In response to excessive DNA damage, human cells can activate p53 to induce apoptosis. Cells lacking p53 can still undergo apoptosis upon DNA damage, yet the responsible pathways are unknown. We observed that p53-independent apoptosis in response to DNA damage coincided with translation inhibition, which was characterized by ribosome stalling on rare leucine-encoding UUA codons and globally curtailed translation initiation. A genetic screen identified the transfer RNAse SLFN11 and the kinase GCN2 as factors required for UUA stalling and global translation inhibition, respectively. Stalled ribosomes activated a ribotoxic stress signal conveyed by the ribosome sensor ZAKα to the apoptosis machinery. These results provide an explanation for the frequent inactivation of SLFN11 in chemotherapy-unresponsive tumors and highlight ribosome stalling as a signaling event affecting cell fate in response to DNA damage.

中文翻译：

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DNA 损伤通过核糖体停滞诱导不依赖于 p53 的细胞凋亡


为了应对过度的 DNA 损伤，人类细胞可以激活 p53 来诱导细胞凋亡。缺乏 p53 的细胞在 DNA 损伤后仍会发生凋亡，但其相关途径尚不清楚。我们观察到 DNA 损伤引起的不依赖于 p53 的细胞凋亡与翻译抑制同时发生，其特征是核糖体在罕见的亮氨酸编码 UUA 密码子上停滞，并且翻译起始受到全局限制。遗传筛选将转移 RNAse SLFN11 和激酶 GCN2 分别确定为 UUA 停滞和全局翻译抑制所需的因子。停滞的核糖体激活核糖体传感器 ZAKα 向细胞凋亡机制传递的核糖毒性应激信号。这些结果为化疗无反应的肿瘤中 SLFN11 频繁失活提供了解释，并强调核糖体停滞是响应 DNA 损伤而影响细胞命运的信号事件。