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    Investigation of the role of VHL-HIF signaling in DNA repair and apoptosis in zebrafish

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    El-Khamisy_Oncotarget_Final (6.745Mb)
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    Publication date
    2020-03
    Author
    Kim, H.R.
    Santhakumar, K.
    Markham, E.
    Baldera, D.
    Greenald, D.
    Bryant, H.E.
    El-Khamisy, Sherif F.
    van Eeden, F.J.
    Keyword
    Hif
    Vhl
    DNA repair
    Apoptosis
    Chemo/radio-resistance
    Rights
    Copyright: Kim et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
    Peer-Reviewed
    Yes
    
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    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.
    URI
    http://hdl.handle.net/10454/18019
    Version
    Published version
    Citation
    Kim HR, Santhakumar K, Markham E et al (2020) Investigation of the role of VHL-HIF signaling in DNA repair and apoptosis in zebrafish. Oncotarget. 11(13): 1109-1130.
    Link to publisher’s version
    https://doi.org/10.18632/oncotarget.27521
    Type
    Article
    Collections
    Life Sciences Publications

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