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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.

La naturaleza de la asociación entre radicales libres y cáncer es compleja y paradójica. Parece que los radicales libres y el estrés oxidativo pueden inducir cáncer, pero al mismo tiempo las células transformadas, es decir, las células cancerosas, generan más radicales libres que las células normales. Compuestos endógenos antioxidantes, entre ellos el glutatión y la lisozima, pueden limitar los efectos del estrés oxidativo; sin embargo, dichos sistemas pueden ser rápidamente acaparados por elevadas cantidades de radicales libres. De ahí la importancia de incrementar la concentración de antioxidantes de la célula para prevenir posibles agentes adversos que podrían llegar a originar un proceso canceroso. Una buena alimentación, así como conocer y emplear alimentos con propiedades antioxidantes, puede ser de gran ayuda para la prevención del cáncer.

Nuclear factor (NF)-κB participates in ischemia/reperfusion (I/R) hepatic signaling, stimulating both protective mechanisms and the generation of inflammatory cytokines. After analyzing NF-κB activation during increasing times of ischemia in murine I/R, we observed that the nuclear translocation of p65 paralleled Src and IκB tyrosine phosphorylation, which peaked after 60 minutes of ischemia. After extended ischemic periods (90 to 120 minutes) however, nuclear p65 levels were inversely correlated with the progressive induction of oxidative stress. Despite this profile of NF-κB activation, inflammatory genes, such as tumor necrosis factor (TNF) and interleukin (IL)-1β, predominantly induced by Kupffer cells, increased throughout time during ischemia (30 to 120 minutes), whereas protective NF-κB-dependent genes, such as manganese superoxide dismutase (Mn-SOD), expressed in parenchymal cells, decreased. Consistent with this behavior, gadolinium chloride pretreatment abolished TNF/IL-1β up-regulation during ischemia without affecting Mn-SOD levels. Interestingly, specific glutathione (GSH) up-regulation in hepatocytes by S-adenosylmethionine increased Mn-SOD expression and protected against I/R-mediated liver injury despite TNF/IL-1β induction. Similar protection was achieved by administration of the SOD mimetic MnTBAP. In contrast, indiscriminate hepatic GSH depletion by buthionine-sulfoximine before I/R potentiated oxidative stress and decreased both nuclear p65 and Mn-SOD expression levels, increasing TNF/IL-1β up-regulation and I/R-induced liver damage. Thus, the divergent role of NF-κB activation in selective liver cell populations underlies the dichotomy of NF-κB in hepatic I/R injury, illustrating the relevance of specifically maintaining NF-κB activation in parenchymal cells.