Alkylating DNA damage stimulates a regulated form of necrotic cell death.

By W. Zong, D. Ditsworth, Daniel E. Bauer, Zhao-Qi Wang, Craig B. Thompson. Genes & Development, 2004

677 citations recorded by the source corpus.

Necrosis has been considered a passive form of cell death in which the cell dies as a result of a bioenergetic catastrophe imposed by external conditions. However, in response to alkylating DNA damage, cells undergo necrosis as a self-determined cell fate. This form of death does not require the central apoptotic mediators p53, Bax/Bak, or caspases and actively induces an inflammatory response. Necrosis in response to DNA damage requires activation of the DNA repair protein poly(ADP-ribose) polymerase (PARP), but PARP activation is not sufficient to determine cell fate. Cell death is determined by the effect of PARP-mediated beta-nicotinamide adenine dinucleotide (NAD) consumption on cellular metabolism. Cells using aerobic glycolysis to support their bioenergetics undergo rapid ATP depletion and death in response to PARP activation. In contrast, cells catabolizing nonglucose substrates to maintain oxidative phosphorylation are resistant to ATP depletion and death in response to PARP activation. Because most cancer cells maintain their ATP production through aerobic glycolysis, these data may explain the molecular basis by which DNA-damaging agents can selectively induce tumor cell death independent of p53 or Bcl-2 family proteins.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/f0967a9aae99cb1128fb65c39cc8ce199d1f7a77

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Citations in the corpus

Necrotic death as a cell fate. (2006, background): “Evidence exists that PARP may be required for the nucleus-cytosol translocation of HMGB1 in order to prime it for diffusion through disrupted plasma membrane (Zong et al. 2004; D. Ditsworth, W.X. Zong, and C.B. Thompson, unpubl.).”
PARP inhibition: PARP1 and beyond (2010, background): “The observation that PARP2 consumes much less NAD + than PARP1 provides an explanation for the observation that NAD + levels are preserved and necrosis is diminished when Parp1 −/− cells sustain DNA damag”
NAD+/NADH and NADP+/NADPH in Cellular Functions and Cell Death: Regulation and Biological Consequences (2008, neutral): “mediator of programmed necrosis (350, 351), there have been”
Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity. (2011, background): “In vivo, treatment with cyclophosphamide (CTX) also did not trigger substantial apoptosis (data not shown) or release of the necrotic marker high-mobility group box 1 (HMGB1) protein (Fig. 4G; Scaffidi et al. 2002; Zong et al. 2004).”
Role of autophagy in cancer (2007, background): “Indeed, the mechanism of cell death induction by alkylating agents involves poly(ADP-ribose) polymerase (PARP) activation and ATP consumption resulting in acute necrotic tumour cell death, which probably accounts for their success in the clini”
Crosstalk between apoptosis, necrosis and autophagy. (2013, background): “PARP1 over-activation leads to ATP depletion, thereby inducing necrotic cell death and preventing energy-dependent apoptosis [7,28,133].”
Cell death by necrosis: towards a molecular definition. (2007, background): “In necrosis induced by alkylation of DNA and activation of poly(ADP-ribose)polymerase (PARP), for example, knock down of RIP1 expression can interrupt the lethal signal transduction cascade [ 36 ,37].”
Autophagy in metazoans: cell survival in the land of plenty (2005, neutral): “pl?Q16611">Bak resist various pro-apoptotic stimul”
Glycolysis inhibition for anticancer treatment (2006, background): “Interestingly, a recent study showed that cells using aerobic glycolysis to support their bioenergetics undergo rapid ATP depletion and necrotic cell death in response to activation of poly(ADP-ribose) polymerase (PARP) when treated with DNA-alkylating agents (Zong et al., 2004).”
Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012 (2011, background): “citotoxins and the ligation of death receptors, at least under selected circumstances.(9,11,12,84,85) Indeed, when caspases (and in particular caspase-8) are inhibited by genetic”
Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. (2006, background): “Indeed, PARP deficiency mitigates necrotic cell death by delaying ATP consumption in response to alkylating agents (Zong et al., 2004).”
Necrosis, a well-orchestrated form of cell demise: signalling cascades, important mediators and concomitant immune response. (2006, background): “Approaches for inducing necrotic cell death in cancer cells include administering alkylating DNAdamaging agents [235] and photosensitizing molecules that preferentially accumulate in tumour cells and generate ROS following excitation with light from various spectra [236,237].”
Cellular Stress Responses: Cell Survival and Cell Death (2010, neutral): “[61] W.”
Growth factor regulation of autophagy and cell survival in the absence of apoptosis. (2005, methodology): “Akt maintains cell size (Zong et al., 2004).”