DNA damage induces p53-independent apoptosis through ribosome stalling

Area of Science:

• Molecular Biology
• Cell Biology
• Genetics

Background:

• The tumor suppressor p53 is a key mediator of apoptosis following DNA damage.
• However, p53-independent apoptotic pathways in response to DNA damage remain largely uncharacterized.
• Understanding these alternative pathways is crucial for cancer therapy.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying p53-independent apoptosis induced by DNA damage.
• To identify key factors and signaling events involved in this process.

Main Methods:

• Utilized genetic screening to identify factors involved in DNA damage-induced apoptosis.
• Analyzed translation inhibition, ribosome stalling on UUA codons, and ribotoxic stress signaling.
• Investigated the roles of SLFN11, GCN2, and ZAKα in the apoptotic pathway.

Main Results:

• p53-independent apoptosis upon DNA damage was associated with translation inhibition.
• Ribosome stalling on UUA codons and global translation initiation curtailment were observed.
• SLFN11 and GCN2 were identified as critical for UUA stalling and translation inhibition, respectively.
• Stalled ribosomes initiated a ribotoxic stress signal via ZAKα, leading to apoptosis.

Conclusions:

• Ribosome stalling acts as a critical signaling event in p53-independent apoptosis following DNA damage.
• The SLFN11-mediated pathway explains ribosome stalling and contributes to DNA damage-induced cell death.
• Findings offer insights into chemotherapy resistance in tumors with SLFN11 inactivation.