TEX264 drives selective autophagy of DNA lesions to promote DNA repair and cell survival

Lascaux, Pauline; Hoslett, Gwendoline; Tribble, Sara; Trugenberger, Camilla; Antičević, Ivan; Otten, Cécile; Torrecilla, Ignacio; Koukouravas, Stelios; Zhao, Yichen; Yang, Hongbin; Aljarbou, Ftoon; Ruggiano, Annamaria; Song, Wei; Peron, Cristiano; Deangeli, Giulio; Domingo, Enric; Bancroft, James; Carrique, Loic; Johnson, Errin; Vendrell, Iolanda; Fischer, Roman; Wei Tian Ng, Alvin; Ngeow, Joanne; D’Angiolella, Vincenzo; Raimundo, Nuno; Maughan, Tim; Popović, Marta; Milosevic, Ira; Ramadan, Kristijan (2024) TEX264 drives selective autophagy of DNA lesions to promote DNA repair and cell survival. Cell, 187 . 5698-5718e26. ISSN 0092-8674

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Abstract

DNArepair 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 dosesoftopoisomerase1inhibitors.TOP1ccareexportedfromthenucleustolysosomesthroughatransient 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-kinasedependent manner.Wefoundanevolutionarily conservedrole for selective autophagy in DNA repair that enables cell survival, protects genome stability, and is clinically relevant for colorectal cancer patients.

Item Type:	Article
Uncontrolled Keywords:	DNA repair; TEX264; autophagy; zebrafish; cancer
Subjects:	NATURAL SCIENCES NATURAL SCIENCES > Biology NATURAL SCIENCES > Biology > Biochemistry and Molecular Biology INTERDISCIPLINARY FIELDS OF ART
Divisions:	Division for Marine and Enviromental Research
Projects:	Project title Project leader Project code Project type Razumijevanje popravka unakrsnog vezanja DNA-Protein in vivo koristeći zebricu kao istraživački model-DNAPRO Marta Popović UIP-2017-05-5258 HRZZ Strukturna karakterizacija faktora uključenih u popravak unakrsnog vezanja DNA-protein- Marta Popović IPS-2020-01-4225 HRZZ STIM-REI-STIM-REI Vlasta Bonačić-Koutecky; Tvrtko Smital; Sandi Orlić; Ante Bilušić; Mile Dželalija; Damir Kovačić; Darko Koračin; Željka Sanader Maršić KK.01.1.1.01.0003 EK
Depositing User:	Marta Popović
Date Deposited:	12 Jan 2026 11:48
URI:	http://fulir.irb.hr/id/eprint/10766
DOI:	10.1016/j.cell.2024.08.020

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