The induction of p53 correlates with defects in the production, but not the levels, of the small ribosomal subunit and stalled large ribosomal subunit biogenesis.
The induction of p53 correlates with defects in the production, but not the levels, of the small ribosomal subunit and stalled large ribosomal subunit biogenesis.
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DOI：
10.1093/nar/gkad637
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发表时间：
2023-09-22
影响因子：
14.9
通讯作者：
中科院分区：
文献类型：
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作者：
核糖体生物合成是细胞能量的最大消耗者之一。超过20种遗传疾病（核糖体病）和多种癌症是由40 S（SSU）和60 S（LSU）核糖体亚基产生缺陷引起的。SSU或LSU生产中的缺陷通过5S RNP（LSU组装中间体）的积累导致p53诱导。虽然LSU的机制是理解的，但仍然不清楚SSU生产缺陷如何通过5S RNP诱导p53，因为这两个亚基的生产被认为是解偶联的。在这里，我们检查了对SSU生产缺陷的反应，以了解这是如何通过5S RNP激活p53的。我们发现，p53激活后迅速发生SSU生产被阻断，在成熟的核糖体RNA（rRNA）水平的变化之前，但与早期，中期和晚期SSU前rRNA加工缺陷。此外，无论是核仁/核LSU成熟，特别是在5.8S rRNA加工的后期阶段，和前LSU出口SSU生产缺陷的影响。因此，我们发现了人类细胞中SSU和LSU生产途径之间的新联系，这解释了p53如何响应SSU生产缺陷而被诱导。
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.
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影响因子：
--
作者：
Fancello L;Kampen KR;Hofman IJ;Verbeeck J;De Keersmaecker K
通讯作者：
De Keersmaecker K
影响因子：
4.8
作者：
Kelley, Joshua B.;Paschal, Bryce M.
通讯作者：
Paschal, Bryce M.
影响因子：
5.3
作者：
Kallstrom, G;Hedges, J;Johnson, A
通讯作者：
Johnson, A
影响因子：
--
作者：
Freed EF;Bleichert F;Dutca LM;Baserga SJ
通讯作者：
Baserga SJ
影响因子：
30.8
作者：
De Keersmaecker K;Atak ZK;Li N;Vicente C;Patchett S;Girardi T;Gianfelici V;Geerdens E;Clappier E;Porcu M;Lahortiga I;Lucà R;Yan J;Hulselmans G;Vranckx H;Vandepoel R;Sweron B;Jacobs K;Mentens N;Wlodarska I;Cauwelier B;Cloos J;Soulier J;Uyttebroeck A;Bagni C;Hassan BA;Vandenberghe P;Johnson AW;Aerts S;Cools J
通讯作者：
Cools J