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Targeting PUS7 suppresses tRNA pseudouridylation and glioblastoma tumorigenesis.

Qi Cui | Kailin Yin | Xiaoting Zhang | Peng Ye | Xianwei Chen | Jianfei Chao | Haowei Meng | Jiangbo Wei | Daniel Roeth | Li Li | Yue Qin | Guihua Sun | Mingzi Zhang | Jeremy Klein | Marvin Huynhle | Cheng Wang | Leying Zhang | Behnam Badie | Markus Kalkum | Chuan He | Chengqi Yi | Yanhong Shi
Nature cancer | 2021

Pseudouridine is the most frequent epitranscriptomic modification. However, its cellular functions remain largely unknown. Here, we show that pseudouridine synthase 7 (PUS7) is highly expressed in glioblastoma versus normal brain tissues, and high PUS7 expression levels are associated with worse survival in patients with glioblastoma. PUS7 expression and catalytic activity are required for glioblastoma stem cell (GSC) tumorigenesis. Mechanistically, we identify PUS7 targets in GSCs through small RNA pseudouridine sequencing and show that pseudouridylation of PUS7-regulated transfer RNA is critical for codon-specific translational control of key regulators of GSCs. Moreover, we identify chemical inhibitors for PUS7 and show that these compounds prevent PUS7-mediated pseudouridine modification, suppress tumorigenesis and extend the life span of tumor-bearing mice. Overall, we identify an epitranscriptomic regulatory mechanism in glioblastoma and provide preclinical evidence of a potential therapeutic strategy for glioblastoma.

Pubmed ID: 35121864

Associated grants

  • Agency: NIA NIH HHS, United States
    Id: R56 AG061171
  • Agency: NIA NIH HHS, United States
    Id: RF1 AG061794
  • Agency: NIA NIH HHS, United States
    Id: R01 AG056305
  • Agency: NCI NIH HHS, United States
    Id: P30 CA033572

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Addgene (tool)

RRID:SCR_002037

Non-profit plasmid repository dedicated to helping scientists around the world share high-quality plasmids. Facilitates archiving and distributing DNA-based research reagents and associated data to scientists worldwide. Repository contains over 65,000 plasmids, including special collections on CRISPR, fluorescent proteins, and ready-to-use viral preparations. There is no cost for scientists to deposit plasmids, which saves time and money associated with shipping plasmids themselves. All plasmids are fully sequenced for validation and sequencing data is openly available. We handle the appropriate Material Transfer Agreements (MTA) with institutions, facilitating open exchange and offering intellectual property and liability protection for depositing scientists. Furthermore, we curate free educational resources for the scientific community including a blog, eBooks, video protocols, and detailed molecular biology resources.

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RRID:SCR_003199

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RRID:SCR_003496

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RRID:SCR_005476

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RRID:SCR_005514

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RRID:SCR_018933

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RRID:CVCL_0063

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