快速基因组催化DNA损伤切除和伴随核体和核体核心颗粒中的蛋白质修饰
Liwei Weng1, Marc M Greenberg1
1Department of Chemistry, Johns Hopkins University , 3400 North Charles Street, Baltimore, Maryland 21218, United States.
Journal of the American Chemical Society
|August 21, 2015
概括
氧化DNA可以产生一种叫做5'--2--1,4-二氧化的病变 (DOB). 在核酶体内,DOB被快速去除,基因组催化其切除,影响基因调节.
科学领域:
- 生物化学
- 分子生物学
- 化学生物学
背景情况:
- DNA氧化产生反应性物种,包括C5'基.
- 这种C5'-根可以被氧化,形成基底性损伤5'-(2--1,4-二氧化) (DOB).
- DOB是一种已知的DNA聚合酶β抑制剂,可以在DNA中形成跨链.
研究的目的:
- 调查核体和核体核心粒子 (NCP) 中的DOB损伤的反应性和稳定性.
- 确定核体结构对DOB切除率的影响.
- 探索DOB与基因组蛋白的相互作用及其对基因组修饰的潜在影响.
主要方法:
- 在合成核体和NCP中生成DOB.
- 使用DNA修复试验量化DOB切除率.
- 使用质谱测量对DOB-希斯添加物的分析.
- 在lysine残留物中调查希夫基形成和pyrrolone形成.
主要成果:
- 从核体DNA的DOB切除速度是自由DNA的275-1500倍.
- 在NCP中,DOB的半衰期 (7. 0 - 16. 8分钟) 比其他基底病变和细胞基底部位的寿命更短.
- 基因组在DNA链接区域催化了DOB切除.
- 希夫基和皮洛隆形成发生在DOB和基因组溶酶之间,包括翻译后修饰的溶酶.
结论:
- 核体结构显著加快了DOB切除,这表明体内快速修复.
- 可以在细胞内形成DOB- 希斯 adduct,随后形成pyrrolone.
- 这些基因素修饰可能会影响基因表达调节,并有助于产生DOB的细胞毒性.
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