The Open UniversitySkip to content
 

Novel DNA lesions generated by the interaction between therapeutic thiopurines and UVA light

Zhang, Xiaohong; Jeffs, Graham; Ren, Xiaolin; O'Donovan, Peter; Montaner, Beatriz; Perrett, Conal M.; Karran, Peter and Xu, Yao-Zhong (2007). Novel DNA lesions generated by the interaction between therapeutic thiopurines and UVA light. DNA Repair, 6(3) pp. 344–354.

DOI (Digital Object Identifier) Link: http://dx.doi.org/10.1016/j.dnarep.2006.11.003
Google Scholar: Look up in Google Scholar

Abstract

The therapeutic effect of the thiopurines, 6-thioguanine (6-TG), 6-mercaptopurine, and its prodrug azathioprine, depends on the incorporation of 6-TG into cellular DNA. Unlike normal DNA bases, 6-TG absorbs UVA radiation, and UVA-mediated photochemical damage of DNA 6-TG has potentially harmful side effects. When free 6-TG is UVA irradiated in solution in the presence of molecular oxygen, reactive oxygen species are generated and 6-TG is oxidized to guanine-6-sulfonate (GSO3) and guanine-6 thioguanine in reactions involving singlet oxygen. This conversion is prevented by antioxidants, including the dietary vitamin ascorbate. DNA GSO3 is also the major photoproduct of 6-TG in DNA and it can be selectively introduced into DNA or oligonucleotides in vitro by mild chemical oxidation. Thermal stability measurements indicate that GSO3 does not form stable base pairs with any of the normal DNA bases in duplex oligonucleotides and is a powerful block for elongation by Klenow DNA polymerase in primer extension experiments. In cultured human cells, DNA damage produced by 6-TG and UVA treatment is associated with replication inhibition and provokes a p53-dependent DNA damage response.

Item Type: Journal Article
ISSN: 1568-7864
Keywords: 6-Thioguanine; Ultraviolet light; Photochemistry; Oxidative DNA damage; Antioxidants; Guanine-6-sulfonate; Reactive oxygen species; Rose Bengal; UVA; DNA photoproducts;
Academic Unit/Department: Science > Life, Health and Chemical Sciences
Other Departments > Other Departments
Interdisciplinary Research Centre: Biomedical Research Network (BRN)
Item ID: 7116
Depositing User: Yao Xu
Date Deposited: 12 Mar 2007
Last Modified: 24 Jul 2014 09:10
URI: http://oro.open.ac.uk/id/eprint/7116
Share this page:

Actions (login may be required)

View Item
Report issue / request change

Policies | Disclaimer

© The Open University   + 44 (0)870 333 4340   general-enquiries@open.ac.uk