PUBLICATION
atm Mutation and Oxidative Stress Enhance the Pre-Cancerous Effects of UHRF1 Overexpression in Zebrafish Livers
- Authors
- Ajouaou, Y., Magnani, E., Madakashira, B., Jenkins, E., Sadler, K.C.
- ID
- ZDB-PUB-230516-52
- Date
- 2023
- Source
- Cancers 15(8): (Journal)
- Registered Authors
- Ajouaou, Yousra, Magnani, Elena, Sadler Edepli, Kirsten C.
- Keywords
- Tp53, UHRF1, ataxia-telangiectasia mutated, atm, liver, oxidative stress, zebrafish
- Datasets
- GEO:GSE227735
- MeSH Terms
- none
- PubMed
- 37190230 Full text @ Cancers
Citation
Ajouaou, Y., Magnani, E., Madakashira, B., Jenkins, E., Sadler, K.C. (2023) atm Mutation and Oxidative Stress Enhance the Pre-Cancerous Effects of UHRF1 Overexpression in Zebrafish Livers. Cancers. 15(8):.
Abstract
The ataxia-telangiectasia mutated (atm) gene is activated in response to genotoxic stress and leads to activation of the tp53 tumor suppressor gene which induces either senescence or apoptosis as tumor suppressive mechanisms. Atm also serves non-canonical functions in the response to oxidative stress and chromatin reorganization. We previously reported that overexpression of the epigenetic regulator and oncogene Ubiquitin Like with PHD and Ring Finger Domains 1 (UHRF1) in zebrafish hepatocytes resulted in tp53-dependent hepatocyte senescence, a small liver and larval lethality. We investigated the role of atm on UHRF1-mediated phenotypes by generating zebrafish atm mutants. atm-/- adults were viable but had reduction in fertility. Embryos developed normally but were protected from lethality caused by etoposide or H2O2 exposure and failed to fully upregulate Tp53 targets or oxidative stress response genes in response to these treatments. In contrast to the finding that Tp53 prevents the small liver phenotype caused by UHRF1 overexpression, atm mutation and exposure to H2O2 further reduced the liver size in UHRF1 overexpressing larvae whereas treatment with the antioxidant N-acetyl cysteine suppressed this phenotype. We conclude that UHRF1 overexpression in hepatocytes causes oxidative stress, and that loss of atm further enhances this, triggering elimination of these precancerous cells, leading to a small liver.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping