期刊
BLOOD
卷 122, 期 1, 页码 44-54出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2012-12-472845
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资金
- Spanish Ministerio de Economia y Competitividad [HA2008-0010, SAF2008-01572, SAF2011-26900]
- Generalitat de Catalunya [2009/SGR/524]
- Fundacion Mutua Madrilena
- Juan de la Cierva fellowship program
- Austrian Science Fund (FWF) [Y212-B12, SFB021]
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.
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