Reactive oxygen-mediated damage to a human DNA replication and repair protein
Reactive oxygen-mediated damage to a human DNA replication and repair protein
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DOI：
10.1038/sj.embor.7401084
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发表时间：
2007-11-01
期刊：
影响因子：
7.7
通讯作者：
Karran, Peter
中科院分区：
文献类型：
--
作者：
Montaner, Beatriz;O'Donovan, Peter;Karran, Peter
紫外线A(UVA)占入射地面紫外线辐射的90%以上。与直接破坏DNA的短波紫外线不同，UVA被DNA吸收得很差，因此被认为危害较小。接受免疫抑制剂硫唑嘌呤治疗的器官移植患者经常患皮肤癌。他们的DNA含有6-硫鸟嘌呤--一种碱基类似物，暴露在UVA中会产生破坏DNA的单线态氧(O-1(2))。在这里，我们证明了这种O-1(2)损伤增殖细胞核抗原(增殖细胞核抗原)，同源三聚体DNA聚合酶滑动钳。它通过亚基间域中的组氨酸残基引起增殖细胞核抗原亚基之间的共价氧化交联。在单独使用较高剂量的UVA或使用化学氧化剂处理后，也会发生交联。氧化蛋白的慢性积累与神经退行性疾病和衰老有关。我们的发现发现，对一种重要的DNA复制和修复蛋白的氧化损伤是以前未被认识的急性氧化应激的危险。
Ultraviolet A ( UVA) makes up more than 90% of incident terrestrial ultraviolet radiation. Unlike shorter wavelength UVB, which damages DNA directly, UVA is absorbed poorly by DNA and is therefore considered to be less hazardous. Organ transplant patients treated with the immunosuppressant azathioprine frequently develop skin cancer. Their DNA contains 6- thioguanine - a base analogue that generates DNA- damaging singlet oxygen ( O-1(2)) when exposed to UVA. Here, we show that this O-1(2) damages proliferating cell nuclear antigen ( PCNA), the homotrimeric DNA polymerase sliding clamp. It causes covalent oxidative crosslinking between the PCNA subunits through a histidine residue in the intersubunit domain. Crosslinking also occurs after treatment with higher - although still moderate doses of UVA alone or with chemical oxidants. Chronic accumulation of oxidized proteins is linked to neurodegenerative disorders and ageing. Our findings identify oxidative damage to an important DNA replication and repair protein as a previously unrecognized hazard of acute oxidative stress.