PUBLICATION
TEX264 drives selective autophagy of DNA lesions to promote DNA repair and cell survival
- Authors
- Lascaux, P., Hoslett, G., Tribble, S., Trugenberger, C., Antičević, I., Otten, C., Torrecilla, I., Koukouravas, S., Zhao, Y., Yang, H., Aljarbou, F., Ruggiano, A., Song, W., Peron, C., Deangeli, G., Domingo, E., Bancroft, J., Carrique, L., Johnson, E., Vendrell, I., Fischer, R., Ng, A.W.T., Ngeow, J., D'Angiolella, V., Raimundo, N., Maughan, T., Popović, M., Milošević, I., Ramadan, K.
- ID
- ZDB-PUB-240913-5
- Date
- 2024
- Source
- Cell 187(20): 5698-5718.e26 (Journal)
- Registered Authors
- Keywords
- DNA repair, DNA replication, TEX264, colorectal cancer, genome stability, nucleophagy, protein degradation, selective autophagy, topoisomerase 1 cleavage complex, zebrafish
- MeSH Terms
-
- Humans
- Autophagy*
- Ataxia Telangiectasia Mutated Proteins/metabolism
- DNA Repair*
- Cell Survival*
- DNA Topoisomerases, Type I*/metabolism
- DNA Damage*
- Genomic Instability
- Membrane Proteins*/genetics
- Membrane Proteins*/metabolism
- Mice
- DNA Replication
- Topoisomerase I Inhibitors/pharmacology
- Colorectal Neoplasms/genetics
- Colorectal Neoplasms/metabolism
- Colorectal Neoplasms/pathology
- Animals
- MRE11 Homologue Protein/metabolism
- Lysosomes*/metabolism
- PubMed
- 39265577 Full text @ Cell
Citation
Lascaux, P., Hoslett, G., Tribble, S., Trugenberger, C., Antičević, I., Otten, C., Torrecilla, I., Koukouravas, S., Zhao, Y., Yang, H., Aljarbou, F., Ruggiano, A., Song, W., Peron, C., Deangeli, G., Domingo, E., Bancroft, J., Carrique, L., Johnson, E., Vendrell, I., Fischer, R., Ng, A.W.T., Ngeow, J., D'Angiolella, V., Raimundo, N., Maughan, T., Popović, M., Milošević, I., Ramadan, K. (2024) TEX264 drives selective autophagy of DNA lesions to promote DNA repair and cell survival. Cell. 187(20):5698-5718.e26.
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 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping