NEMO and RIP1 control cell fate in response to extensive DNA damage via TNF-α feedforward signaling

Area of Science:

• Cellular biology
• Molecular mechanisms of DNA damage response

Background:

• DNA damage triggers cellular responses mediated by ataxia telangiectasia mutated (ATM) kinase.
• ATM promotes cell survival via NF-κB but its role in cytokine production and apoptosis is unclear.
• Existing knowledge gaps regarding ATM's signaling pathways in response to genotoxic stress.

Purpose of the Study:

• To elucidate the p53-independent mechanism by which ATM induces cytokine secretion and apoptosis following extensive DNA damage.
• To identify the key signaling molecules and pathways involved in ATM-mediated cell fate determination.

Main Methods:

• Investigated DNA damage response pathways using cell models.
• Analyzed sequential NF-κB activation phases dependent on ATM and NEMO/IKK-γ.
• Examined the roles of TNF-α-TNFR1 signaling, RIP1 kinase, JNK3/MAPK10, and FADD in downstream signaling.

Main Results:

• Discovered two sequential NF-κB activation phases upon extensive DNA lesions, dependent on ATM and NEMO/IKK-γ.
• Identified TNF-α-TNFR1 feedforward signaling that promotes RIP1 phosphorylation.
• Demonstrated RIP1 kinase-mediated interleukin-8 secretion and caspase-8 activation via JNK3/MAPK10 and FADD, respectively.

Conclusions:

• ATM utilizes NEMO and RIP1 kinase through autocrine TNF-α signaling to activate cytokine production and apoptosis in response to excessive DNA damage.
• This p53-independent pathway provides critical insights into cell fate regulation following genotoxic stress.
• The findings highlight a novel mechanism controlling cellular decisions between survival and elimination.