Unravelling the structural features and repair pathways of alcohol and fatty acid-derived DNA interstrand crosslinks

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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.