p53 activation during ribosome biogenesis regulates normal erythroid differentiation. [expression]

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 shows that ribosome biogenesis is abruptly interrupted by the drop of rDNA transcription and the collapse of ribosomal protein neo-synthesis. Its premature arrest by RNA polI inhibitor, CX-5461 targets the proliferation of immature erythroblasts. We also show that p53 is activated spontaneously or in response to CX-5461 concomitantly to ribosome biogenesis arrest, and drives a transcriptional program in which genes involved in cell cycle arrest, negative regulation of apoptosis and DNA damage response were upregulated. RNA polI transcriptional stress results in nucleolar disruption and activation of ATR-CHK1-p53 pathway. Our results imply that the timing of ribosome biogenesis extinction and p53 activation are crucial for erythroid development. In ribosomopathies in which ribosome availability is altered by unbalanced production of ribosomal proteins, the threshold of ribosome biogenesis down-regulation could be prematurely reached and together with pathological p53 activation prevents a normal expansion of erythroid progenitors. The purpose of the dataset is to profile analyze the effect of ribosome biogenesis in erythroblast cells

核糖体生物发生（ribosome biogenesis）在红细胞发育中的作用，已通过对戴-布二氏贫血（Diamond-Blackfan anemia）与5q-综合征（5q- syndrome）这两种核糖体病中红细胞缺陷的识别得到证实。目前，核糖体生物发生是否对正常红细胞发育具有调控功能仍不明确。本研究对人类及小鼠红细胞生成过程中核糖体生物发生的动态变化进行了详细表征，结果显示，核糖体生物发生会因核糖体DNA（rDNA）转录水平下降与核糖体蛋白新合成崩溃而被骤然阻断。使用RNA聚合酶I抑制剂（RNA polI inhibitor）CX-5461使其提前阻滞，可靶向抑制未成熟成红细胞的增殖。本研究还发现，p53会在核糖体生物发生阻滞的同时被自发激活，或经CX-5461诱导激活，并驱动一套转录程序，其中涉及细胞周期阻滞、细胞凋亡负调控以及DNA损伤应答的基因均被上调。RNA聚合酶I转录应激会引发核仁紊乱，并激活ATR-CHK1-p53通路（ATR-CHK1-p53 pathway）。本研究结果表明，核糖体生物发生的终止时机与p53激活对于红细胞发育至关重要。在因核糖体蛋白合成失衡导致核糖体可用性改变的核糖体病中，核糖体生物发生下调的阈值可能会被提前达到，加之病理性p53激活，会阻碍红细胞祖细胞的正常扩增。本数据集旨在表征并分析核糖体生物发生对成红细胞的影响。