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

// Hyejeong Rosemary Kim 1 , Kirankumar Santhakumar 2 , Eleanor Markham 1 , Davide Baldera 1 , David Greenald 5 , Helen E. Bryant 3 , Sherif F. El-Khamisy 4 and Fredericus J. van Eeden 1 1 Bateson Centre/BMS, Firth Court, University of Sheffield, Sheffield S10 2TN, UK 2 Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur 603203, India 3 Department of Oncology & Metabolism, The Medical School, Sheffield S10 2RX, UK 4 Department of Molecular Biology and Biotechnology, Firth Court, University of Sheffield, Sheffield S10 2TN, UK 5 Centre for Discovery Brain Sciences, University of Edinburgh, Chancellor’s Building, Edinburgh EH16 4SB, UK Correspondence to: Fredericus J. van Eeden, email: f.j.vaneeden@sheffield.ac.uk Keywords: Hif; Vhl; DNA repair; apoptosis; chemo/radio-resistance Received: August 14, 2019     Accepted: February 17, 2020     Published: March 31, 2020 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.