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拓展DNA聚合酶底物的种类：DNA聚合酶β和λ通过模板指导掺入非核苷三磷酸类似物

Expanding the repertoire of DNA polymerase substrates: template-instructed incorporation of non-nucleoside triphosphate analogues by DNA polymerases beta and lambda.

作者信息

Crespan Emmanuele, Alexandrova Ludmila, Khandazhinskaya Anastasiya, Jasko Maxim, Kukhanova Marina, Villani Giuseppe, Hübscher Ulrich, Spadari Silvio, Maga Giovanni

机构信息

Istituto di Genetica Molecolare, IGM-CNR, via Abbiategrasso 207, I-27100 Pavia, Italy.

出版信息

Nucleic Acids Res. 2007;35(1):45-57. doi: 10.1093/nar/gkl1016. Epub 2006 Dec 5.

DOI:10.1093/nar/gkl1016
PMID:17148482
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1761426/
Abstract

We have recently shown that neither the base nor the sugar moieties of a nucleotide is an essential feature for its incorporation by DNA polymerases (pols) lambda and beta. Here we present the identification of novel non-nucleoside triphosphate (NNTP) derivatives belonging to three classes: (i) non-substrate-specific inhibitors of DNA pol lambda; (ii) substrate inhibitors which could preferentially be incorporated by either DNA pol lambda wild type or its Y505A mutant and (iii) the substrate inhibitor N-(Biphenylcarbonyl)-4-oxobutyl triphosphate which could be incorporated exclusively by DNA pol beta in a Mg2+-dependent manner, and preferentially pairs with A on the template. This compound represents the first example of a substrate lacking both nucleobase and ribose residue, showing distinct base-pairing properties with normal bases. Therefore, this NNTP analog can be considered as the prototype of an entirely novel class of DNA pol substrates.

摘要

我们最近发现，核苷酸的碱基和糖基部分都不是DNA聚合酶（pols）λ和β将其掺入的必要特征。在此，我们展示了属于三类的新型非核苷三磷酸（NNTP）衍生物的鉴定：（i）DNA pol λ的非底物特异性抑制剂；（ii）可被DNA pol λ野生型或其Y505A突变体优先掺入的底物抑制剂；以及（iii）底物抑制剂N-（联苯甲酰基）-4-氧代丁基三磷酸，其可仅以Mg2+依赖的方式被DNA pol β掺入，并优先与模板上的A配对。该化合物代表了第一个既缺乏核碱基又缺乏核糖残基的底物实例，显示出与正常碱基不同的碱基配对特性。因此，这种NNTP类似物可被视为一类全新的DNA pol底物的原型。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06e8/1802554/e6b193f505cf/gkl1016f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06e8/1802554/1c408d7f4b76/gkl1016f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06e8/1802554/8053befd017e/gkl1016f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06e8/1802554/438b6ec95e08/gkl1016f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06e8/1802554/d89c09085032/gkl1016f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06e8/1802554/a0d63885d7b2/gkl1016f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06e8/1802554/e6b193f505cf/gkl1016f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06e8/1802554/1c408d7f4b76/gkl1016f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06e8/1802554/8053befd017e/gkl1016f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06e8/1802554/438b6ec95e08/gkl1016f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06e8/1802554/d89c09085032/gkl1016f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06e8/1802554/a0d63885d7b2/gkl1016f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06e8/1802554/e6b193f505cf/gkl1016f6.jpg

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Human terminal deoxynucleotidyl transferases as novel targets for anticancer chemotherapy.人末端脱氧核苷酸转移酶作为抗癌化疗的新靶点。
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Human replication protein A can suppress the intrinsic in vitro mutator phenotype of human DNA polymerase lambda.
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DNA polymerase catalysis in the absence of Watson-Crick hydrogen bonds: analysis by single-turnover kinetics.无沃森-克里克氢键时的DNA聚合酶催化作用：单轮动力学分析
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A thymine isostere in the templating position disrupts assembly of the closed DNA polymerase beta ternary complex.模板位置上的胸腺嘧啶类似物会破坏封闭型DNA聚合酶β三元复合物的组装。
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