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Title: Photochemical reactions of DNA 6-TG and their biological consequences
Author: O'Donovan, Peter John
ISNI:       0000 0000 3853 9950
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2006
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6-Thioguanine (6-TG) incorporation into DNA is an inevitable consequence of treatment with the immunosuppressive drug Azathioprine (Aza). On administration, Aza is chemically cleaved to form 6-mercaptopurine which, after further metabolism, results in the accumulation of DNA 6-TG. Unlike the standard DNA bases, 6-TG absorbs strongly in the UVA region of the electromagnetic spectrum. I have shown that 6-TG and UVA interact in solution to form two major photoproducts. These have been identified as guanine-6-thioguanine (G-S-G) and guanine-6-sulfonate (G-6-SO3). These photoproducts are formed via singlet oxygen generated by 6-TG acting as a Type II photosensitiser. G-6-SO3 is also formed by UVA irradiation of the 6-TG deoxyribonucleoside as well as from 6-TG in both single- and double-stranded DNA. A significant level of DNA 6-TG has been measured in a number of human cell lines following growth in medium containing 6-TG. This DNA 6-TG sensitises the cells to killing by low doses of UVA. Cytotoxicity is not influenced by mismatch repair or nucleotide excision repair status. Sub-lethal combinations of 6-TG and UVA are synergistically mutagenic. I show that the 6-TG/UVA mutation spectrum differs from spontaneous and UVA spectra, and contains a high number of G to C and A to C transversions. 6-TG/UVA treatment of cells generates measurable levels of potentially mutagenic reactive oxygen species, a significant fraction of which is produced in DNA itself. 6-TG/UVA inhibits replication in cells. In response, PCNA becomes mono- ubiquitinated, suggesting possible translesion synthesis at the photochemical DNA lesions. Strikingly, 6-TG/UVA also causes covalent crosslinking of PCNA at the replication fork. This may also reflect reactions of singlet oxygen. DNA 6-TG has been quantified in skin biopsies from Aza treated patients. An investigation into the possible role of 6-TG/UVA-induced mutagenic DNA damage in the development of basal cell carcinoma in Aza patients has been initiated.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available