The BRUCE-ATR Signaling Axis Is Required for Accurate DNA Replication and Suppression of Liver Cancer Development.
Animals
Ataxia Telangiectasia Mutated Proteins
/ genetics
Carcinogenesis
Carcinoma, Hepatocellular
/ genetics
DNA Repair
/ genetics
DNA Replication
/ genetics
Disease Models, Animal
Female
Gene Expression Regulation, Neoplastic
Genomic Instability
Humans
Inhibitor of Apoptosis Proteins
/ genetics
Liver Neoplasms
/ genetics
Male
Mice
Mice, Knockout
Random Allocation
Sensitivity and Specificity
Signal Transduction
/ genetics
Tumor Suppressor Proteins
/ genetics
Journal
Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
14
08
2018
accepted:
23
01
2019
pubmed:
30
1
2019
medline:
17
6
2020
entrez:
30
1
2019
Statut:
ppublish
Résumé
Replication fork stability during DNA replication is vital for maintenance of genomic stability and suppression of cancer development in mammals. ATR (ataxia-telangiectasia mutated [ATM] and RAD3-related) is a master regulatory kinase that activates the replication stress response to overcome replication barriers. Although many downstream effectors of ATR have been established, the upstream regulators of ATR and the effect of such regulation on liver cancer remain unclear. The ubiquitin conjugase BRUCE (BIR Repeat containing Ubiquitin-Conjugating Enzyme) is a guardian of chromosome integrity and activator of ATM signaling, which promotes DNA double-strand break repair through homologous recombination. Here we demonstrate the functions for BRUCE in ATR activation in vitro and liver tumor suppression in vivo. BRUCE is recruited to induced DNA damage sites. Depletion of BRUCE inhibited multiple ATR-dependent signaling events during replication stress, including activation of ATR itself, phosphorylation of its downstream targets CHK1 and RPA, and the mono-ubiquitination of FANCD2. Consequently, BRUCE deficiency resulted in stalled DNA replication forks and increased firing of new replication origins. The in vivo impact of BRUCE loss on liver tumorigenesis was determined using the hepatocellular carcinoma model induced by genotoxin diethylnitrosamine. Liver-specific knockout of murine Bruce impaired ATR activation and exacerbated inflammation, fibrosis and hepatocellular carcinoma, which exhibited a trabecular architecture, closely resembling human hepatocellular carcinoma (HCC). In humans, the clinical relevance of BRUCE down-regulation in liver disease was found in hepatitis, cirrhosis, and HCC specimens, and deleterious somatic mutations of the Bruce gene was found in human hepatocellular carcinoma in the Cancer Genome Atlas database. Conclusion: These findings establish a BRUCE-ATR signaling axis in accurate DNA replication and suppression of liver cancer in mice and humans and provides a clinically relevant HCC mouse model.
Identifiants
pubmed: 30693543
doi: 10.1002/hep.30529
pmc: PMC6541504
mid: NIHMS1008475
doi:
Substances chimiques
BIRC6 protein, mouse
0
Inhibitor of Apoptosis Proteins
0
Tumor Suppressor Proteins
0
Atr protein, mouse
EC 2.7.1.-
Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
2608-2622Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM109768
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA117846
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA158323
Pays : United States
Organisme : NIEHS NIH HHS
ID : P30 ES006096
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR027015
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA129537
Pays : United States
Informations de copyright
© 2019 by the American Association for the Study of Liver Diseases.
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