p53 activation during ribosome biogenesis regulates normal erythroid differentiation

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 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.

Effect of Glucocorticosteroids in Diamond-Blackfan Anaemia: Maybe Not as Elusive as It Seems

“…However, this hypothesis has been partially refuted since the haploinsufficiency of most RPs does not lead to p53 stimulation via ribosomal stress mechanisms [55]. Even though ribosomal stress and p53 signalling are critical for normal erythropoiesis [56], the activation of p53 in DBA is most likely mediated by impaired metabolism and DNA damage [6,57].…”

Circulating primitive murine erythroblasts undergo complex proteomic and metabolomic changes during terminal maturation

“…49 Despite decreases in the transcription of p53, primitive OrthoE were characterized by increases in the cholesterol transporter Abca1, a p53 target, 37 and were mirrored by increases in intracellular esterified cholesterol and corresponding decreases in transcript levels of several rate-limiting cholesterol synthesis enzymes that are regulated by p53 (Hmgcr, Mvk, and Pmvk). 37 These observations highlight an additional role for p53 in erythropoiesis, on top of its function to drive a transcriptional program in maturing progenitors in coordination with arrested ribosome biogenesis 50 . A role for p53 in modulating cholesterol dynamics 51 highlights a complex reprogramming for membrane dynamics as well.…”

Dynamic regulation and requirement for ribosomal RNA transcription during mammalian development

“…Collectively our data suggests that it is not p53 RNA transcription, but cell and tissue specific sensitivity to perturbations in rRNA transcription that result in cell autonomous tissue-specific post-translational activation of p53 protein in NCC which underpins the pathogenesis of craniofacial anomalies characteristic of TCS and AFDCIN. This mechanism may also account for other ribosomopathies in which deficiencies in specific ribosomal proteins or increased rRNA transcription 49 are associated with p53-dependent cell death 50,51 and emphasizes the importance of balanced rRNA and ribosomal protein production in these pathologies.…”