结合DNA的结构和突变体显示了由APE1和DNA修复协调的基底DNA结合[修复]
1Skaggs Institute for Chemical Biology, and the Department of Molecular Biology, La Jolla, California 92037-1027, USA.
Nature
|February 10, 2000
概括
人类APE1酶通过扭曲螺旋和结合基底部位来修复DNA. 结构和突变数据揭示了APE1.
科学领域:
- 分子生物学分子生物学
- 结构生物学 结构生物学
- 生物化学 生物化学
背景情况:
- 阿普里尼克/阿普里米迪尼克 (AP) 位点是由自发衰变或DNA糖酶活性形成的DNA病变.
- 基因切除修复 (BER) 对于保持基因组完整性至关重要.
- 人类AP内核酶1 (APE1) 酶通过在AP位点分裂DNA来启动BER.
研究的目的:
- 阐明人类APE1识别和结合基底DNA的结构机制.
- 为了确定APE1介导的DNA裂变的催化机制.
- 了解APE1在基切割修复过程中如何与DNA损伤中间体相互作用.
主要方法:
- 人类APE1与基底DNA结合的X射线晶体学.
- APE1与裂开的DNA和Mn2+联合结晶.
- 关键APE1残留物的位点定向突变发生 (氨酸替代).
主要成果:
- 人类APE1利用一个刚性,正电荷的表面来扭曲和吞AP-DNA链.
- APE1将循环插入DNA槽,并将一个翻转出来的AP位点绑定到一个基本不包含的口袋中.
- 结构和突变数据支持APE1.1的可测试,基于结构的催化机制.
- APE1被优化以保留分裂的DNA产物,可能会取代葡萄糖酶.
结论:
- APE1采用独特的结构策略来结合和处理基底DNA病变.
- 这些发现为APE1在协调DNA修复中的作用提供了机制性的见解.
- APE1保留分裂DNA的能力表明它在管理修复中间体的过程中发挥了作用,以实现高效的DNA合成.
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