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.
摘要：
细胞衰老是由各种应激引起的细胞周期停滞的不可逆状态。包括异常的癌基因激活，端粒缩短，和DNA损伤。通过一个全基因组的屏幕,我们发现了一种保守的小核仁RNA（snoRNA），SNORA13，是人类细胞和小鼠多种形式衰老所必需的。尽管SNORA13指导了核糖体解码中心保守核苷酸的假尿苷化，这种snoRNA的丢失对翻译的影响最小。相反，我们发现SNORA13负调节核糖体生物发生。诱导衰老的应激干扰核糖体生物发生，导致触发p53激活的游离核糖体蛋白（RP）的积累。SNORA13与RPL23直接相互作用，减少其掺入成熟的60S亚基，因此,增加免费RPs池，从而促进p53介导的衰老。因此，SNORA13通过与其在引导RNA修饰中的作用不同的非规范机制调节核糖体生物发生和p53途径。这些发现扩展了我们对snoRNA功能及其在细胞信号传导中的作用的理解。
