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Article Dans Une Revue Blood Année : 2021

p53 activation during ribosome biogenesis regulates normal erythroid differentiation

Salomé Le Goff
  • Fonction : Auteur
Ismael Boussaid
  • Fonction : Auteur
Anna Raimbault
Mohammad Salma
  • Fonction : Auteur
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Emilie-Fleur Gautier
Boris Guyot
Diane D’allard
  • Fonction : Auteur
Nathalie Montel-Lehry
  • Fonction : Auteur
Sarah Ducamp
  • Fonction : Auteur
Amandine Houvert
  • Fonction : Auteur
François Guillonneau
Stéphane Giraudier
Elisabeth Cramer-Bordé
  • Fonction : Auteur
François Morlé
  • Fonction : Auteur
Jean-Jacques Diaz
Olivier Hermine
Naomi Taylor
Sandrina Kinet
  • Fonction : Auteur
Frédérique Verdier
Rose-Ann Padua
Narla Mohandas
Pierre-Emmanuel Gleizes
Eric Soler
Patrick Mayeux
  • Fonction : Auteur
Michaela Fontenay

Résumé

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.

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Salomé Le Goff, Ismael Boussaid, Celia Floquet, Anna Raimbault, Isabelle Hatin, et al.. p53 activation during ribosome biogenesis regulates normal erythroid differentiation. Blood, 2021, 137 (1), pp.89-102. ⟨10.1182/blood.2019003439⟩. ⟨hal-03442857⟩
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