核糖体生物合成是一种细胞能量消耗最为巨大的过程。40S（小亚基）和60S（大亚基）核糖体亚基的生产缺陷导致了20多种遗传性疾病（核糖体病）和多种癌症的发生。无论是小亚基还是大亚基的生产缺陷都会引发p53的激活，其机制是通过5S RNP的积累导致的，该物质是大亚基组装过程中的中间体。尽管大亚基的机制已经被理解，但是目前仍不清楚小亚基生产缺陷如何通过5S RNP诱导p53的激活，因为人们认为两个亚基的生产是脱耦合的。在本研究中，我们研究了小亚基生产缺陷对应答的影响，以了解其如何通过5S RNP导致p53的激活。我们发现，在小亚基的生产被阻断之后，p53的激活迅速发生，尽管成熟核糖体RNA（rRNA）水平尚未发生改变，但早期、中期和晚期小亚基前rRNA处理缺陷与之相关。此外，小亚基生产缺陷还影响到核仁/细胞核内大亚基成熟，特别是5.8S rRNA处理的晚期阶段以及前大亚基的输出。因此，我们发现了人类细胞中小亚基和大亚基生产途径之间的新的联系，这解释了p53在小亚基生产缺陷应答中如何被诱导。© 作者2023年 牛津大学出版社代表核酸研究杂志发布

Ribosome biogenesis is one of the biggest consumers of cellular energy. More than 20 genetic diseases (ribosomopathies) and multiple cancers arise from defects in the production of the 40S (SSU) and 60S (LSU) ribosomal subunits. Defects in the production of either the SSU or LSU result in p53 induction through the accumulation of the 5S RNP, an LSU assembly intermediate. While the mechanism is understood for the LSU, it is still unclear how SSU production defects induce p53 through the 5S RNP since the production of the two subunits is believed to be uncoupled. Here, we examined the response to SSU production defects to understand how this leads to the activation of p53 via the 5S RNP. We found that p53 activation occurs rapidly after SSU production is blocked, prior to changes in mature ribosomal RNA (rRNA) levels but correlated with early, middle and late SSU pre-rRNA processing defects. Furthermore, both nucleolar/nuclear LSU maturation, in particular late stages in 5.8S rRNA processing, and pre-LSU export were affected by SSU production defects. We have therefore uncovered a novel connection between the SSU and LSU production pathways in human cells, which explains how p53 is induced in response to SSU production defects.© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.