A chemical and kinetic perspective on base excision repair of DNA.
A chemical and kinetic perspective on base excision repair of DNA.
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DOI：
10.1021/ar400275a
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发表时间：
2014-04-15
影响因子：
18.3
通讯作者：
Delaney, Sarah
中科院分区：
文献类型：
--
作者：
Schermerhorn, Kelly M.;Delaney, Sarah
我们的细胞基因组持续暴露于多种外源性和内源性 DNA 损伤剂中。这些试剂可导致形成广泛的 DNA 损伤，包括单链和双链断裂、链间和链内交联、脱碱基位点和 DNA 核碱基修饰。这些 DNA 损伤的持续存在可能具有诱变性和细胞毒性，并可能导致基因表达改变和细胞凋亡，从而导致衰老、癌症和各种神经系统疾病。为了对抗 DNA 损伤的有害影响，细胞具有多种 DNA 修复途径，负责将受损的 DNA 恢复到其规范形式。在这里，我们检查其中一种修复途径，即碱基切除修复（BER）途径，这是一种高度调控的酶网络，负责修复修饰的核碱基和脱碱基位点损伤。体外重建 BER 所需的酶已被鉴定，并且修复事件可被认为分两部分发生：(1) DNA 糖基化酶切除修饰的核碱基，以及 (2) 通过一系列下游酶用未损坏的核碱基填充由此产生的“孔”。 DNA 糖基化酶启动 BER 事件，识别并去除特定的修饰核碱基，并产生脱碱基位点作为产物。无碱基位点是一种高反应性 BER 中间体，由 AP 核酸内切酶 1 (APE1) 进一步加工，将 DNA 主链 5' 切割至无碱基位点，在 DNA 主链中产生切口。 APE1 作用后，BER 可以遵循两种子路径之一，即短补丁 (SP) 或长补丁 (LP) 版本，这两种子路径的不同取决于聚合酶在切口位点掺入的核苷酸数量。 DNA 连接酶负责密封主链中的切口并再生未损坏的双链体。毫不奇怪，与 BER 维持遗传稳定性的观点一致，BER 酶的缺乏和/或失活可能是有害的并导致癌症。有趣的是，这种 DNA 修复途径还通过促进与多种神经系统疾病相关的三核苷酸重复扩增而导致遗传不稳定。在这篇文章中，我们概述了人类 BER 通路的化学原理，重点关注启动修复事件的 DNA 糖基化酶。此外，我们描述了许多 BER 酶的动力学研究，作为理解这一高度调控事件期间发生的复杂协调的一种手段。最后，我们研究了与 BER 活动不足相关的陷阱，以及 BER 出错的情况。
Our cellular genome is continuously exposed to a wide spectrum of exogenous and endogenous DNA damaging agents. These agents can lead to formation of an extensive array of DNA lesions including single- and double-stranded breaks, inter- and intrastrand cross-links, abasic sites, and modification of DNA nucleobases. Persistence of these DNA lesions can be both mutagenic and cytotoxic, and can cause altered gene expression and cellular apoptosis leading to aging, cancer, and various neurological disorders. To combat the deleterious effects of DNA lesions, cells have a variety of DNA repair pathways responsible for restoring damaged DNA to its canonical form. Here we examine one of those repair pathways, the base excision repair (BER) pathway, a highly regulated network of enzymes responsible for repair of modified nucleobase and abasic site lesions. The enzymes required to reconstitute BER in vitro have been identified, and the repair event can be considered to occur in two parts: (1) excision of the modified nucleobase by a DNA glycosylase, and (2) filling the resulting “hole” with an undamaged nucleobase by a series of downstream enzymes. DNA glycosylases, which initiate a BER event, recognize and remove specific modified nucleobases and yield an abasic site as the product. The abasic site, a highly reactive BER intermediate, is further processed by AP endonuclease 1 (APE1), which cleaves the DNA backbone 5′ to the abasic site, generating a nick in the DNA backbone. After action of APE1, BER can follow one of two subpathways, the short-patch (SP) or long-patch (LP) version, which differ based on the number of nucleotides a polymerase incorporates at the nick site. DNA ligase is responsible for sealing the nick in the backbone and regenerating undamaged duplex. Not surprisingly, and consistent with the idea that BER maintains genetic stability, deficiency and/or inactivity of BER enzymes can be detrimental and result in cancer. Intriguingly, this DNA repair pathway has also been implicated in causing genetic instability by contributing to the trinucleotide repeat expansion associated with several neurological disorders. Within this Account, we outline the chemistry of the human BER pathway with a mechanistic focus on the DNA glycosylases that initiate the repair event. Furthermore, we describe kinetic studies of many BER enzymes as a means to understand the complex coordination that occurs during this highly regulated event. Finally, we examine the pitfalls associated with deficiency in BER activity, as well as instances when BER goes awry.
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影响因子：
5.7
作者：
Dalhus, Bjorn;Forsbring, Monika;Bjoras, Magnar
通讯作者：
Bjoras, Magnar
影响因子：
5.3
作者：
Fisher, Anna E. O.;Hochegger, Helfrid;Caldecott, Keith W.
通讯作者：
Caldecott, Keith W.
DOI：
10.1073/pnas.88.24.11450
发表时间：
1991-12-01
影响因子：
11.1
作者：
DEMPLE, B;HERMAN, T;CHEN, DS
通讯作者：
CHEN, DS
影响因子：
4.1
作者：
Ahn, JW;Kraynov, VS;Tsai, MD
通讯作者：
Tsai, MD
影响因子：
4.8
作者：
Fitzgerald, Megan E.;Drohat, Alexander C.
通讯作者：
Drohat, Alexander C.