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人类 OGG1 在核小体核心颗粒中处理 8-oxodGuo 的结构基础。

Structural basis for human OGG1 processing 8-oxodGuo within nucleosome core particles.

机构信息

School of Chemistry, Tiangong University, Tianjin, 300387, China.

Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, 81377, Germany.

出版信息

Nat Commun. 2024 Oct 31;15(1):9407. doi: 10.1038/s41467-024-53811-3.

DOI:10.1038/s41467-024-53811-3
PMID:39477986
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11526172/
Abstract

Base excision repair (BER) is initialized by DNA glycosylases, which recognize and flip damaged bases out of the DNA duplex into the enzymes active site, followed by cleavage of the glycosidic bond. Recent studies have revealed that all types of DNA glycosylases repair base lesions less efficiently within nucleosomes, and their repair activity is highly depended on the lesion's location within the nucleosome. To reveal the underlying molecular mechanism of this phenomenon, we determine the 3.1 Å cryo-EM structure of human 8-oxoguanine-DNA glycosylase 1 (hOGG1) bound to a nucleosome core particle (NCP) containing a common oxidative base lesion, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo). Our structural analysis shows that hOGG1 can recognize and flip 8-oxodGuo even within NCPs; however, the interaction between 8-oxodGuo and hOGG1 in a NCP context is weaker than in free DNA due to competition for nucleosomal DNA by the histones. Binding of OGG1 and the flipping of 8-oxodGuo by hOGG1 leads to a partial detachment of DNA from the histone core and a ratchet-like inward movement of nucleosomal DNA. Our findings provide insights into how the dynamic structure of nucleosomes modulate the activity of repair enzymes within chromatin.

摘要

碱基切除修复 (BER) 由 DNA 糖苷酶起始，该酶识别并将受损碱基从 DNA 双链体中翻转到酶的活性部位，随后糖苷键被切断。最近的研究表明，所有类型的 DNA 糖苷酶在核小体中修复碱基损伤的效率都较低，其修复活性高度依赖于损伤在核小体中的位置。为了揭示这一现象的潜在分子机制，我们确定了与人 8-氧鸟嘌呤-DNA 糖苷酶 1 (hOGG1) 结合的核小体核心颗粒 (NCP) 的 3.1 Å 冷冻电镜结构，其中包含常见的氧化碱基损伤 8-氧代-7,8-二氢-2'-脱氧鸟苷 (8-oxodGuo)。我们的结构分析表明，hOGG1 即使在 NCP 中也可以识别并翻转 8-oxodGuo；然而，由于组蛋白对核小体 DNA 的竞争，8-oxodGuo 与 hOGG1 之间在 NCP 环境中的相互作用比在游离 DNA 中弱。OGG1 的结合和 hOGG1 对 8-oxodGuo 的翻转导致 DNA 与核小体核心的部分分离以及核小体 DNA 的棘轮样向内运动。我们的发现提供了关于核小体的动态结构如何调节染色质中修复酶活性的见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b17/11526172/4649104baead/41467_2024_53811_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b17/11526172/0c1990035c8e/41467_2024_53811_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b17/11526172/e9658f869e9f/41467_2024_53811_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b17/11526172/e70ca09e3d0d/41467_2024_53811_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b17/11526172/8520e49fd5ea/41467_2024_53811_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b17/11526172/4649104baead/41467_2024_53811_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b17/11526172/0c1990035c8e/41467_2024_53811_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b17/11526172/e9658f869e9f/41467_2024_53811_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b17/11526172/e70ca09e3d0d/41467_2024_53811_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b17/11526172/8520e49fd5ea/41467_2024_53811_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b17/11526172/4649104baead/41467_2024_53811_Fig5_HTML.jpg

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