DNA repair and autophagy are distinct biological processes vital for cell survival. Although autophagy helps maintain genome stability, there is no evidence of its direct role in the repair of DNA lesions. We discovered that lysosomes process topoisomerase 1 cleavage complexes (TOP1cc) DNA lesions in vertebrates. Selective degradation of TOP1cc by autophagy directs DNA damage repair and cell survival at clinically relevant doses of topoisomerase 1 inhibitors. TOP1cc are exported from the nucleus to lysosomes through a transient alteration of the nuclear envelope and independent of the proteasome. Mechanistically, the autophagy receptor TEX264 acts as a TOP1cc sensor at DNA replication forks, triggering TOP1cc processing by the p97 ATPase and mediating the delivery of TOP1cc to lysosomes in an MRE11-nuclease- and ATR-kinase-dependent manner. We found an evolutionarily conserved role for selective autophagy in DNA repair that enables cell survival, protects genome stability, and is clinically relevant for colorectal cancer patients.
Journal article
Cell
10/2024
187
5698 - 5718.e26
The MRC Weatherall Institute of Molecular Medicine, Department of Oncology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
Lysosomes, Animals, Humans, Mice, Colorectal Neoplasms, DNA Damage, Genomic Instability, DNA Topoisomerases, Type I, Membrane Proteins, Cell Survival, DNA Repair, DNA Replication, Autophagy, Topoisomerase I Inhibitors, Ataxia Telangiectasia Mutated Proteins, MRE11 Homologue Protein