Autophagy as a way to remove DNA lesions

Area of Science:

• Molecular Biology
• Cell Biology
• Genetics

Background:

• Type I topoisomerases (TOP1) resolve DNA topological stress during unwinding.
• TOP1 cleavage complexes (TOP1cc) are transient intermediates.
• TOP1cc inhibitors like camptothecin (CPT) stabilize these complexes, potentially causing DNA damage and cytotoxicity.

Discussion:

• The proteasome pathway degrades TOP1, facilitating DNA repair, but this is primarily observed at high, clinically unachievable CPT concentrations.
• Lascaux et al. reveal macroautophagy/autophagy as a novel mechanism for DNA lesion removal under clinically relevant low-dose CPT treatment.
• The autophagy receptor TEX264 binds TOP1, directing the protein-DNA complex to the phagophore for lysosomal degradation.

Key Insights:

• Autophagy actively participates in maintaining genome stability by clearing TOP1cc-induced DNA lesions.
• TEX264 acts as a crucial receptor, linking TOP1cc to the autophagic machinery.
• This study highlights a new pathway for DNA damage resolution at pharmacologically achievable drug concentrations.

Outlook:

• The findings offer a new perspective on genome maintenance and DNA repair mechanisms.
• Targeting the TEX264-mediated autophagy pathway could be a strategy to enhance the efficacy of TOP1cc inhibitors.
• This research may provide insights into overcoming resistance to topoisomerase inhibitors in cancer therapy.