Whilst undertaking an integrated masters degree (MBiolSci) in Molecular Biology at The University of Sheffield I was lucky enough to obtain a summer placement in the lab of Professor Sherif El-Khamisy. I had discovered a keen interest for the mechanisms of DNA repair during my undergraduate lectures and now had the opportunity to work on human cancer cell lines, studying their response when key components of DNA repair pathways were inhibited. My experience here led me to pursue a PhD in the area of DNA repair.
I am now working with both Dr Fredericus Van Eeden and Professor Sherif El-Khamisy investigating the redundancy of DNA repair mechanisms in an in vivo model.
A cell can experience ~1 million DNA lesions per day from endogenous and exogenous genotoxins. A variety of lesions also result from aberrant replication, or DNA repair itself. DNA lesions threaten essential processes such as transcription and replication and can lead to apoptosis and cancer.
There are many mechanisms of screening and repair to prevent DNA lesions that occur, resulting in their resolution with little or no negative effects. Nonetheless, mutations that render important constituents of DNA repair pathways non-functional can result in debilitating and life threatening neurological diseases. Mutations in two repair proteins, TDP1 and RNaseH2a, have been identified in humans as causes of SCAN1 and AGS respectively. Despite the advancements made through cell culture analysis, animal models are required to enable the study of redundancy and interaction at an organismal level.
Mouse models have been instrumental in progressing our knowledge around neurological disease but knockouts are often embryonic lethal. The small size of the zebrafish, rapid reproduction and ease of genetic manipulation has led them to be a less expensive alternative for mammalian systems. In some cases, knockouts in zebrafish can result in a homozygous mutant, indistinguishable from the wild type, suggesting compensatory pathways.
My aim will be to investigate the role of compensatory pathways in DNA repair mechanisms and their link to neurological disease. Identification of members in these alternative pathways will enable the development of treatments that can work alongside established clinical techniques to increase treatment efficiency through dual targeting of diseases
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