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The p53-cathepsin axis cooperates with ROS to activate programmed necrotic death upon DNA damage
Ho-Chou Tu1, Decheng Ren, Gary X Wang
1Department of Medicine, Molecular Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Abstract:
Three forms of cell death have been described: apoptosis, autophagic cell death, and necrosis. Although genetic and biochemical studies have formulated a detailed blueprint concerning the apoptotic network, necrosis is generally perceived as a passive cellular demise resulted from unmanageable physical damages. Here, we conclude an active de novo genetic program underlying DNA damage-induced necrosis, thus assigning necrotic cell death as a form of "programmed cell death." Cells deficient of the essential mitochondrial apoptotic effectors, BAX and BAK, ultimately succumbed to DNA damage, exhibiting signature necrotic characteristics. Importantly, this genotoxic stress-triggered necrosis was abrogated when either transcription or translation was inhibited. We pinpointed the p53-cathepsin axis as the quintessential framework underlying necrotic cell death. p53 induces cathepsin Q that cooperates with reactive oxygen species (ROS) to execute necrosis. Moreover, we presented the in vivo evidence of p53-activated necrosis in tumor allografts. Current study lays the foundation for future experimental and therapeutic discoveries aimed at "programmed necrotic death."
Insights
Necrosis, previously thought passive, is now identified as programmed cell death triggered by DNA damage. This process involves the p53-cathepsin axis and occurs even when apoptosis is blocked.
Area of Science:
- Cell Biology
- Molecular Biology
- Genetics
Background:
- Cell death occurs via apoptosis, autophagy, or necrosis.
- Necrosis is traditionally viewed as a passive response to cellular injury.
- The molecular mechanisms of necrosis remain less understood compared to apoptosis.
Purpose of the Study:
- To investigate the existence of a programmed cell death pathway for necrosis.
- To elucidate the molecular players involved in DNA damage-induced necrosis.
- To explore the therapeutic potential of targeting programmed necrosis.
Main Methods:
- Utilizing cell lines deficient in apoptotic effectors (BAX and BAK).
- Inducing DNA damage and observing cell death phenotypes.
- Employing transcription and translation inhibitors to block specific cellular processes.
- Analyzing the role of the p53-cathepsin axis and reactive oxygen species (ROS).
- Validating findings in vivo using tumor allografts.
Main Results:
- Cells lacking BAX and BAK undergo necrosis upon DNA damage, indicating an active pathway.
- Inhibition of transcription or translation prevents DNA damage-induced necrosis.
- The p53-cathepsin axis, specifically p53-induced cathepsin Q, is crucial for executing necrosis.
- Reactive oxygen species (ROS) cooperate with cathepsin Q in the necrotic process.
- Evidence of p53-activated necrosis was observed in vivo in tumor models.
Conclusions:
- DNA damage-induced necrosis is an active, genetically programmed form of cell death.
- Necrosis can occur independently of the canonical apoptotic machinery.
- The p53-cathepsin Q-ROS axis represents a key pathway for programmed necrosis.
- This research redefines necrosis as a programmed event with potential therapeutic implications.
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