Published June 2022
| Version v1
Journal article
Replication stress triggered by nucleotide pool imbalance drives DNA damage and cGAS-STING pathway activation in NAFLD
Creators
- Donne, Romain
- Saroul-Ainama, Maëva
- Cordier, Pierre
- Hammoutene, Adel
- Kabore, Christelle
- Stadler, Mira
- Nemazanyy, Ivan
- Galy-Fauroux, Isabelle
- Herrag, Mounia
- Riedl, Tobias
- Chansel-da Cruz, Marie
- Caruso, Stefano
- Bonnafous, Stéphanie
- Öllinger, Rupert
- Rad, Roland
- Unger, Kristian
- Tran, Albert
- Couty, Jean-Pierre
- Gual, Philippe
- Paradis, Valérie
- Celton-Morizur, Séverine
- Heikenwalder, Mathias
- Revy, Patrick
- Desdouets, Chantal
Contributors
Others:
- Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)) ; École pratique des hautes études (EPHE) ; Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)
- Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
- German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ)
- Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24) ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
- Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
- Labex Immuno-oncology [Paris] ( Université Paris Descartes - Paris 5 - PRES Sorbonne Paris Cité) ; Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité
- Centre méditerranéen de médecine moléculaire (C3M) ; Université Nice Sophia Antipolis (1965 - 2019) (UNS) ; COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)
- Klinikums rechts der Isar
- Helmholtz Zentrum München = German Research Center for Environmental Health
- Hôpital Beaujon [AP-HP] ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Description
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.
Abstract
International audienceAdditional details
Identifiers
- URL
- https://www.hal.inserm.fr/inserm-03711260
- URN
- urn:oai:HAL:inserm-03711260v1
Origin repository
- Origin repository
- UNICA