Parp-2 is required to maintain hematopoiesis following sublethal γ-irradiation in mice

• Published in: Blood 2013-07, Vol.122 (1), p.44-54
• Main Authors: Farrés, Jordi, Martín-Caballero, Juan, Martínez, Carlos, Lozano, Juan J., Llacuna, Laura, Ampurdanés, Coral, Ruiz-Herguido, Cristina, Dantzer, Françoise, Schreiber, Valérie, Villunger, Andreas, Bigas, Anna, Yélamos, José
• Format: Article
• Language: English
• Subjects: Anemia, Aplastic; Animals; Apoptosis; Apoptosis - physiology; Apoptosis - radiation effects; Apoptosis Regulatory Proteins; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - physiology; Biochemistry, Molecular Biology; Bone Marrow Diseases; Bone Marrow Failure Disorders; Cell Survival; Cell Survival - physiology; Cell Survival - radiation effects; DNA Damage; DNA Damage - physiology; DNA Repair; DNA Repair - physiology; Female; Gamma Rays; Gamma Rays - adverse effects; Hematopoiesis; Hematopoiesis - physiology; Hematopoiesis - radiation effects; Hemoglobinuria, Paroxysmal; Hemoglobinuria, Paroxysmal - genetics; Hemoglobinuria, Paroxysmal - physiopathology; Homeostasis; Homeostasis - physiology; Homeostasis - radiation effects; Life Sciences; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases; Poly(ADP-ribose) Polymerases - genetics; Poly(ADP-ribose) Polymerases - physiology; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - physiology; Radiation Injuries, Experimental; Radiation Injuries, Experimental - genetics; Radiation Injuries, Experimental - physiopathology; Tumor Suppressor Protein p53; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - physiology; Tumor Suppressor Proteins; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - physiology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2012-12-472845

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. • Genetic inactivation of Parp-2 in mice, but not of Parp-1, resulted in bone marrow failure in response to sublethal γ-irradiation dose.• Parp-2 plays an essential role in the DNA damage response in HSPC maintaining hematopoietic homeostasis under stress conditions.