title: PARP-2 sustains erythropoiesis in mice by limiting replicative stress in erythroid progenitors.
abstract: 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 γ-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.
authors.affiliation: Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Farrés
authors.affiliation: Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Llacuna
authors.affiliation: Barcelona Biomedical Research Park (PRBB), Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Martin-Caballero
authors.affiliation: CIBERehd, Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Martínez
authors.affiliation: CIBERehd, Barcelona, Spain.
authors.forename: J J
authors.initials: JJ
authors.lastname: Lozano
authors.affiliation: Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Ampurdanés
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: A J
authors.initials: AJ
authors.lastname: López-Contreras
authors.affiliation: 1] Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain [2] Deparment of Pathology, Hospital del Mar, Barcelona, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Florensa
authors.affiliation: Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Navarro
authors.affiliation: Division of Developmental Immunology, Biocenter, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: E
authors.initials: E
authors.lastname: Ottina
authors.affiliation: Biotechnology and Cell Signaling, UMR7242-CNRS, Laboratory of Excellence Medalis, ESBS, Illkirch, France.
authors.forename: F
authors.initials: F
authors.lastname: Dantzer
authors.affiliation: Biotechnology and Cell Signaling, UMR7242-CNRS, Laboratory of Excellence Medalis, ESBS, Illkirch, France.
authors.forename: V
authors.initials: V
authors.lastname: Schreiber
authors.affiliation: Division of Developmental Immunology, Biocenter, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Villunger
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: O
authors.initials: O
authors.lastname: Fernández-Capetillo
authors.affiliation: 1] Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain [2] CIBERehd, Barcelona, Spain [3] Department of Immunology, Hospital del Mar, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Yélamos
mesh_terms: D000818:Animals; D017209:Apoptosis; D004261:DNA Replication; D015672:Erythroid Precursor Cells / Q000378:metabolism*; D004920:Erythropoiesis / Q000235:genetics / Q000502:physiology*; D059565:G2 Phase Cell Cycle Checkpoints; D017353:Gene Deletion; D006657:Histones / Q000378:metabolism; D051379:Mice; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics*; D013312:Stress, Physiological / Q000235:genetics*
chemical_list: D006657:Histones; D011065:Poly(ADP-ribose) Polymerases; C459820:Parp2 protein, mouse; C475961:gamma-H2AX protein, mouse