An unprecedented nucleic acid capture mechanism for excision of DNA damage

Emily H. Rubinson; A. S. Prakasha Gowda; Thomas E. Spratt; Barry Gold; Brandt F. Eichman

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An unprecedented nucleic acid capture mechanism for excision of DNA damage

机译：前所未有的核酸捕获机制可消除DNA损伤

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DNA glycosylases that remove alkylated and deaminated purine nucleobases are essential DNA repair enzymes that protect the genome, and at the same time confound cancer alkylation therapy, by excising cytotoxic N3-methyladenine bases formed by DNA-targeting anticancer compounds. The basis for glycosylase specificity towards N3- and N7-alkylpurines is believed to result from intrinsic instability of the modified bases and not from direct enzyme functional group chemistry. Here we present crystal structures of the recently discovered Bacillus cereus AlkD glycosylase in complex with DNAs containing alkylated, mismatched and abasic nucleotides. Unlike other glycosylases, AlkD captures the extrahelical lesion in a solvent-exposed orientation, providing an illustration for how hydrolysis of N3- and N7-alkylated bases may be facilitated by increased lifetime out of the DNA helix. The structures and supporting biochemical analysis of base flipping and catalysis reveal how the HEAT repeats of AlkD distort the DNA backbone to detect non-Watson-Crick base pairs without duplex intercalation.

机译：去除烷基化和脱氨基的嘌呤核苷碱基的DNA糖基化酶是保护基因组的必需的DNA修复酶，同时通过切除由靶向DNA的抗癌化合物形成的细胞毒性N3-甲基腺嘌呤碱基，使癌症烷基化疗法感到困惑。据信，针对N3-和N7-烷基嘌呤的糖基化酶特异性的基础是由于修饰的碱基固有的不稳定性，而不是直接由酶官能团化学反应引起的。在这里，我们介绍了新发现的蜡状芽孢杆菌AlkD糖基化酶的晶体结构，其与含有烷基化，错配和无碱基核苷酸的DNA形成复合体。与其他糖基化酶不同，AlkD在溶剂暴露的方向上捕获了螺旋外病变，从而为如何通过增加DNA螺旋的寿命来促进N3-和N7-烷基化碱基的水解提供了例证。碱基翻转和催化的结构和支持的生化分析揭示了AlkD的HEAT重复序列如何扭曲DNA骨架，以检测没有双重插入的非Watson-Crick碱基对。

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来源
《Nature》 |2010年第7322期|p.406-411|共6页
作者
Emily H. Rubinson; A. S. Prakasha Gowda; Thomas E. Spratt; Barry Gold; Brandt F. Eichman;
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作者单位

Department of Biological Sciences and Center for Structural Biology, Vanderbilt University, Nashville, Tennessee 37232, USA;

rnDepartment of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA;

rnDepartment of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA;

rnDepartment of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA;

rnDepartment of Biological Sciences and Center for Structural Biology, Vanderbilt University, Nashville, Tennessee 37232, USA;

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收录信息美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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机译：碱基序列对体外核苷酸切除修复机制去除DNA损伤的影响。
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8. Molecular Mechanisms of Radiation Induced Damage to Nucleic Acids [R] . Ward, J. F. 1973

机译：辐射诱导核酸损伤的分子机制

An unprecedented nucleic acid capture mechanism for excision of DNA damage

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