WDR43

WDR43 is a WD-repeat protein with a dual role in nucleolar ribosome biogenesis and the regulation of transcription, and it is co-opted in cancer to drive proliferation (PMID:24219289, PMID:31128943, PMID:36525936). In nucleoli it forms the t-UTP sub-complex of the SSU processome together with CIRH1A and UTP15, three WD-repeat proteins that bind directly to one another and localize to nucleolar fibrillar centers as tightly bound, slowly mobile assemblies whose dynamics are largely independent of rDNA transcription (PMID:24219289, PMID:24754225). Its C-terminus is necessary and sufficient for nucleolar localization and protein interactions, and proper nucleolar positioning of other nucleolar proteins including TCOF1 depends on WDR43; loss of WDR43 disrupts ribosome biogenesis and produces developmental defects through a p53-dependent pathway (PMID:24497835). WDR43-containing snoRNP complexes capture distinct snoRNA–target RNA interactions linked to ribosome and spliceosome biogenesis (PMID:40001124). Beyond the nucleolus, WDR43 acts as a chromatin-associated RNA-binding protein in embryonic stem cells, recruited to active promoters and enhancers by nascent transcripts, where it facilitates P-TEFb release and Pol II pause-release to promote transcription elongation and pluripotency gene expression (PMID:31128943). During mitosis WDR43 assembles with NOL11 and Cirhin into the NWC complex that relocates from nucleoli to perichromosomal regions and is required for centromeric enrichment of Aurora B, histone H3 Thr3 phosphorylation, chromosome congression, and sister chromatid cohesion (PMID:32479628). In cancer, WDR43 promotes proliferation, chemoresistance, and cell-cycle progression: it binds RPL11 to enhance MDM2-mediated p53 ubiquitination downstream of c-MYC, and it directly interacts with CDK2 to drive cyclin expression and G1/S progression (PMID:36525936, PMID:36041702).

1. 2013 Medium

   Established the biochemical identity of WDR43 as a direct partner of CIRH1A and UTP15 in the nucleolar t-UTP sub-complex, defining its place in ribosome biogenesis machinery and revealing mitotic phospho-regulation of the complex.

   Evidence In vitro GST-pulldown binding, GFP-fusion FRAP live-cell imaging, nuclear matrix fractionation, and Xenopus egg extract phosphorylation assays in human cells

   PMID:24219289

   Open questions at the time

   • Stoichiometry and architecture of the t-UTP sub-complex not resolved
   • Functional consequence of CIRH1A Thr131 phosphorylation on processome assembly in cells not shown
   • No structural model of WDR43 within the SSU processome
2. 2014 High

   Mapped the WDR43 C-terminus as the determinant of nucleolar localization and showed WDR43 organizes the localization of other nucleolar proteins, linking its loss to ribosome biogenesis failure and p53-dependent developmental defects.

   Evidence Zebrafish fantome mutant, truncation/rescue constructs, p53 morpholino epistasis, and immunofluorescence of nucleolar protein localization

   PMID:24497835

   Open questions at the time

   • Direct molecular interactions mediated by the C-terminus not enumerated
   • Mechanism linking ribosome biogenesis defects to p53 activation not detailed
   • Whether TCOF1 mislocalization is cause or consequence of nucleolar disruption unclear
3. 2014 Medium

   Refined the dynamic behavior of WDR43 in nucleoli, showing it is essentially immobilized in fibrillar centers as part of large complexes with only partial dependence on rRNA transcription.

   Evidence GFP-fusion FRAP with rRNA transcription inhibition across multiple t-UTP components

   PMID:24754225

   Open questions at the time

   • Identity of the immobilizing binding partners not defined
   • Relationship between immobile fraction and functional processome activity unknown
4. 2019 High

   Revealed an unexpected extranucleolar role: WDR43 is a chromatin-associated RNA-binding protein recruited to active promoters by nascent RNA to promote Pol II pause-release and elongation, connecting it to transcriptional control of pluripotency.

