Abstract P11: TEX264 DRIVES SELECTIVE AUTOPHAGY OF DNA LESIONS TO PROMOTE DNA REPAIR AND CELL SURVIVAL

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Abstract 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 human cancer cell. TOP1 resolves DNA topological stress ahead of DNA replication and transcription. If not promptly repaired, TOP1cc hinder the progression of DNA replication and transcription fostering genomic instability. Thus, stabilising TOP1cc with TOP1 poisons, such as Camptothecin or its analogue, is highly effective and widely used in cancer therapy. Proteolysis of TOP1cc by the proteasome is described at excessively high doses of CPT that are not relevant in a clinical setting, calling into question the relevance of the proteasome role in TOP1cc repair for cancer therapy and patient response. Here we described that repair of TOP1cc induced by clinically relevant dose of Camptothecin depends on selective autophagy. Proteomics, sequencing, biochemistry techniques and live imaging all demonstrate the lysosomal uptake of TOP1cc upon induction of replication stress. Selective degradation of TOP1cc by autophagy directs DNA damage repair and cell survival. TOP1cc are exported from the nucleus to lysosomes through 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 damage repair that enables cell survival, protects genome stability, and is clinically relevant for colorectal cancer patients. Citation Format: Pauline Lascaux, Gwendoline Hoslett, Sara Tribble, Ivan Antičević, Cecile Otten, Ignacio Torrecilla, Yichen Zhao, Wei Song, Cristiano Peron, Giulio Deangeli, Enric Domingo, James Bancroft, Loïc Carrique, Errin Johnson, Alvin Wei Tian Ng, Joanne Ngeow, Nuno Raimundo, Tim Maughan, Marta Popović, Ira Milošević, and Kristijan Ramadan. TEX264 DRIVES SELECTIVE AUTOPHAGY OF DNA LESIONS TO PROMOTE DNA REPAIR AND CELL SURVIVAL [abstract]. In: Proceedings of Frontiers in Cancer Science 2024; 2024 Nov 13-15; Singapore. Philadelphia (PA): AACR; Cancer Res 2025;85(15_Suppl):Abstract nr P11.

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