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

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 VendrellRoman Fischer, Alvin Wei Tian Ng, Joanne Ngeow, Vincenzo D'Angiolella, Nuno Raimundo, Tim Maughan, Marta Popović, Ira Milošević, Kristijan Ramadan

Research output: Contribution to journal › Article › peer-review

9 Citations (Scopus)

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.

Original language	English
Pages (from-to)	5698-5718
Number of pages	21
Journal	Cell
Volume	187
Issue number	20
DOIs	https://doi.org/10.1016/j.cell.2024.08.020
Publication status	Published - Oct 3 2024
Externally published	Yes

Bibliographical note

Publisher Copyright:
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

ASJC Scopus Subject Areas

General Biochemistry,Genetics and Molecular Biology

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.cell.2024.08.020

Cite this

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., ... Ramadan, K. (2024). TEX264 drives selective autophagy of DNA lesions to promote DNA repair and cell survival. Cell, 187(20), 5698-5718. https://doi.org/10.1016/j.cell.2024.08.020

@article{16308bd8c8e0499b9914912eba8e04df,

title = "TEX264 drives selective autophagy of DNA lesions to promote DNA repair and cell survival",

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 = "colorectal cancer, DNA repair, DNA replication, genome stability, nucleophagy, protein degradation, selective autophagy, TEX264, topoisomerase 1 cleavage complex, zebrafish",

author = "Pauline Lascaux and Gwendoline Hoslett and Sara Tribble and Camilla Trugenberger and Ivan Anti{\v c}evi{\'c} and Cecile Otten and Ignacio Torrecilla and Stelios Koukouravas and Yichen Zhao and Hongbin Yang and Ftoon Aljarbou and Annamaria Ruggiano and Wei Song and Cristiano Peron and Giulio Deangeli and Enric Domingo and James Bancroft and Lo{\"i}c Carrique and Errin Johnson and Iolanda Vendrell and Roman Fischer and Ng, {Alvin Wei Tian} and Joanne Ngeow and Vincenzo D'Angiolella and Nuno Raimundo and Tim Maughan and Marta Popovi{\'c} and Ira Milo{\v s}evi{\'c} and Kristijan Ramadan",

year = "2024",

month = oct,

day = "3",

doi = "10.1016/j.cell.2024.08.020",

language = "English",

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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, AWT, 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, vol. 187, no. 20, pp. 5698-5718. https://doi.org/10.1016/j.cell.2024.08.020

TY - JOUR

T1 - TEX264 drives selective autophagy of DNA lesions to promote DNA repair and cell survival

AU - Lascaux, Pauline

AU - Hoslett, Gwendoline

AU - Tribble, Sara

AU - Trugenberger, Camilla

AU - Antičević, Ivan

AU - Otten, Cecile

AU - Torrecilla, Ignacio

AU - Koukouravas, Stelios

AU - Zhao, Yichen

AU - Yang, Hongbin

AU - Aljarbou, Ftoon

AU - Ruggiano, Annamaria

AU - Song, Wei

AU - Peron, Cristiano

AU - Deangeli, Giulio

AU - Domingo, Enric

AU - Bancroft, James

AU - Carrique, Loïc

AU - Johnson, Errin

AU - Vendrell, Iolanda

AU - Fischer, Roman

AU - Ng, Alvin Wei Tian

AU - Ngeow, Joanne

AU - D'Angiolella, Vincenzo

AU - Raimundo, Nuno

AU - Maughan, Tim

AU - Popović, Marta

AU - Milošević, Ira

AU - Ramadan, Kristijan

PY - 2024/10/3

Y1 - 2024/10/3

N2 - 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.

AB - 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.

KW - colorectal cancer

KW - DNA repair

KW - DNA replication

KW - genome stability

KW - nucleophagy

KW - protein degradation

KW - selective autophagy

KW - TEX264

KW - topoisomerase 1 cleavage complex

KW - zebrafish

UR - http://www.scopus.com/inward/record.url?scp=85206018267&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85206018267&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2024.08.020

DO - 10.1016/j.cell.2024.08.020

M3 - Article

C2 - 39265577

AN - SCOPUS:85206018267

SN - 0092-8674

VL - 187

SP - 5698

EP - 5718

JO - Cell

JF - Cell

IS - 20

ER -

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

Abstract

Bibliographical note

ASJC Scopus Subject Areas

Keywords

UN SDGs

Access to Document

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Nucleophagy identified as key DNA repair mechanism in cancer treatments

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

Abstract

Bibliographical note

ASJC Scopus Subject Areas

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Press/Media

Nucleophagy identified as key DNA repair mechanism in cancer treatments

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