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
Q8 p97 ATPase and mediating the delivery of TOP1cc to lysosomes in an MRE11-nuclease- and ATR-kinasedependent
manner. We found an evolutionarily conserved role for selective autophagy in DNA repair that enQ2
ables cell survival, protects genome stability, and is clinically relevant for colorectal cancer patients.