Reactive oxygen species generated by thiopurine/UVA cause irreparable transcription-blocking DNA lesions.

Abstract

Long-term treatment with the anticancer and immunosuppressant thiopurines, azathioprine or 6-mercaptopurine, is associated with acute skin sensitivity to ultraviolet A (UVA) radiation and a high risk of skin cancer. 6-thioguanine (6-TG) that accumulates in the DNA of thiopurine-treated patients interacts with UVA to generate reactive oxygen species. These cause lethal and mutagenic DNA damage. Here we show that the UVA/DNA 6-TG interaction rapidly, and essentially irreversibly, inhibits transcription in cultured human cells and provokes polyubiquitylation of the major subunit of RNA polymerase II (RNAPII). In vitro, 6-TG photoproducts, including the previously characterized guanine-6-sulfonate, in the transcribed DNA strand, are potent blocks to RNAPII transcription whereas 6-TG is only slightly inhibitory. In vivo, guanine-6-sulfonate is removed poorly from DNA and persists to a similar extent in the DNA of nucleotide excision repair-proficient and defective cells. Furthermore, transcription coupled repair-deficient Cockayne syndrome cells are not hypersensitive to UVA/6-TG, indicating that potentially lethal photoproducts are not selectively excised from transcribed DNA. Since persistent transcription-blocking DNA lesions are associated with acute skin responses to sunlight and the development of skin cancer, our findings have implications for skin cancer in patients undergoing thiopurine therapy.

• Authors: Reto Brem, Feng Li, Peter Karran
• Journal: Nucleic acids research (Nucleic Acids Res) Vol. 37 Issue 6 Pg. 1951-61 (Apr 2009) ISSN: 1362-4962 [Electronic] England
• PMID: 19208641 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• Reactive Oxygen Species
• DNA
• RNA Polymerase II
• Thioguanine

Topics

• Antimetabolites, Antineoplastic (metabolism, pharmacology, radiation effects)
• Cell Line
• DNA (chemistry, metabolism)
• DNA Damage
• DNA Repair
• Humans
• RNA Polymerase II (metabolism)
• Reactive Oxygen Species (metabolism)
• Thioguanine (metabolism, pharmacology, radiation effects)
• Transcription, Genetic (drug effects, radiation effects)
• Ultraviolet Rays