美国约翰霍普金斯大学医学院Rachel Green，Sergi Regot和美国纪念斯隆凯特琳癌症中心Alban Ordureau共同合作，近期取得重要工作进展。他们研究提出，核糖毒性应激反应驱动紫外线（UV）介导的细胞死亡。相关研究成果2024年6月5日在线发表于《细胞》杂志上。

据介绍，虽然已知紫外线（UV）辐射损害DNA，引发DNA损伤反应（DDR），但UV也损害RNA，引起转录组范围内的核糖体碰撞，并导致核糖毒性应激反应（RSR）。然而，这些途径在决定细胞命运方面的相对贡献、时间和调节尚不清楚。

研究人员使用时间分辨的磷酸蛋白质组学、化学遗传学、单细胞成像和生物化学方法来创建细胞对UV损伤反应中激活的信号事件的时间图谱。研究人员发现，UV诱导的细胞凋亡是由RSR激酶ZAK介导的，而不是通过DDR介导的。

研究人员确定了调节ZAK介导的细胞凋亡的两个负反馈模块：（1）GCN2激活限制核糖体碰撞并减弱ZAK介导的RSR；（2）ZAK活性导致磷酸化蛋白发生自磷酸化及其随后的降解。这些事件将ZAK的活性调整到碰撞水平，以建立稳态、耐受和死亡机制，揭示其作为核酸损伤的细胞哨兵的关键作用。

附：英文原文

Title: The ribotoxic stress response drives UV-mediated cell death

Author: Niladri K. Sinha, Connor McKenney, Zhong Y. Yeow, Jeffrey J. Li, Ki Hong Nam, Tomer M. Yaron-Barir, Jared L. Johnson, Emily M. Huntsman, Lewis C. Cantley, Alban Ordureau, Sergi Regot, Rachel Green

Issue&Volume: 2024-06-05

Abstract: While ultraviolet (UV) radiation damages DNA, eliciting the DNA damage response (DDR), it also damages RNA, triggering transcriptome-wide ribosomal collisions and eliciting a ribotoxic stress response (RSR). However, the relative contributions, timing, and regulation of these pathways in determining cell fate is unclear. Here we use time-resolved phosphoproteomic, chemical-genetic, single-cell imaging, and biochemical approaches to create a chronological atlas of signaling events activated in cells responding to UV damage. We discover that UV-induced apoptosis is mediated by the RSR kinase ZAK and not through the DDR. We identify two negative-feedback modules that regulate ZAK-mediated apoptosis: (1) GCN2 activation limits ribosomal collisions and attenuates ZAK-mediated RSR and (2) ZAK activity leads to phosphodegron autophosphorylation and its subsequent degradation. These events tune ZAK's activity to collision levels to establish regimes of homeostasis, tolerance, and death, revealing its key role as the cellular sentinel for nucleic acid damage.

DOI: 10.1016/j.cell.2024.05.018

Source: https://www.cell.com/cell/fulltext/S0092-8674(24)00527-0