   Evidence CLIP-seq, ChIP-seq, auxin-mediated degron, Pol II ChIP-seq, and Co-IP in embryonic stem cells

   PMID:31128943

   Open questions at the time

   • Molecular mechanism by which WDR43 promotes P-TEFb release not resolved
   • Whether this role requires or is separable from nucleolar ribosome biogenesis function unclear
   • Direct binding interface between WDR43 and Pol II/P-TEFb machinery not mapped
5. 2020 High

   Identified a mitosis-specific NWC complex (WDR43–NOL11–Cirhin) that relocalizes from nucleoli to perichromosomal regions and is required for Aurora B centromeric enrichment and faithful chromosome segregation, extending WDR43 function into mitotic fidelity.

   Evidence Reciprocal Co-IP, mitotic immunofluorescence, siRNA knockdown with chromosome alignment/cohesion readouts in human cells

   PMID:32479628

   Open questions at the time

   • How the NWC complex promotes Aurora B centromeric loading mechanistically unknown
   • Trigger for nucleolar-to-perichromosomal translocation not defined
   • Relationship between NWC and the t-UTP processome subunits unclear
6. 2021 Medium

   Placed vimentin downstream of WDR43 in colorectal cancer, providing an effector link between WDR43 and proliferative/invasive phenotypes.

   Evidence siRNA knockdown with VIM overexpression rescue, xenograft model, apoptosis and migration/invasion assays

   PMID:34372874

   Open questions at the time

   • Mechanism by which WDR43 regulates VIM expression not defined
   • Whether the effect is direct or transcriptional unknown
7. 2022 Medium

   Defined two cancer-relevant mechanisms: WDR43 binds RPL11 to enhance MDM2-mediated p53 degradation downstream of c-MYC driving chemoresistance, and it interacts with CDK2 to induce cyclins and drive cell-cycle progression.

   Evidence Co-IP (RPL11, CDK2), ubiquitination assays, p53 western blot, c-MYC ChIP, siRNA knockdown with cell-cycle analysis, in vitro and in vivo tumor models

   PMID:36041702 PMID:36525936

   Open questions at the time

   • Whether RPL11 binding is linked to WDR43's nucleolar/ribosome biogenesis role unclear
   • Direct vs. indirect nature of CDK2 interaction not structurally defined
   • Reciprocal validation of interactions limited
8. 2025 Medium

   Used WDR43 as bait to profile snoRNP-associated snoRNA–target RNA interactions, distinguishing subsets directed at ribosome versus spliceosome biogenesis.

   Evidence Chimeric eCLIP with WDR43 as bait in mouse and human cell lines

   PMID:40001124

   Open questions at the time

   • Functional requirement of WDR43 for the captured snoRNA interactions not tested
   • Whether WDR43 is a stable snoRNP component or transient interactor unclear
9. 2025 Low

   Identified WDR43 as a direct binding target of narciclasine mediating its inhibition of NRF2, implicating WDR43 in a redox/drug-response axis.

   Evidence In vitro binding with recombinant WDR43 and siRNA knockdown with NRF2 activity readout

   PMID:39783823

   Open questions at the time

   • Single in vitro binding assay; mechanism by which WDR43 affects NRF2 not established
   • Not independently confirmed
   • Physiological relevance of the WDR43-NRF2 link unclear

• How WDR43's distinct nucleolar (ribosome biogenesis), chromatin (transcription elongation), and mitotic (NWC/Aurora B) roles are coordinated by a single protein, and which interactions are direct versus complex-mediated, remains unresolved.
• No structural model integrating WDR43's WD-repeat surface across its multiple complexes
• Determinants partitioning WDR43 between nucleolus, chromatin, and perichromosomal regions unknown
• Unclear whether cancer phenotypes derive from ribosome biogenesis, transcription, or mitotic functions