DNA breakage and cell cycle checkpoint abrogation induced by a therapeutic thiopurine and UVA radiation.
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.
Brem
R
R
Mammalian DNA Repair Laboratory, Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Herts, UK.
Li
F
F
Montaner
B
B
Reelfs
O
O
Karran
P
P
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016466:CHO Cells; D002453:Cell Cycle / Q000187:drug effects* / Q000528:radiation effects*; D000071877:Checkpoint Kinase 1; D006224:Cricetinae; D003412:Cricetulus; D053960:DNA Breaks / Q000187:drug effects* / Q000528:radiation effects*; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D053904:DNA Breaks, Single-Stranded / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D004261:DNA Replication / Q000187:drug effects / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D045325:HCT116 Cells; D006801:Humans; D055668:Photochemical Processes; D011494:Protein Kinases / Q000378:metabolism; D013866:Thioguanine / Q000494:pharmacology*; D014466:Ultraviolet Rays
D000970:Antineoplastic Agents; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D013866:Thioguanine