DNA breakage and cell cycle checkpoint abrogation induced by a therapeutic thiopurine and UVA radiation

• Published in: Oncogene Vol. 29; no. 27; pp. 3953 - 3963
• Main Authors: Brem, R, Li, F, Montaner, B, Reelfs, O, Karran, P
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.07.2010; Nature Publishing Group
• Subjects: 631/337/1427/2567; 692/699/67/1813/1352; 692/700/565/251/1574; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Biological and medical sciences; Cell Biology; Cell cycle; Cell Cycle - drug effects; Cell Cycle - radiation effects; Cell cycle, cell proliferation; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Checkpoint Kinase 1; Chemotherapy; CHK1 protein; CHK2 protein; CHO Cells; Chromophores; Cricetinae; Cricetulus; Deoxyribonucleic acid; Dermatology; DNA; DNA Breaks - drug effects; DNA Breaks - radiation effects; DNA Breaks, Double-Stranded - drug effects; DNA Breaks, Double-Stranded - radiation effects; DNA Breaks, Single-Stranded - drug effects; DNA Breaks, Single-Stranded - radiation effects; DNA damage; DNA Repair - drug effects; DNA Repair - radiation effects; DNA Replication - drug effects; DNA Replication - radiation effects; Dose-Response Relationship, Radiation; Double-strand break repair; Fundamental and applied biological sciences. Psychology; Gene expression; Genetic aspects; HCT116 Cells; Health aspects; Human Genetics; Humans; Immunosuppressive agents; Internal Medicine; Medical sciences; Medicine; Medicine & Public Health; Molecular and cellular biology; Oncology; original-article; Photochemical Processes; Physiological aspects; Proteasomes; Protein Kinases - metabolism; Radiation therapy; Risk factors; S phase; Skin cancer; Skin carcinoma; Squamous cell carcinoma; Sunlight; Thioguanine - pharmacology; Tumors of the skin and soft tissue. Premalignant lesions; Ultraviolet radiation; Ultraviolet Rays; United Kingdom; UVA; skin cancer; cell cycle checkpoints; thiopurines; DNA breakage; Skin disease; UVA radiation; Malignant tumor; Carcinogenesis; Skin cancer; DNA; Cell cycle; Control point; Cancer
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2010.140

The frequency of squamous cell skin carcinoma in organ transplant patients is around 100-fold higher than normal. This dramatic example of therapy-related cancer reflects exposure to sunlight and to immunosuppressive drugs. Here, we show that the interaction between low doses of UVA, the major ultraviolet component of incident sunlight, and 6-TG, a UVA chromophore that is introduced into DNA by one of the most widely prescribed immunosuppressive drugs, causes DNA single- and double-strand breaks (DSB). S phase cells are particularly vulnerable to this DNA breakage and cells defective in rejoining of S-phase DSB are hypersensitive to the combination of low-dose UVA and DNA 6-TG. 6-TG/UVA-induced DNA lesions provoke canonical DNA damage responses involving activation of the ATM/Chk2 and ATR/Chk1 pathways and appropriate cell cycle checkpoints. Higher levels of photochemical DNA damage induce a proteasome-mediated degradation of Chk1 and checkpoint abrogation that is consistent with persistent unrepaired DNA damage. These findings indicate that the interaction between UVA and an immunosuppressant drug causes photochemical DNA lesions, including DNA breaks, and can compromise cell cycle checkpoints. These two properties could contribute to the high risk of sunlight-related skin cancer in long-term immunosuppressed patients.