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

Pauline Lascaux; Gwendoline Hoslett; Sara Tribble; Camilla Trugenberger; Ivan Antičević; Cecile Otten; Ignacio Torrecilla; Stelios Koukouravas; Yichen Zhao; Hongbin Yang; Ftoon Aljarbou; Annamaria Ruggiano; Wei Song; Cristiano Peron; Giulio Deangeli; Enric Domingo; James Bancroft; Loïc Carrique; Errin Johnson; Iolanda Vendrell; Roman Fischer; Alvin Wei Tian Ng; Joanne Ngeow; Vincenzo D'Angiolella; Nuno Raimundo; Tim Maughan; Marta Popović; Ira Milošević; Kristijan Ramadan

doi:10.1016/j.cell.2024.08.020

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

Cell. 2024 Sep 5:S0092-8674(24)00911-5. doi: 10.1016/j.cell.2024.08.020. Online ahead of print.

Authors

Pauline Lascaux¹, Gwendoline Hoslett¹, Sara Tribble¹, Camilla Trugenberger¹, Ivan Antičević², Cecile Otten², Ignacio Torrecilla¹, Stelios Koukouravas¹, Yichen Zhao¹, Hongbin Yang¹, Ftoon Aljarbou¹, Annamaria Ruggiano¹, Wei Song¹, Cristiano Peron¹, Giulio Deangeli³, Enric Domingo⁴, James Bancroft⁵, Loïc Carrique⁶, Errin Johnson⁷, Iolanda Vendrell⁸, Roman Fischer⁸, Alvin Wei Tian Ng⁹, Joanne Ngeow¹⁰, Vincenzo D'Angiolella¹¹, Nuno Raimundo¹², Tim Maughan¹³, Marta Popović², Ira Milošević¹⁴, Kristijan Ramadan¹⁵

Affiliations

¹ The MRC Weatherall Institute of Molecular Medicine, Department of Oncology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
² DNA Damage Group, Laboratory for Molecular Ecotoxicology, Department for Marine and Environmental Research, Institute Ruđer Bošković, 10000 Zagreb, Croatia.
³ Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 2PY, UK.
⁴ Department of Oncology, Medical Sciences Division, Old Road Campus Research Building, University of Oxford, Oxford OX3 7DQ, UK.
⁵ Centre for Human Genetics, Nuffield Department of Medicine (NDM), University of Oxford, Oxford OX3 7BN, UK.
⁶ Division of Structural Biology, Centre for Human Genetics, Nuffield Department of Medicine (NDM), University of Oxford, Oxford OX3 7BN, UK.
⁷ Dunn School Bioimaging Facility, Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
⁸ Target Discovery Institute, Nuffield Department of Medicine (NDM), University of Oxford, Oxford OX3 7FZ, UK; Chinese Academy for Medical Sciences Oxford Institute, Nuffield Department of Medicine (NDM), University of Oxford, Oxford OX3 7FZ, UK.
⁹ Lee Kong Chian School of Medicine (LKCMedicine), Nanyang Technological University, Singapore 636921, Singapore.
¹⁰ Lee Kong Chian School of Medicine (LKCMedicine), Nanyang Technological University, Singapore 636921, Singapore; Cancer Genetics Service, Division of Medical Oncology, National Cancer Centre Singapore, Singapore 169610, Singapore.
¹¹ The MRC Weatherall Institute of Molecular Medicine, Department of Oncology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK; Edinburgh Cancer Research, CRUK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, EH4 2XU Edinburgh, UK.
¹² Penn State College of Medicine, Department of Cellular and Molecular Physiology, Hershey, PA 17033, USA; Multidisciplinary Institute for Aging, Center for Innovation in Biomedicine and Biotechnology, University of Coimbra, Coimbra 3000-370, Portugal.
¹³ Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7BE, UK.
¹⁴ Centre for Human Genetics, Nuffield Department of Medicine (NDM), University of Oxford, Oxford OX3 7BN, UK; Multidisciplinary Institute for Aging, Center for Innovation in Biomedicine and Biotechnology, University of Coimbra, Coimbra 3000-370, Portugal.
¹⁵ The MRC Weatherall Institute of Molecular Medicine, Department of Oncology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK; Lee Kong Chian School of Medicine (LKCMedicine), Nanyang Technological University, Singapore 636921, Singapore. Electronic address: kristijan.ramadan@ntu.edu.sg.

PMID: 39265577
DOI: 10.1016/j.cell.2024.08.020

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.

Keywords: DNA repair; DNA replication; TEX264; colorectal cancer; genome stability; nucleophagy; protein degradation; selective autophagy; topoisomerase 1 cleavage complex; zebrafish.