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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)
Verlagsversion Postprint DOI PMC
Open Access Green
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Dna Damage ; Cgas/sting ; Cell Proliferation ; Dntp Pools ; Hepatocyte ; Non-alcoholic Fatty Liver Disease ; Replication Stress
ISSN (print) / ISBN 1534-5807
e-ISSN 1878-1551
Zeitschrift Developmental Cell
Quellenangaben Band: 57, Heft: 14, Seiten: 1728-1741.e6 Artikelnummer: , Supplement: ,
Verlag Elsevier
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Radiation Cytogenetics (ZYTO)