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<p>WD40-repeat (WDR) proteins constitute one of the largest and most functionally diverse scaffold families in eukaryotes. By folding tandem WD repeats into β-propeller domains, they provide modular interaction surfaces that assemble multi-protein complexes governing transcription and epigenetic control, ubiquitin-dependent proteostasis, RNA metabolism, and cell-cycle progression. Despite their pervasive involvement in oncogenic signaling and hallmark cancer phenotypes, the cancer field still lacks an integrated framework that connects WDR structural logic to context-dependent mechanisms and, critically, to actionable biomarkers and therapeutic strategies; existing evidence remains dispersed across tumor types and molecular pathways. This review synthesizes current knowledge to address that gap. We first summarize core structural principles of WD40 β-propellers and explain how multivalent binding and partner selection enable WDR proteins to function as assembly platforms in oncogenic networks. We then consolidate mechanistic evidence showing how representative WDR proteins shape malignant state transitions, including sustained proliferation, survival under stress, epigenetic plasticity, invasion and metastasis, and therapy resistance, by rewiring chromatin programs, ubiquitination circuits, and RNA and translation outputs across cancers. Finally, we highlight translational progress and opportunities. Overall, this review integrates the fragmented WDR research into a clinically oriented framework that clarifies their potential as biomarkers for early detection, stratified diagnosis, and treatment-response prediction, and delineates druggable entry points and rational combination strategies, thereby providing a translational roadmap to enable more precise cancer diagnosis and more effective targeted therapies in the future.</p>

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The role of the WD40-repeat protein family in cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月27日

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  • Jiale Li,
  • Haixu Zhou,
  • Qisheng Luo,
  • Duorong Wu,
  • Maximo Lin,
  • Ge Mai,
  • Xindong Xu,
  • Yongping He,
  • Yanhong Liu,
  • Jiachong Wang,
  • Changfeng Miao,
  • Zigui Chen,
  • Chunhai Tang

摘要

WD40-repeat (WDR) proteins constitute one of the largest and most functionally diverse scaffold families in eukaryotes. By folding tandem WD repeats into β-propeller domains, they provide modular interaction surfaces that assemble multi-protein complexes governing transcription and epigenetic control, ubiquitin-dependent proteostasis, RNA metabolism, and cell-cycle progression. Despite their pervasive involvement in oncogenic signaling and hallmark cancer phenotypes, the cancer field still lacks an integrated framework that connects WDR structural logic to context-dependent mechanisms and, critically, to actionable biomarkers and therapeutic strategies; existing evidence remains dispersed across tumor types and molecular pathways. This review synthesizes current knowledge to address that gap. We first summarize core structural principles of WD40 β-propellers and explain how multivalent binding and partner selection enable WDR proteins to function as assembly platforms in oncogenic networks. We then consolidate mechanistic evidence showing how representative WDR proteins shape malignant state transitions, including sustained proliferation, survival under stress, epigenetic plasticity, invasion and metastasis, and therapy resistance, by rewiring chromatin programs, ubiquitination circuits, and RNA and translation outputs across cancers. Finally, we highlight translational progress and opportunities. Overall, this review integrates the fragmented WDR research into a clinically oriented framework that clarifies their potential as biomarkers for early detection, stratified diagnosis, and treatment-response prediction, and delineates druggable entry points and rational combination strategies, thereby providing a translational roadmap to enable more precise cancer diagnosis and more effective targeted therapies in the future.