76:SPIN1 Complex. bioRxiv : the preprint server for biology 0 36778327

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