Protein oxidation and DNA repair inhibition by 6-thioguanine and UVA radiation
Quentin Gueranger1, Feng Li1, Matthew Peacock1
1Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Herts, UK.
Abstract:
Damage to skin DNA by solar UV is largely unavoidable, and an optimal cellular response to it requires the coordinated operation of proteins in numerous pathways. A fully functional DNA repair proteome for removing harmful DNA lesions is a prerequisite for an appropriate DNA damage response. Genetically determined failure to repair UV-induced DNA damage is associated with skin photosensitivity and increased skin cancer risk. Patients treated with immunosuppressant/anti-inflammatory thiopurines are also photosensitive and have high rates of sun-related skin cancer. Their DNA contains the base analog 6-thioguanine (6-TG), which acts as a UVA photosensitizer to generate reactive oxygen species (ROS), predominantly singlet oxygen ((1)O2). ROS damage both DNA and proteins. Here we show that UVA irradiation of cultured human cells containing DNA 6-TG causes significant protein oxidation and damages components of the DNA repair proteome, including the Ku, OGG-1, MYH, and RPA proteins. Assays of DNA repair in intact cells or in cell extracts indicate that this protein damage compromises DNA break rejoining and base and nucleotide excision repair. As these experimental conditions simulate those in the skin of patients taking thiopurines, our findings suggest a mechanism whereby UVA in sunlight may contribute to skin carcinogenesis in immunosuppressed patients.
Insights
Solar UVA light damages DNA repair proteins in patients taking thiopurines, increasing skin cancer risk. This damage impairs crucial DNA repair pathways, highlighting a mechanism for photosensitivity and carcinogenesis.
Area of Science:
- Molecular biology
- Dermatology
- Cancer research
Background:
- Solar ultraviolet (UV) radiation damages skin DNA, necessitating robust cellular repair mechanisms.
- Impaired DNA repair is linked to photosensitivity and increased skin cancer risk.
- Patients on thiopurine medications exhibit photosensitivity and elevated skin cancer rates due to 6-thioguanine (6-TG) in their DNA.
Purpose of the Study:
- To investigate the molecular mechanisms by which UVA radiation, in the presence of 6-TG, affects DNA repair proteins and cellular DNA repair capacity.
- To determine if UVA-induced damage to DNA repair proteins contributes to skin carcinogenesis in patients taking thiopurines.
Main Methods:
- Cultured human cells containing DNA 6-TG were irradiated with UVA.
- Protein oxidation and damage to specific DNA repair proteins (Ku, OGG-1, MYH, RPA) were assessed.
- DNA repair assays (break rejoining, base excision repair, nucleotide excision repair) were performed on cells and cell extracts.
Main Results:
- UVA irradiation of 6-TG-containing cells caused significant protein oxidation.
- Key DNA repair proteins, including Ku, OGG-1, MYH, and RPA, were damaged by UVA.
- This protein damage resulted in compromised DNA repair, affecting multiple repair pathways.
Conclusions:
- UVA irradiation damages essential DNA repair proteins in cells containing 6-TG, simulating conditions in patients on thiopurines.
- The observed protein damage impairs DNA repair capacity, suggesting a mechanism for increased skin cancer risk.
- These findings provide a potential explanation for photosensitivity and sun-related skin cancer in immunosuppressed patients taking thiopurines.
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