美国德克萨斯大学西南医学中心Joshua T. Mendell团队近期取得重要工作进展，他们研究提出了小核仁RNA（snoRNA）在核糖体生物发生和衰老过程中的非典型作用。相关研究成果2024年7月8日在线发表于《细胞》杂志上。
据介绍，细胞衰老是由各种应激诱导的细胞周期停滞的不可逆状态，包括异常癌基因激活、端粒缩短和DNA损伤。
通过全基因组筛选，研究人员发现了一种保守的snoRNA，即SNORA13，它是人类细胞和小鼠多种形式衰老所必需的。尽管SNORA13引导核糖体解码中心保守核苷酸的假尿苷化，但这种snoRNA的缺失对翻译的影响较小。相反，SNORA13对核糖体的生物发生有负调控作用。衰老诱导的应激会干扰核糖体的生物发生，导致游离核糖体蛋白（RP）的积累，从而触发p53的激活。
SNORA13直接与RPL23相互作用，减少其掺入成熟的60S亚基，增加游离RP的数量，从而促进p53介导的衰老。因此，SNORA13通过一种不同于其在引导RNA修饰中的非经典机制调节核糖体生物发生和p53途径。因此，SNORA13通过一种非经典机制调节核糖体生物发生和p53通路，这种机制不同于其在引导RNA修饰方面的作用。
总之，这一研究扩展了人们对snoRNA功能及其在细胞信号传导中的作用的理解。
附：英文原文
Title: A non-canonical role for a small nucleolar RNA in ribosome biogenesis and senescence
Author: Yujing Cheng, Siwen Wang, He Zhang, Jong-Sun Lee, Chunyang Ni, Jason Guo, Eric Chen, Shenming Wang, Asha Acharya, Tsung-Cheng Chang, Michael Buszczak, Hao Zhu, Joshua T. Mendell
Issue&Volume: 2024-07-08
Abstract: Cellular senescence is an irreversible state of cell-cycle arrest induced by various stresses, including aberrant oncogene activation, telomere shortening, and DNA damage. Through a genome-wide screen, we discovered a conserved small nucleolar RNA (snoRNA), SNORA13, that is required for multiple forms of senescence in human cells and mice. Although SNORA13 guides the pseudouridylation of a conserved nucleotide in the ribosomal decoding center, loss of this snoRNA minimally impacts translation. Instead, we found that SNORA13 negatively regulates ribosome biogenesis. Senescence-inducing stress perturbs ribosome biogenesis, resulting in the accumulation of free ribosomal proteins (RPs) that trigger p53 activation. SNORA13 interacts directly with RPL23, decreasing its incorporation into maturing 60S subunits and, consequently, increasing the pool of free RPs, thereby promoting p53-mediated senescence. Thus, SNORA13 regulates ribosome biogenesis and the p53 pathway through a non-canonical mechanism distinct from its role in guiding RNA modification. These findings expand our understanding of snoRNA functions and their roles in cellular signaling.
DOI: 10.1016/j.cell.2024.06.019
Source: https://www.cell.com/cell/fulltext/S0092-8674(24)00693-7