1. Parp-2 is required to maintain hematopoiesis following sublethal γ-irradiation in mice.
- Author
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Farrés J, Martín-Caballero J, Martínez C, Lozano JJ, Llacuna L, Ampurdanés C, Ruiz-Herguido C, Dantzer F, Schreiber V, Villunger A, Bigas A, and Yélamos J
- Subjects
- Anemia, Aplastic, Animals, Apoptosis physiology, Apoptosis radiation effects, Apoptosis Regulatory Proteins genetics, Apoptosis Regulatory Proteins physiology, Bone Marrow Diseases, Bone Marrow Failure Disorders, Cell Survival physiology, Cell Survival radiation effects, DNA Damage physiology, DNA Repair physiology, Female, Hemoglobinuria, Paroxysmal genetics, Hemoglobinuria, Paroxysmal physiopathology, Homeostasis physiology, Homeostasis radiation effects, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Poly (ADP-Ribose) Polymerase-1, Proto-Oncogene Proteins c-bcl-2 genetics, Proto-Oncogene Proteins c-bcl-2 physiology, Radiation Injuries, Experimental genetics, Radiation Injuries, Experimental physiopathology, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 physiology, Tumor Suppressor Proteins genetics, Tumor Suppressor Proteins physiology, Gamma Rays adverse effects, Hematopoiesis physiology, Hematopoiesis radiation effects, Poly(ADP-ribose) Polymerases genetics, Poly(ADP-ribose) Polymerases physiology
- Abstract
Hematopoietic stem cells self-renew for life to guarantee the continuous supply of all blood cell lineages. Here we show that Poly(ADP-ribose) polymerase-2 (Parp-2) plays an essential role in hematopoietic stem/progenitor cells (HSPC) survival under steady-state conditions and in response to stress. Increased levels of cell death were observed in HSPC from untreated Parp-2-/- mice, but this deficit was compensated by increased rates of self-renewal, associated with impaired reconstitution of hematopoiesis upon serial bone marrow transplantation. Cell death after γ-irradiation correlated with an impaired capacity to repair DNA damage in the absence of Parp-2. Upon exposure to sublethal doses of γ-irradiation, Parp-2-/- mice exhibited bone marrow failure that correlated with reduced long-term repopulation potential of irradiated Parp-2-/- HSPC under competitive conditions. In line with a protective role of Parp-2 against irradiation-induced apoptosis, loss of p53 or the pro-apoptotic BH3-only protein Puma restored survival of irradiated Parp-2-/- mice, whereas loss of Noxa had no such effect. Our results show that Parp-2 plays essential roles in the surveillance of genome integrity of HSPC by orchestrating DNA repair and restraining p53-induced and Puma-mediated apoptosis. The data may affect the design of drugs targeting Parp proteins and the improvement of radiotherapy-based therapeutic strategies.
- Published
- 2013
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