美国怀特海生物医学研究所Iain M. Cheeseman研究组在研究中取得进展。他们发现在有丝分裂过程中，eIF1的出核过程限制了起始密码子的选择。相关论文于2024年10月23日发表在《自然》杂志上。

研究人员利用全转录组翻译起始位点图谱分析，发现哺乳动物有丝分裂过程中全身性起始密码子的选择受到严控调控。在有丝分裂过程中，低效率的起始位点会首先受到抑制，从而导致成千上万个起始位点及其相应蛋白质产物的翻译发生普遍变化。

有丝分裂过程中起始密码子选择的强度增强，这是由于40S核糖体与起始密码子选择的关键调控因子eIF1之间的关联增强。研究发现，在有丝分裂过程中eIF1-40S核糖体相互作用的增强是由核包膜破裂时释放的eIF1所介导。选择性耗竭核eIF1可消除有丝分裂过程中翻译的变化，从而改变数千种蛋白质同工酶的合成。

此外，在抗有丝分裂化疗药物诱导的有丝分裂延迟细胞中，防止有丝分裂翻译重新布线可大幅增加细胞死亡，减少有丝分裂滑动。因此，细胞可全方位控制翻译启动的严格程度，这在哺乳动物细胞周期中对维持有丝分裂细胞的生理机能起着至关重要的作用。

据了解，起始密码子的选择可能通过调控上游开放阅读框、典型蛋白和替代翻译异构体产生不同的重塑蛋白质组。然而，起始密码子选择发生改变的机制尚不得知。

附：英文原文

Title: Nuclear release of eIF1 restricts start-codon selection during mitosis

Author: Ly, Jimmy, Xiang, Kehui, Su, Kuan-Chung, Sissoko, Gunter B., Bartel, David P., Cheeseman, Iain M.

Issue&Volume: 2024-10-23

Abstract: 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 isoforms1,2,3. 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.

DOI: 10.1038/s41586-024-08088-3

Source: https://www.nature.com/articles/s41586-024-08088-3