PUBLICATION
Investigation of the role of VHL-HIF signaling in DNA repair and apoptosis in zebrafish
- Authors
- Kim, H.R., Santhakumar, K., Markham, E., Baldera, D., Greenald, D., Bryant, H.E., El-Khamisy, S.F., van Eeden, F.J.
- ID
- ZDB-PUB-200422-106
- Date
- 2020
- Source
- Oncotarget 11: 1109-1130 (Journal)
- Registered Authors
- Baldera, Davide, Markham, Elenor R., Santhakumar, Kiran, van Eeden, Freek
- Keywords
- DNA repair, Hif, Vhl, apoptosis, chemo/radio-resistance
- MeSH Terms
- none
- PubMed
- 32284789 Full text @ Oncotarget
Citation
Kim, H.R., Santhakumar, K., Markham, E., Baldera, D., Greenald, D., Bryant, H.E., El-Khamisy, S.F., van Eeden, F.J. (2020) Investigation of the role of VHL-HIF signaling in DNA repair and apoptosis in zebrafish. Oncotarget. 11:1109-1130.
Abstract
pVHL is a tumor suppressor. The lack of its function leads to various tumors, among which ccRCC (clear cell renal cell carcinoma) has the most serious outcome due to its resistance to chemotherapies and radiotherapies. Although HIF promotes the progression of ccRCC, the precise mechanism by which the loss of VHL leads to tumor initiation remains unclear. We exploited two zebrafish vhl mutants, vhl and vll, and Tg(phd3:: EGFP)i144 fish to identify crucial functions of Vhl in tumor initiation. Through the mutant analysis, we found that the role of pVHL in DNA repair is conserved in zebrafish Vll. Interestingly, we also discovered that Hif activation strongly suppressed genotoxic stress induced DNA repair defects and apoptosis in vll and brca2 mutants and in embryos lacking ATM activity. These results suggest the potential of HIF as a clinical modulator that can protect cells from accumulating DNA damage and apoptosis which can lead to cancers and neurodegenerative disorders.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping