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GPATCH4 functions as a regulator of nucleolar R-loops in hepatocellular carcinoma cells.

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  • Additional Information
    • Source:
      Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE
    • Publication Information:
      Publication: 1992- : Oxford : Oxford University Press
      Original Publication: London, Information Retrieval ltd.
    • Subject Terms:
      Carcinoma, Hepatocellular*/genetics ; Carcinoma, Hepatocellular*/pathology ; Carcinoma, Hepatocellular*/metabolism ; Liver Neoplasms*/genetics ; Liver Neoplasms*/pathology ; Liver Neoplasms*/metabolism ; Cell Nucleolus*/metabolism ; Cell Nucleolus*/genetics ; RNA-Binding Proteins*/genetics ; RNA-Binding Proteins*/metabolism ; R-Loop Structures*/genetics; Humans ; RNA, Ribosomal/genetics ; RNA, Ribosomal/metabolism ; Cell Proliferation/genetics ; Cell Line, Tumor ; DEAD-box RNA Helicases/metabolism ; DEAD-box RNA Helicases/genetics ; Animals ; Gene Expression Regulation, Neoplastic ; Mice ; DNA, Ribosomal/genetics ; DNA, Ribosomal/metabolism
    • Abstract:
      Emerging evidence suggests that dysregulated RNA-binding proteins (RBPs) are associated with a wide variety of cancers. However, the exact roles and pathways of RBPs in the tumorigenesis of hepatocellular carcinoma (HCC), the most common subtype of liver cancer, remain largely unknown. Here, we systematically searched for altered RBP candidates in HCC through multi-omics data integrative analyses and identified that GPATCH4 gene is amplified in >70% HCC patients and its high expression predicts poor prognosis. We mapped the in vivo RNA binding sites of GPATCH4 by iCLIP-seq and characterized that GPATCH4 primarily bound ribosomal RNA (rRNAs). GPATCH4 promoted HCC cell proliferation and transformation both in vitro and in vivo through increasing rRNA transcription and global protein synthesis. GPATCH4 is mainly localized in the nucleolus and helps to unwind RNA loops formed at the rDNA through interacting with DDX21 via its C-terminal intrinsically disordered region. Removal of accumulated R-loops induced by GPATCH4 depletion rescued decreased rRNA transcription and cell proliferation. Taken together, we characterized the understudied GPATCH4 as an RBP with oncogenic function in HCC and revealed a new mechanism by which GPATCH4 functions as a regulator of nucleolar R-loops to control rRNA transcription through interacting with DDX21.
      (© The Author(s) 2025. Published by Oxford University Press on behalf of Nucleic Acids Research.)
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    • Grant Information:
      2022YFA1303300 National Key R&D Program of China; 2021YFA1300500 National Key R&D Program of China; XDB0570000 Chinese Academy of Sciences; 32271349 National Natural Science Foundation of China; 32071288 National Natural Science Foundation of China; 32401076 National Natural Science Foundation of China; 32301081 National Natural Science Foundation of China; GZC20241714 China Postdoctoral Science Foundation; 2024M753223 China Postdoctoral Science Foundation; 2023M733488 China Postdoctoral Science Foundation; Shanghai Postdoctoral Excellence Program
    • Accession Number:
      0 (RNA, Ribosomal)
      0 (RNA-Binding Proteins)
      EC 3.6.1.- (DDX21 protein, human)
      EC 3.6.4.13 (DEAD-box RNA Helicases)
      0 (DNA, Ribosomal)
    • Publication Date:
      Date Created: 20250522 Date Completed: 20250522 Latest Revision: 20250525
    • Publication Date:
      20250525
    • Accession Number:
      PMC12096074
    • Accession Number:
      10.1093/nar/gkaf438
    • Accession Number:
      40401559