| EPSRC Reference: |
EP/H002464/1 |
| Title: |
Investigating nitration-damaged DNA using a mimic of 8-nitro-2'-deoxyguanosine |
| Principal Investigator: |
Cosstick, Professor R |
| Other Investigators: |
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| Researcher Co-Investigators: |
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| Project Partners: |
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| Department: |
Chemistry |
| Organisation: |
University of Liverpool |
| Scheme: |
Standard Research |
| Starts: |
11 January 2010 |
Ends: |
10 August 2013 |
Value (£): |
334,515
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| EPSRC Research Topic Classifications: |
| Biological & Medicinal Chem. |
Chemical Biology |
| Chemical Synthetic Methodology |
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| EPSRC Industrial Sector Classifications: |
| No relevance to Underpinning Sectors |
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| Related Grants: |
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| Panel History: |
| Panel Date | Panel Name | Outcome |
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30 Jun 2009
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Physical Sciences Panel - Chemistry
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Announced
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Summary on Grant Application Form |
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For some years chronic inflammation has been closely associated with an increased risk for human cancer. Specific examples include: lung cancer which results from inflammation caused by years of inhaled tobacco smoke and the association between inflammatory stomach infections (such as Helicobacter pylori) and gastric cancer. The molecular basis for this link stems from excess production of nitric oxide (NO) in inflamed tissues. Accumulating evidence indicates that reactive nitrogen species derived from NO are involved in cancer as they are able to damage DNA through chemical reactions with the DNA bases. The guanine base in DNA is major target of these reactions and leads to oxidation or nitration of the guanine base. Nitration produces 8-nitroguanine (8-nitro-G), which is the subject of this application and about which very little is known, whilst oxidation leads to 8-oxoguanine (8-oxo-G) whose deleterious affects have been widely studied. Once nitration of the guanine base has occurred the bond between the sugar and the guanine base (the glycosidic bond) is weakened and 8-nitroguanine is released from the DNA with a half-life of around 24 h, ultimately generating abasic sites in the DNA. The release of 8-nitro-G can be used as a marker for nitrative damage and it has been detected in lung tissues in cigarette smokers. Interestingly, smoking has been shown to greatly increase the amount of 8-nitro-G found in urine (6-70 fold), whereas the elevation of 8-oxo-G in smokers is only very modest (10-50%). Whilst these observations suggest that a detailed and systematic study of the biological effect of guanine nitration is very timely, the instability of the glycosidic bond in 8-nitrodeoxyguanosine (8-nitro-dG) means that it is impractical to incorporate this nucleoside into DNA using chemical methods and thus very little chemical and biochemical information currently exists regarding the effect of this modification on DNA. Indeed, at present there is not even an efficient and unambiguous chemical preparation of the 8-nitro-G base. The aim of this proposal is to develop an efficient chemical synthesis of 8-nitro-G, which will be used to prepare a very close mimic of the 8-nitro-dG nucleoside, replacing the deoxyribose sugar with a cyclohexenyl ring. This analogue will have a stable glycosidic bond and hence can be incorporated into DNA. The incorporation of a mimic of 8-nitro-dG into DNA will enable, for the first time, a study of the base pairing properties of 8-nitro-G within a DNA duplex, establish its coding properties in in vitro DNA replication and allow preliminary studies on the possible mutagenic effects of the nitrated base in vivo, and whether DNA containing this modification can be repaired. Overall this project will provide considerable information on the mutagenic properties 8-nitro-G and thus start to shed some light on its role in carcinogenesis.
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Key Findings |
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This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk
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Potential use in non-academic contexts |
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This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk
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Impacts |
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| Description |
This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk |
| Summary |
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| Date Materialised |
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Sectors submitted by the Researcher |
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This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk
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| Project URL: |
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| Further Information: |
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| Organisation Website: |
http://www.liv.ac.uk |