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人酪氨酰-DNA磷酸二酯酶1对DNA 3'末端加工的结构基础

Structural basis for DNA 3'-end processing by human tyrosyl-DNA phosphodiesterase 1.

作者信息

Flett Fiona J, Ruksenaite Emilija, Armstrong Lee A, Bharati Shipra, Carloni Roberta, Morris Elizabeth R, Mackay C Logan, Interthal Heidrun, Richardson Julia M

机构信息

Institute of Cell Biology, School of Biological Sciences, University of Edinburgh, The King's Buildings, Roger Land Building, Alexander Crum Brown Road, Edinburgh, EH9 3FF, UK.

Institute of Quantitative Biology, Biochemistry and Biotechnology, School of Biological Sciences, University of Edinburgh, The King's Buildings, Max Born Crescent, Edinburgh, EH9 3BF, UK.

出版信息

Nat Commun. 2018 Jan 2;9(1):24. doi: 10.1038/s41467-017-02530-z.

DOI:10.1038/s41467-017-02530-z
PMID:29295983
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5750209/
Abstract

Tyrosyl-DNA phosphodiesterase (Tdp1) is a DNA 3'-end processing enzyme that repairs topoisomerase 1B-induced DNA damage. We use a new tool combining site-specific DNA-protein cross-linking with mass spectrometry to identify Tdp1 interactions with DNA. A conserved phenylalanine (F259) of Tdp1, required for efficient DNA processing in biochemical assays, cross-links to defined positions in DNA substrates. Crystal structures of Tdp1-DNA complexes capture the DNA repair machinery after 3'-end cleavage; these reveal how Tdp1 coordinates the 3'-phosphorylated product of nucleosidase activity and accommodates duplex DNA. A hydrophobic wedge splits the DNA ends, directing the scissile strand through a channel towards the active site. The F259 side-chain stacks against the -3 base pair, delimiting the junction of duplexed and melted DNA, and fixes the scissile strand in the channel. Our results explain why Tdp1 cleavage is non-processive and provide a molecular basis for DNA 3'-end processing by Tdp1.

摘要

酪氨酰-DNA磷酸二酯酶（Tdp1）是一种DNA 3'末端加工酶，可修复拓扑异构酶1B诱导的DNA损伤。我们使用一种将位点特异性DNA-蛋白质交联与质谱相结合的新工具来鉴定Tdp1与DNA的相互作用。Tdp1的一个保守苯丙氨酸（F259）在生化分析中对高效DNA加工是必需的，它与DNA底物中的特定位置发生交联。Tdp1-DNA复合物的晶体结构捕获了3'末端切割后的DNA修复机制；这些结构揭示了Tdp1如何协调核苷酶活性的3'-磷酸化产物并容纳双链DNA。一个疏水楔将DNA末端分开，引导可切割链通过一个通道朝向活性位点。F259侧链堆积在-3碱基对上，界定双链和熔解DNA的交界处，并将可切割链固定在通道中。我们的结果解释了为什么Tdp1切割是非连续性的，并为Tdp1进行DNA 3'末端加工提供了分子基础。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/249b/5750209/1fb60c0b13f6/41467_2017_2530_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/249b/5750209/fe4939c756ce/41467_2017_2530_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/249b/5750209/746bdb0e7cd3/41467_2017_2530_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/249b/5750209/462b741fa5ac/41467_2017_2530_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/249b/5750209/cd119e724c65/41467_2017_2530_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/249b/5750209/168e6d72a018/41467_2017_2530_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/249b/5750209/b0f1635c0450/41467_2017_2530_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/249b/5750209/ecf20662af8a/41467_2017_2530_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/249b/5750209/1fb60c0b13f6/41467_2017_2530_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/249b/5750209/fe4939c756ce/41467_2017_2530_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/249b/5750209/746bdb0e7cd3/41467_2017_2530_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/249b/5750209/462b741fa5ac/41467_2017_2530_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/249b/5750209/cd119e724c65/41467_2017_2530_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/249b/5750209/168e6d72a018/41467_2017_2530_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/249b/5750209/b0f1635c0450/41467_2017_2530_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/249b/5750209/ecf20662af8a/41467_2017_2530_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/249b/5750209/1fb60c0b13f6/41467_2017_2530_Fig8_HTML.jpg

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