Publication: Parp-2 is required to maintain hematopoiesis following sublethal γ-irradiation in mice
Authors
Farrés, Jordi ; Martín Caballero, Juan ; Lozano, Juan J. ; Llacuna, Laura ; Ampurdan, Coral ; Ruiz Hergugido, Cristina ; Dantzer, Françoise ; Schreiber, Valérie ; Villunger, Andreas ; Bigas, Anna ; Yélamos, José ; Martínez Cáceres, Carlos Manuel
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Publisher
American Society of Hematology (ASH Publications)
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DOI
https://doi.org/10.1182/blood-2012-12-472845
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info:eu-repo/semantics/article
Description
© 2013 by The American Society of Hematology. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
This document is the Published version of a Published Work that appeared in final form in Blood. To access the final edited and published work see https://doi.org/10.1182/blood-2012-12-472845
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.
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Citation
Blood, 2013, Vol. 122 (1): pp. 44-54.
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