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

作者：Yun Yang, Xiaojuan Fan, Yanwen Ye, Zhenzhen Zhang, Chuyun Chen, Sebastian Ludwig, Sirui Zhang, Qianyun Lu, Cindy L. Will, Henning Urlaub, Jing Sun, Reinhard Lührmann, Zefeng Wang · 发表于：Nature Communications · 年份：2026 · DOI：10.1038/s41467-026-75574-9 · 被引用次数：4 · 研究领域：RNA Research and Splicing、RNA modifications and cancer、RNA and protein synthesis mechanisms

Abstract Although most eukaryotic mRNAs require a 5′-cap for translation initiation, some can also be translated through a poorly studied cap-independent pathway. Here we developed a circRNA-based system and unbiasedly identified 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 showed that the translation of HIF1A mRNA, an endogenous DHX29 target, is antagonistically regulated by its 5′UTR structure and a new 3′-CiTI in response to hypoxia. Therefore, deletion of 3′-CiTI suppresses cell growth in hypoxia and tumor progression in vivo . Collectively, our study uncovers a new regulatory mode for translation where the 3′UTR actively participate in the translation initiation.