Nuclear release of eIF1 restricts start-codon selection during mitosis

• 成果类型: Article
• 署名作者: Ly, Jimmy; Xiang, Kehui; Su, Kuan-Chung; Sissoko, Gunter B.; Bartel, David P.; Cheeseman, Iain M.
• 署名单位: Massachusetts Institute of Technology (MIT); Whitehead Institute; Massachusetts Institute of Technology (MIT); Howard Hughes Medical Institute
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6561
• DOI: 10.1038/s41586-024-08088-3
• 发表日期: 2024-11-14
• 关键词: translation initiation; modulates autoregulation; rna; protein; reveals; aug; elongation; DYNAMICS; complex; sites

摘要

Regulated start-codon selection has the potential to reshape the proteome through the differential production of upstream open reading frames, canonical proteins, and alternative translational isoforms1-3. However, conditions under which start codon selection is altered remain poorly defined. Here, using transcriptome-wide translation-initiation-site profiling4, we reveal a global increase in the stringency of start-codon selection during mammalian mitosis. Low-efficiency initiation sites are preferentially repressed in mitosis, resulting in pervasive changes in the translation of thousands of start sites and their corresponding protein products. This enhanced stringency of start-codon selection during mitosis results from increased association between the 40S ribosome and the key regulator of start-codon selection, eIF1. We find that increased eIF1-40S ribosome interaction during mitosis is mediated by the release of a nuclear pool of eIF1 upon nuclear envelope breakdown. Selectively depleting the nuclear pool of eIF1 eliminates the change to translational stringency during mitosis, resulting in altered synthesis of thousands of protein isoforms. In addition, preventing mitotic translational rewiring results in substantially increased cell death and decreased mitotic slippage in cells that experience a mitotic delay induced by anti-mitotic chemotherapies. Thus, cells globally control stringency of translation initiation, which has critical roles during the mammalian cell cycle in preserving mitotic cell physiology. Transcriptome-wide profiling studies in mammalian cells show that the stringency of start-codon selection is increased during mitosis, and that this is regulated by nuclear eIF1 to preserve mitotic arrest physiology.