The metabolism of alcohol and various fatty acids can produce highly reactive aldehydes such as acetaldehyde and trans-4-hydroxynonenal (4-HNE). These can react with the bases in DNA to produce interstrand crosslinks (ICLs) that block DNA replication and if not repaired, can lead to cell death. An inability to repair ICLs is a characteristic of genetic diseases such as Fanconi Anaemia (FA). FA patients are more likely to develop growth abnormalities and have a significantly higher risk of developing cancer. Despite this, information about the properties of ICL-containing DNA is limited and the mechanisms by which ICLs are repaired are not fully understood. To address these challenges requires the ready availability of suitable substrates containing ICLs of defined structure at specific sites within the DNA. This project will involve the chemical synthesis of modified nucleotides for the preparation of ICL-containing DNA using standard automated DNA synthesis. A variety of biophysical techniques will be used to study the properties and characteristics of such ICL-containing DNA. Mechanisms for repair of ICL DNA will be studied using proteins that have been implicated in ICL repair and alternative non-enzymatic pathways that have been proposed will also be explored.
The BBSRC WR DTP and the University of Sheffield are committed to recruiting future scientists regardless of age, ethnicity, gender, gender identity, disability, sexual orientation or career pathway to date. We understand that commitment and excellence can be shown in many ways and we have built our recruitment process to reflect this. We welcome applicants from all backgrounds, particularly those underrepresented in science, who have curiosity, creativity and a drive to learn new skills.
Entry Requirements: Students with, or expecting to gain, at least an upper second class honours degree, or equivalent, are invited to apply. The interdisciplinary nature of this programme means that we welcome applications from students with backgrounds in any biological, chemical, and/or physical science, or students with mathematical backgrounds who are interested in using their skills in addressing biological questions.
Note: Relocation costs for international students to the UK (visa, insurance, NHS fees, flights, etc) will be the responsibility of the student
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Programme: PhD in Mechanistic Biology (4 years)
Start Date: 1st October 2023
Shortlisted candidates will be interviewed mid February 2023