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Donne, R.* ; Saroul-Ainama, M.* ; Cordier, P.* ; Hammoutene, A.* ; Kabore, C.* ; Stadler, M.* ; Nemazanyy, I.* ; Galy-Fauroux, I.* ; Herrag, M.* ; Riedl, T.* ; Chansel-Da Cruz, M.* ; Caruso, S.* ; Bonnafous, S.* ; Öllinger, R.* ; Rad, R.* ; Unger, K. ; Tran, A.* ; Couty, J.P.* ; Gual, P.* ; Paradis, V.* ; Celton-Morizur, S.* ; Heikenwalder, M.* ; Revy, P.* ; Desdouets, C.*

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

Dev. Cell 57, 1728-1741.e6 (2022)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Dna Damage ; Cgas/sting ; Cell Proliferation ; Dntp Pools ; Hepatocyte ; Non-alcoholic Fatty Liver Disease ; Replication Stress
Language english
Publication Year 2022
HGF-reported in Year 2022
ISSN (print) / ISBN 1534-5807
e-ISSN 1878-1551
Journal Developmental Cell
Quellenangaben Volume: 57, Issue: 14, Pages: 1728-1741.e6 Article Number: , Supplement: ,
Publisher Elsevier
Reviewing status Peer reviewed
Institute(s) Translational Metabolic Oncology (IDC-TMO)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Radiation Sciences
PSP Element(s) G-501000-001
DOI 10.1016/j.devcel.2022.06.003
WOS ID WOS:000877952400006
Scopus ID 85134981516
PubMed ID 35768000
Erfassungsdatum 2022-11-02
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