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    p53 activation during ribosome biogenesis regulates normal erythroid differentiation.

    A study from the team Normal and pathological hematopoiesis, Department DRC

    p53 activation during ribosome biogenesis regulates normal erythroid differentiation.

     

    In a paper published in the journal Blood, the team led by Michaela Fontenay describes the role of the p53 protein in erythroid differentiation, linked to the formation of ribosomes. This study has potential implications for the treatment of anemia due to ribosome abnormalities.

     

    The differentiation of hematopoietic progenitors in erythroid precursors and red cells require morphological changes which are coordinated by their response to the major cytokines of erythropoiesis, stem cell factor and erythropoietin. This implicates transcriptome reprogramming through the activation or repression of transcription factor GATA1 target genes and of the proteome through the translation regulation by the RNA amounts, the translation initiation rate and the cellular concentration of ribosomes.

     

    Using proteomic approaches (3P5 Platform, Université de Paris) allowing either the absolute quantification of ribosomal proteins or the measurement of ribosomal proteins renewal rate by the pulse SILAC method, the team showed that ribosome biogenesis decreases in a balanced manner in basophilic erythroblasts and that the resulting ribosomal stress and a p53 activation are concomitant. In vitro and in vivo experiments in Tp53-/- mice showed that p53 activation represses the proliferation of immature erythroblasts. ChIP-seq experiment in primary erythroblasts allowed the identification of p53 direct targets which are involved in the regulation of cell cycle, the negative regulation of apoptosis and DNA damage. Some p53 targets are also GATA1 targets. p53 activation induced by the ribosomal stress involved the ATR-CHK1 pathway.

     

    The kinetics of ribosome biogenesis extinction is crucial for the onset of terminal erythroid differentiation in normal conditions.

    In ribosomopathies which are constitutive (Diamond-Blackfan anemia) or acquired (5q- syndrome) human diseases related to a heterozygous mutation or mono-allelic deletion of a gene encoding a ribosomal protein, the availability of ribosomes is prematurely decreased because of unbalanced production of ribosomal proteins. This results in a pathological activation of p53 pro-apoptotic targets leading to the blockade of erythroid differentiation and anemia. 

     

    In the future, the characterization of shared transcriptional targets of p53 and GATA1 could identify actors of the transition between proliferation and differentiation and potential targets for the treatment of anemia of patients with ribosomopathies. 

     

     

     

    This work from the team of Michaela Fontenay was conducted in collaboration with the team of Eric Soler from the Institut de Génétique Moléculaire de Montpellier (CNRS), Isabelle Hatin from the Institut de Biologie intégrée de la cellule (I2BC, CEA, CNRS, Université Paris‐Saclay), Narla Mohandas from the New-York Blood Center, Rose-Ann Padua (Institut de recherche Saint-Louis, UMR-S1131) and Frédérique Verdier (Equipe Biologie de la transmission du plasmodium, Institut Cochin) with support of the labEX GREX.

     

    Reference

    Le Goff S,* Boussaid I,* Floquet C,†Raimbault A,† Hatin I, Andrieu-Soler C, Salma M, Leduc M, Gautier E-F, Guyot B, d’Allard D,Montel-Lehry N, Ducamp S, Houvert A, Guillonneau F, Giraudier S, Cramer-Bordé E, Morlé F, Diaz J-J, Hermine O, Taylor N, Kinet S, Verdier F, Padua R-A, Mohandas N, Gleizes P-E, Soler E, Mayeux P, Fontenay M. p53 activation during ribosome biogenesis regulates normal erythroid differentiation. Blood, August 20, online ahead of print. https://doi.org/10.1182/blood.2019003439

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