Fiche publication
Date publication
décembre 2014
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DANTZER Françoise
,
Dr SCHREIBER Valérie
Tous les auteurs :
Farres J, Llacuna L, Martin-Caballero J, Martinez C, Lozano JJ, Ampurdanes C, Lopez-Contreras AJ, Florensa L, Navarro J, Ottina E, Dantzer F, Schreiber V, Villunger A, Fernandez-Capetillo O, Yelamos J
Lien Pubmed
Résumé
Erythropoiesis is a tightly regulated process in which multipotential hematopoietic stem cells produce mature red blood cells. Here we show that deletion of poly(ADP-ribose) polymerase-2 (PARP-2) in mice leads to chronic anemia at steady state, despite increased erythropoietin plasma levels, a phenomenon not observed in mice lacking PARP-1. Loss of PARP-2 causes shortened lifespan of erythrocytes and impaired differentiation of erythroid progenitors. In erythroblasts, PARP-2 deficiency triggers replicative stress, as indicated by the presence of micronuclei, the accumulation of gamma-H2AX (phospho-histone H2AX) in S-phase cells and constitutive CHK1 and replication protein A phosphorylation. Transcriptome analyses revealed the activation of the p53-dependent DNA-damage response pathways in PARP-2-deficient cells, culminating in the upregulation of cell-cycle and cell death regulators, concomitant with G2/M arrest and apoptosis. Strikingly, while loss of the proapoptotic p53 target gene Puma restored hematocrit levels in the PARP-2-deficient mice, loss of the cell-cycle regulator and CDK inhibitor p21 leads to perinatal death by exacerbating impaired fetal liver erythropoiesis in PARP-2-deficient embryos. Although the anemia displayed by PARP-2-deficient mice is compatible with life, mice die rapidly when exposed to stress-induced enhanced hemolysis. Our results pinpoint an essential role for PARP-2 in erythropoiesis by limiting replicative stress that becomes essential in the absence of p21 and in the context of enhanced hemolysis, highlighting the potential effect that might arise from the design and use of PARP inhibitors that specifically inactivate PARP proteins.Cell Death and Differentiation advance online publication, 12 December 2014; doi:10.1038/cdd.2014.202.
Référence
Cell Death Differ. 2014 Dec 12
