The analysis of HIF function in DNA repair and genome stability


   School of Biosciences

  ,  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

DNA damage is a factor that underlies many human diseases. Such damage results in mutations, and if such genetic alterations occur in tumour suppressor or proto-oncogenes it can lead to cancer. In addition, it is known that DNA damage can drive a cell into a senescent state, contributing to ageing and inflammation. We are using the zebrafish a genetically accessible vertebrate model to study the process of DNA repair.

In our lab, while working on mutants in the Van Hippel Lindau orthologs of the zebrafish, we discovered that these mutants are highly resistant to DNA damaging treatments. Embryos survived treatments that were lethal to control larvae. The VHL gene is a tumour suppressor gene that has a number of functions, most importantly, its loss leads to activation of the HIF pathway. Subsequent analysis showed that HIF was indeed the crucial transcription factor that led to genoprotection in larvae.

As HIF is a transcription factor, we therefore hypothesize that under conditions of DNA damage it drives a specific set of target genes that lead to genoprotection, and that differs from the hypoxic targets of HIF. We will start this project by an RNAseq experiment to identify such genes in relevant genetic mutants. These will be bioinformatically analysed to identify promising targets. We will use CRISPR/Cas9 technology that is well established in the zebrafish, transgenesis, or mRNA injection to modulate the function of the most promising candidate mediators to identify the crucial players. Understanding the mechanism by which HIF offers genoprotection will open up clinical opportunities, as HIF activators have recently been approved in the clinic.

Biological Sciences (4)

Funding Notes

Self funding only

References

https://www.oncotarget.com/article/27521/text/

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