Replication stress triggered by nucleotide pool imbalance drives DNA damage and cGAS-STING pathway activation in NAFLD.

Autor:	Donne R; Team Proliferation, Stress and Liver Physiopathology, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris-Cité, 75006 Paris, France., Saroul-Ainama M; Team Proliferation, Stress and Liver Physiopathology, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris-Cité, 75006 Paris, France., Cordier P; Team Proliferation, Stress and Liver Physiopathology, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris-Cité, 75006 Paris, France., Hammoutene A; Université Paris-Cité, Centre de recherche sur l'inflammation, INSERM U1149, CNRS, ERL8252, 75018 Paris, France., Kabore C; Team Proliferation, Stress and Liver Physiopathology, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris-Cité, 75006 Paris, France., Stadler M; Division of Chronic Inflammation and Cancer (F180), German Cancer Research Center, Heidelberg, Germany., Nemazanyy I; Platform for Metabolic Analyses, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS 3633, Paris, France., Galy-Fauroux I; Team Proliferation, Stress and Liver Physiopathology, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris-Cité, 75006 Paris, France., Herrag M; Laboratory of Genome Dynamics in the Immune System, Labellisé Ligue, INSERM UMR 1163, Université Paris-Cité, Institut Imagine, Paris, France., Riedl T; Division of Chronic Inflammation and Cancer (F180), German Cancer Research Center, Heidelberg, Germany., Chansel-Da Cruz M; Laboratory of Genome Dynamics in the Immune System, Labellisé Ligue, INSERM UMR 1163, Université Paris-Cité, Institut Imagine, Paris, France., Caruso S; Functional Genomics of Solid Tumors Team, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris-Cité, Université Paris 13, Labex Immuno-Oncology, Équipe Labellisée Ligue Contre le Cancer, Paris, France., Bonnafous S; Université Côte d'Azur, INSERM, U1065, C3M, CHU, Nice, France., Öllinger R; Institute of Molecular Oncology and Functional Genomics, Rechts der Isar University Hospital, Munich, Germany., Rad R; Institute of Molecular Oncology and Functional Genomics, Rechts der Isar University Hospital, Munich, Germany., Unger K; Research Unit of Radiation Cytogenetics, Helmholtz Zentrum München, Neuherberg, Germany., Tran A; Université Côte d'Azur, INSERM, U1065, C3M, CHU, Nice, France., Couty JP; Team Proliferation, Stress and Liver Physiopathology, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris-Cité, 75006 Paris, France., Gual P; Université Côte d'Azur, INSERM, U1065, C3M, CHU, Nice, France., Paradis V; Université Paris-Cité, Centre de recherche sur l'inflammation, INSERM U1149, CNRS, ERL8252, 75018 Paris, France; Service d'Anatomie Pathologique, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France., Celton-Morizur S; Team Proliferation, Stress and Liver Physiopathology, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris-Cité, 75006 Paris, France., Heikenwalder M; Division of Chronic Inflammation and Cancer (F180), German Cancer Research Center, Heidelberg, Germany., Revy P; Laboratory of Genome Dynamics in the Immune System, Labellisé Ligue, INSERM UMR 1163, Université Paris-Cité, Institut Imagine, Paris, France., Desdouets C; Team Proliferation, Stress and Liver Physiopathology, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris-Cité, 75006 Paris, France. Electronic address: chantal.desdouets@inserm.fr.
Jazyk:	angličtina
Zdroj:	Developmental cell [Dev Cell] 2022 Jul 25; Vol. 57 (14), pp. 1728-1741.e6. Date of Electronic Publication: 2022 Jun 28.
DOI:	10.1016/j.devcel.2022.06.003
Abstrakt:	Non-alcoholic steatotic liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. NAFLD has a major effect on the intrinsic proliferative properties of hepatocytes. Here, we investigated the mechanisms underlying the activation of DNA damage response during NAFLD. Proliferating mouse NAFLD hepatocytes harbor replication stress (RS) with an alteration of the replication fork's speed and activation of ATR pathway, which is sufficient to cause DNA breaks. Nucleotide pool imbalance occurring during NAFLD is the key driver of RS. Remarkably, DNA lesions drive cGAS/STING pathway activation, a major component of cells' intrinsic immune response. The translational significance of this study was reiterated by showing that lipid overload in proliferating HepaRG was sufficient to induce RS and nucleotide pool imbalance. Moreover, livers from NAFLD patients displayed nucleotide pathway deregulation and cGAS/STING gene alteration. Altogether, our findings shed light on the mechanisms by which damaged NAFLD hepatocytes might promote disease progression. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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