Parp-2 is required to maintain hematopoiesis following sublethal gamma-irradiation in mice.
Fiche publication
Date publication
juillet 2013
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DANTZER Françoise, Dr SCHREIBER Valérie
Tous les auteurs :
Farres J, Martin-Caballero J, Martinez C, Lozano JJ, Llacuna L, Ampurdanes C, Ruiz-Herguido C, Dantzer F, Schreiber V, Villunger A, Bigas A, Yelamos J
Lien Pubmed
Résumé
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 gamma-irradiation correlated with an impaired capacity to repair DNA damage in the absence of Parp-2. Upon exposure to sublethal doses of gamma-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.
Référence
Blood. 2013 Jul 4;122(1):44-54