title: Parp-2 is required to maintain hematopoiesis following sublethal γ-irradiation in mice.
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.
authors.affiliation: Cancer Research Program, Hospital del Mar Medical Research Institute, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Farrés
authors.forename: Juan
authors.initials: J
authors.lastname: Martín-Caballero
authors.forename: Carlos
authors.initials: C
authors.lastname: Martínez
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Lozano
authors.forename: Laura
authors.initials: L
authors.lastname: Llacuna
authors.forename: Coral
authors.initials: C
authors.lastname: Ampurdanés
authors.forename: Cristina
authors.initials: C
authors.lastname: Ruiz-Herguido
authors.forename: Françoise
authors.initials: F
authors.lastname: Dantzer
authors.forename: Valérie
authors.initials: V
authors.lastname: Schreiber
authors.forename: Andreas
authors.initials: A
authors.lastname: Villunger
authors.forename: Anna
authors.initials: A
authors.lastname: Bigas
authors.forename: José
authors.initials: J
authors.lastname: Yélamos
mesh_terms: D000741:Anemia, Aplastic; D000818:Animals; D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000502:physiology; D001855:Bone Marrow Diseases; D000080983:Bone Marrow Failure Disorders; D002470:Cell Survival / Q000502:physiology / Q000528:radiation effects; D004249:DNA Damage / Q000502:physiology; D004260:DNA Repair / Q000502:physiology; D005260:Female; D005720:Gamma Rays / Q000009:adverse effects*; D006410:Hematopoiesis / Q000502:physiology* / Q000528:radiation effects*; D006457:Hemoglobinuria, Paroxysmal / Q000235:genetics / Q000503:physiopathology; D006706:Homeostasis / Q000502:physiology / Q000528:radiation effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics* / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology; D011833:Radiation Injuries, Experimental / Q000235:genetics / Q000503:physiopathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; C488588:PUMA protein, mouse; C408009:Pmaip1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C459820:Parp2 protein, mouse