"Formation and roles of the 5',8-cyclo-2'-deoxygua.. (CYCLOGUO)
"Formation and roles of the 5',8-cyclo-2'-deoxyguanosine lesion"
Start date: Apr 1, 2012,
End date: Mar 31, 2014
"Free radical attack to genetic material leads to damages that are involved in pathologies as well as in aging. Guanine is the preferred oxidation site of DNA, and 8-oxo-dG is used as marker of radical stress, with some drawbacks due to oxidative artefacts during the analysis. The project addresses the chemical biology of 5’,8-cyclo-2’-deoxyguanosine (5’,8-cyclo-dG), a tandem damage produced by free radical insult to the 5’ position of the sugar. The compound has an extra covalent bond between the base and sugar moieties and occurs as 5’S and 5’R diastereomers. Chemical studies on 5’,8-cyclo-dG, paralleled with 8-oxo-dG, are expected to contribute to a full scenario of guanine damage. The project addresses: i) Structure and reactivity features of the 5’,8-cyclo-dG formation and diastereomeric ratios as reporter of different DNA supramolecular organization and environmental factors; ii) chemical and stereochemical issues in different oligosequences and DNA-mimics, including convenient syntheses of various (5’S)- and (5’R)-5’,8-cyclo-dG structures, which represent the limiting step for comprehensive biological and medical research; iii) the 5’,8-cyclo-dG damage in guanine-rich regions such as telomeres, “CpG islands” and introns, intensively studied for cancer and aging processes; iv) aspects of the structural distortion of guanine-rich regions due to the lesion; v) differences in enzymatic recognition and hydrolysis of sequences containing the lesion in the two diastereomeric forms. Main milestones of the project are envisaged: easy access to cyclonucleoside-containing substrates; protocols for characterization of the 5’,8-cyclo-dG lesions and application to damage evaluation in biological samples; assessment of damage in different dietary conditions and cell environments, such as nuclear and mitochondrial DNA; balanced aspects of the damage and repair processes of the 5’,8-cyclo-dG lesion; integration of the 5’,8-cyclo-dG lesion in the whole scenario of DNA damage."
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