TEX264 drives selective autophagy of DNA lesions topromote DNA repair and cell survival

DNA repair and autophagy are distinct biological processes vital for cell survival. Although autophagy helpsmaintain genome stability, there is no evidence of its direct role in the repair of DNA lesions. We discoveredthat lysosomes process topoisomerase 1 cleavage complexes (TOP1cc) DNA lesions in vertebrates. Selectivedegradation of TOP1cc by autophagy directs DNA damage repair and cell survival at clinically relevantdoses of topoisomerase 1 inhibitors. TOP1cc are exported from the nucleus to lysosomes through a transientalteration of the nuclear envelope and independent of the proteasome. Mechanistically, the autophagy receptorTEX264 acts as a TOP1cc sensor at DNA replication forks, triggering TOP1cc processing by theQ8 p97 ATPase and mediating the delivery of TOP1cc to lysosomes in an MRE11-nuclease- and ATR-kinasedependentmanner. We found an evolutionarily conserved role for selective autophagy in DNA repair that enQ2ables cell survival, protects genome stability, and is clinically relevant for colorectal cancer patients.