Unbiased screen of human transcriptome reveals an unexpected role of 3’UTRs in translation initiation
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.
Authors
- Sebastian Ludwig (ORCID: https://orcid.org/0000-0002-6059-9567)
- Chuyun Chen (ORCID: https://orcid.org/0000-0003-0550-9458)
- Sirui Zhang (ORCID: https://orcid.org/0000-0002-1992-3345)
- Qianyun Lu (ORCID: https://orcid.org/0000-0002-0466-5072)
- Reinhard Lührmann (ORCID: https://orcid.org/0000-0003-3253-7518)
- Xiaojuan Fan (ORCID: https://orcid.org/0000-0001-9255-1544)
- Yanwen Ye
- Cindy L. Will (ORCID: https://orcid.org/0000-0003-0012-9106)
- Zefeng Wang (ORCID: https://orcid.org/0000-0002-6605-3637)
- Yun Yang (ORCID: https://orcid.org/0000-0003-2958-5391)
- Jing Sun
- Zhenzhen Zhang
- Henning Urlaub
Institutions
- Chinese Academy of Sciences (CN)
- Southern University of Science and Technology (CN)
- Shanghai Institute of Nutrition and Health (CN)
- Universitätsmedizin Göttingen (DE)
- Health Biomed (China) (CN)
- Center for Excellence in Molecular Cell Science (CN)
- Max Planck Institute for Biophysical Chemistry (DE)
- University of Chinese Academy of Sciences (CN)
- University of Göttingen (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-08-03
- DOI
- https://doi.org/10.1038/s41467-026-75574-9
- Citations
- 4
- Primary Topic
- RNA Research and Splicing
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Max-Planck-Gesellschaft
- National Key Research and Development Program of China