DNA breakage and cell cycle checkpoint abrogation induced by a therapeutic thiopurine and UVA radiation.
DNA breakage and cell cycle checkpoint abrogation induced by a therapeutic thiopurine and UVA radiation.
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DOI：
10.1038/onc.2010.140
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发表时间：
2010-07-08
期刊：
影响因子：
8
通讯作者：
Karran, P.
中科院分区：
文献类型：
--
作者：
Brem, R.;Li, F.;Montaner, B.;Reelfs, O.;Karran, P.
器官移植患者的鳞状细胞皮肤癌的发生率大约是正常的100倍。这个与治疗相关的癌症的戏剧性例子反映了暴露在阳光下和免疫抑制药物。在这里，我们证明了低剂量的UVA和6-TG之间的相互作用，UVA是入射阳光的主要紫外线成分，6-TG是一种UVA发色团，由最广泛的处方免疫抑制药物之一引入DNA，导致DNA单链和双链断裂(DSB)。S期细胞对这种DNA断裂尤为敏感，S期DSB重接缺陷细胞对低剂量UVA和DNA6-TG的联合作用敏感。6-TG/UVA诱导的DNA损伤引起典型的DNA损伤反应，包括激活ATM/Chk2和ATR/Chk1通路和适当的细胞周期检查点。更高水平的光化学DNA损伤诱导蛋白酶体介导的Chk1降解和检查点消除，这与持续的未修复的DNA损伤是一致的。这些发现表明，UVA和一种免疫抑制剂药物之间的相互作用会导致光化学DNA损伤，包括DNA断裂，并可能危及细胞周期检查点。这两种特性可能导致长期免疫抑制患者患与阳光相关的皮肤癌的风险较高。
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 demonstrate 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.
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硫唑嘌呤和UVA光产生诱变的氧化DNA损伤。
DOI：
10.1126/science.1114233
发表时间：
2005-09-16
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
O'Donovan P;Perrett CM;Zhang X;Montaner B;Xu YZ;Harwood CA;McGregor JM;Walker SL;Hanaoka F;Karran P
通讯作者：
Karran P
影响因子：
4.6
作者：
LJUNGMAN, M;HANAWALT, PC
通讯作者：
HANAWALT, PC
影响因子：
14.9
作者：
Cartwright, R;Tambini, CE;Thacker, J
通讯作者：
Thacker, J
影响因子：
10.3
作者：
LENNARD, L;THOMAS, S;MADDOCKS, JL
通讯作者：
MADDOCKS, JL
影响因子：
7.7
作者：
Montaner, Beatriz;O'Donovan, Peter;Karran, Peter
通讯作者：
Karran, Peter