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

Romain Donne; Maëva Saroul-Ainama; Pierre Cordier; Adel Hammoutene; Christelle Kabore; Mira Stadler; Ivan Nemazanyy; Isabelle Galy-Fauroux; Mounia Herrag; Tobias Riedl; Marie Chansel-Da Cruz; Stefano Caruso; Stéphanie Bonnafous; Rupert Öllinger; Roland Rad; Kristian Unger; Albert Tran; Jean Pierre Couty; Philippe Gual; Valérie Paradis; Séverine Celton-Morizur; Mathias Heikenwalder; Patrick Revy; Chantal Desdouets

doi:10.1016/j.devcel.2022.06.003

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

Romain Donne, Maëva Saroul-Ainama, Pierre Cordier, Adel Hammoutene, Christelle Kabore, Mira Stadler, Ivan Nemazanyy, Isabelle Galy-Fauroux, Mounia Herrag, Tobias Riedl, Marie Chansel-Da Cruz, Stefano Caruso, Stéphanie Bonnafous, Rupert Öllinger, Roland Rad, Kristian Unger, Albert Tran, Jean Pierre Couty, Philippe Gual, Valérie ParadisSéverine Celton-Morizur, Mathias Heikenwalder, Patrick Revy, Chantal Desdouets

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

34 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	1728-1741.e6
Journal	Developmental Cell
Volume	57
Issue number	14
DOIs	https://doi.org/10.1016/j.devcel.2022.06.003
State	Published - 25 Jul 2022
Externally published	Yes

Keywords

DNA damage
cGAS/STING
cell proliferation
dNTP pools
hepatocyte
non-alcoholic fatty liver disease
replication stress

Access to Document

10.1016/j.devcel.2022.06.003

Cite this

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., ... Desdouets, C. (2022). Replication stress triggered by nucleotide pool imbalance drives DNA damage and cGAS-STING pathway activation in NAFLD. Developmental Cell, 57(14), 1728-1741.e6. https://doi.org/10.1016/j.devcel.2022.06.003

@article{89e69ec6cb284b21803c6a0070726fb1,

title = "Replication stress triggered by nucleotide pool imbalance drives DNA damage and cGAS-STING pathway activation in NAFLD",

abstract = "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{\textquoteright} 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.",

keywords = "DNA damage, cGAS/STING, cell proliferation, dNTP pools, hepatocyte, non-alcoholic fatty liver disease, replication stress",

author = "Romain Donne and Ma{\"e}va Saroul-Ainama and Pierre Cordier and Adel Hammoutene and Christelle Kabore and Mira Stadler and Ivan Nemazanyy and Isabelle Galy-Fauroux and Mounia Herrag and Tobias Riedl and {Chansel-Da Cruz}, Marie and Stefano Caruso and St{\'e}phanie Bonnafous and Rupert {\"O}llinger and Roland Rad and Kristian Unger and Albert Tran and Couty, {Jean Pierre} and Philippe Gual and Val{\'e}rie Paradis and S{\'e}verine Celton-Morizur and Mathias Heikenwalder and Patrick Revy and Chantal Desdouets",

note = "Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",

year = "2022",

month = jul,

day = "25",

doi = "10.1016/j.devcel.2022.06.003",

language = "English",

volume = "57",

pages = "1728--1741.e6",

journal = "Developmental Cell",

issn = "1534-5807",

publisher = "Cell Press",

number = "14",

}

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, JP, Gual, P, Paradis, V, Celton-Morizur, S, Heikenwalder, M, Revy, P & Desdouets, C 2022, 'Replication stress triggered by nucleotide pool imbalance drives DNA damage and cGAS-STING pathway activation in NAFLD', Developmental Cell, vol. 57, no. 14, pp. 1728-1741.e6. https://doi.org/10.1016/j.devcel.2022.06.003

TY - JOUR

T1 - Replication stress triggered by nucleotide pool imbalance drives DNA damage and cGAS-STING pathway activation in NAFLD

AU - Donne, Romain

AU - Saroul-Ainama, Maëva

AU - Cordier, Pierre

AU - Hammoutene, Adel

AU - Kabore, Christelle

AU - Stadler, Mira

AU - Nemazanyy, Ivan

AU - Galy-Fauroux, Isabelle

AU - Herrag, Mounia

AU - Riedl, Tobias

AU - Chansel-Da Cruz, Marie

AU - Caruso, Stefano

AU - Bonnafous, Stéphanie

AU - Öllinger, Rupert

AU - Rad, Roland

AU - Unger, Kristian

AU - Tran, Albert

AU - Couty, Jean Pierre

AU - Gual, Philippe

AU - Paradis, Valérie

AU - Celton-Morizur, Séverine

AU - Heikenwalder, Mathias

AU - Revy, Patrick

AU - Desdouets, Chantal

PY - 2022/7/25

Y1 - 2022/7/25

N2 - 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.

AB - 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.

KW - DNA damage

KW - cGAS/STING

KW - cell proliferation

KW - dNTP pools

KW - hepatocyte

KW - non-alcoholic fatty liver disease

KW - replication stress

UR - http://www.scopus.com/inward/record.url?scp=85134981516&partnerID=8YFLogxK

U2 - 10.1016/j.devcel.2022.06.003

DO - 10.1016/j.devcel.2022.06.003

M3 - Article

C2 - 35768000

AN - SCOPUS:85134981516

SN - 1534-5807

VL - 57

SP - 1728-1741.e6

JO - Developmental Cell

JF - Developmental Cell

IS - 14

ER -

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

Abstract

Keywords

Access to Document

Fingerprint

Cite this