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p53 activation during ribosome biogenesis regulates normal erythroid differentiation.

核糖体生物合成过程中p53的激活调节正常的红系分化。

  • 影响因子:7.27
  • DOI:10.1182/blood.2019003439
  • 作者列表:"Le Goff S","Boussaid I","Floquet C","Raimbault A","Hatin I","Andrieu-Soler C","Salma M","Leduc M","Gautier EF","Guyot B","d'Allard D","Montel-Lehry N","Ducamp S","Houvert A","Guillonneau F","Giraudier S","Cramer-Bordé E","Morlé F","Diaz JJ","Hermine O","Taylor N","Kinet S","Verdier F","Padua RA","Mohandas N","Gleizes PE","Soler E","Mayeux P","Fontenay M
  • 发表时间:2021-01-07
Abstract

:The role of ribosome biogenesis in erythroid development is supported by the recognition of erythroid defects in ribosomopathies in both Diamond-Blackfan anemia and 5q- syndrome. Whether ribosome biogenesis exerts a regulatory function on normal erythroid development is still unknown. In the present study, a detailed characterization of ribosome biogenesis dynamics during human and murine erythropoiesis showed that ribosome biogenesis is abruptly interrupted by the decline in ribosomal DNA transcription and the collapse of ribosomal protein neosynthesis. Its premature arrest by the RNA Pol I inhibitor CX-5461 targeted the proliferation of immature erythroblasts. p53 was activated spontaneously or in response to CX-5461, concomitant to ribosome biogenesis arrest, and drove a transcriptional program in which genes involved in cell cycle-arrested, negative regulation of apoptosis, and DNA damage response were upregulated. RNA Pol I transcriptional stress resulted in nucleolar disruption and activation of the ATR-CHK1-p53 pathway. Our results imply that the timing of ribosome biogenesis extinction and p53 activation is crucial for erythroid development. In ribosomopathies in which ribosome availability is altered by unbalanced production of ribosomal proteins, the threshold downregulation of ribosome biogenesis could be prematurely reached and, together with pathological p53 activation, prevents a normal expansion of erythroid progenitors.

摘要

: 核糖体生物发生在红系发育中的作用得到了对钻石-黑范贫血和5q综合征核糖体病中红细胞缺陷的识别的支持。核糖体生物合成是否对正常的红系发育发挥调节功能仍然是未知的。在本研究中,人类和小鼠红细胞生成过程中核糖体生物合成动力学的详细表征表明,核糖体生物合成被核糖体DNA转录的下降和核糖体蛋白新合成的崩溃突然中断。由RNA Pol I抑制剂CX-5461引起的它的过早停滞靶向未成熟的成红细胞的增殖。p53被自发激活或响应于CX-5461,伴随核糖体生物发生停滞,并驱动转录程序,其中涉及细胞周期停滞、细胞凋亡的负调节和DNA损伤反应的基因被上调。RNA Pol I转录应激导致核仁破坏和ATR-CHK1-p53途径的激活。我们的结果意味着核糖体生物合成灭绝和p53激活的时间对于红系发育至关重要。在核糖体可用性因核糖体蛋白的不平衡产生而改变的核糖体病中,核糖体生物发生的阈值下调可以过早达到,并且与病理性p53激活一起,阻止红系祖细胞的正常扩增。

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影响因子:2.68
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DOI:10.1007/s11033-021-06299-9
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