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<p>Although most eukaryotic mRNAs require a 5ʹ-cap for translation initiation, some can also be translated through a poorly studied cap-independent pathway. Here we develop a circRNA-based system and unbiasedly identify more than 10,000 sequences in the human transcriptome that contain Cap-independent Translation Initiators (CiTIs). Surprisingly, most of the identified CiTIs are located in 3’UTRs, which mainly promote translation initiation in mRNAs bearing highly structured 5’UTR. Mechanistically, CiTI recruits several translation initiation factors including eIF3 and DHX29, which in turn unwind 5’UTR structures and facilitate ribosome scanning. Functionally, we show that the translation of HIF1A mRNA, an endogenous DHX29 target, is antagonistically regulated by its 5’UTR structure and a new 3ʹ-CiTI in response to hypoxia. Consistently, deletion of 3ʹ-CiTI suppresses cell growth in hypoxia and tumor progression in vivo. Collectively, our study uncovers a new regulatory mode for translation where the 3ʹUTR actively participate in the translation initiation.</p>

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Unbiased screen of human transcriptome reveals an unexpected role of 3’UTRs in translation initiation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月3日

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  • Yun Yang,
  • Xiaojuan Fan,
  • Yanwen Ye,
  • Zhenzhen Zhang,
  • Chuyun Chen,
  • Sebastian E. J. Ludwig,
  • Sirui Zhang,
  • Qianyun Lu,
  • Cindy L. Will,
  • Henning Urlaub,
  • Jing Sun,
  • Reinhard Lührmann,
  • Zefeng Wang

摘要

Although most eukaryotic mRNAs require a 5ʹ-cap for translation initiation, some can also be translated through a poorly studied cap-independent pathway. Here we develop a circRNA-based system and unbiasedly identify more than 10,000 sequences in the human transcriptome that contain Cap-independent Translation Initiators (CiTIs). Surprisingly, most of the identified CiTIs are located in 3’UTRs, which mainly promote translation initiation in mRNAs bearing highly structured 5’UTR. Mechanistically, CiTI recruits several translation initiation factors including eIF3 and DHX29, which in turn unwind 5’UTR structures and facilitate ribosome scanning. Functionally, we show that the translation of HIF1A mRNA, an endogenous DHX29 target, is antagonistically regulated by its 5’UTR structure and a new 3ʹ-CiTI in response to hypoxia. Consistently, deletion of 3ʹ-CiTI suppresses cell growth in hypoxia and tumor progression in vivo. Collectively, our study uncovers a new regulatory mode for translation where the 3ʹUTR actively participate in the translation initiation.