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OGG1 的小分子抑制剂可阻断端粒处的氧化 DNA 损伤修复，并增强甲氨蝶呤的抗癌作用。

Small molecule inhibitor of OGG1 blocks oxidative DNA damage repair at telomeres and potentiates methotrexate anticancer effects.

机构信息

Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), 28029, Madrid, Spain.

Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, 17121, Solna, Sweden.

出版信息

Sci Rep. 2021 Feb 10;11(1):3490. doi: 10.1038/s41598-021-82917-7.

DOI:10.1038/s41598-021-82917-7
PMID:33568707
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7876102/
Abstract

The most common oxidative DNA lesion is 8-oxoguanine which is mainly recognized and excised by the 8-oxoG DNA glycosylase 1 (OGG1), initiating the base excision repair (BER) pathway. Telomeres are particularly sensitive to oxidative stress (OS) which disrupts telomere homeostasis triggering genome instability. In the present study, we have investigated the effects of inactivating BER in OS conditions, by using a specific inhibitor of OGG1 (TH5487). We have found that in OS conditions, TH5487 blocks BER initiation at telomeres causing an accumulation of oxidized bases, that is correlated with telomere losses, micronuclei formation and mild proliferation defects. Moreover, the antimetabolite methotrexate synergizes with TH5487 through induction of intracellular reactive oxygen species (ROS) formation, which potentiates TH5487-mediated telomere and genome instability. Our findings demonstrate that OGG1 is required to protect telomeres from OS and present OGG1 inhibitors as a tool to induce oxidative DNA damage at telomeres, with the potential for developing new combination therapies for cancer treatment.

摘要

最常见的氧化 DNA 损伤是 8-氧鸟嘌呤，它主要被 8-氧鸟嘌呤 DNA 糖基化酶 1（OGG1）识别和切除，启动碱基切除修复（BER）途径。端粒对氧化应激（OS）特别敏感，OS 会破坏端粒稳态，引发基因组不稳定。在本研究中，我们通过使用 OGG1 的特异性抑制剂（TH5487）研究了在 OS 条件下失活 BER 的影响。我们发现，在 OS 条件下，TH5487 阻断了端粒处的 BER 起始，导致氧化碱基的积累，这与端粒丢失、微核形成和轻微的增殖缺陷相关。此外，代谢抑制剂甲氨蝶呤通过诱导细胞内活性氧（ROS）的形成与 TH5487 协同作用，增强了 TH5487 介导的端粒和基因组不稳定性。我们的研究结果表明，OGG1 是保护端粒免受 OS 的必需因子，并提示 OGG1 抑制剂可作为在端粒处诱导氧化 DNA 损伤的工具，为开发新的癌症治疗联合疗法提供了潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f105/7876102/f060f07ddb51/41598_2021_82917_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f105/7876102/4eaac8bf2ed2/41598_2021_82917_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f105/7876102/d37fe24d92f7/41598_2021_82917_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f105/7876102/f060f07ddb51/41598_2021_82917_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f105/7876102/4eaac8bf2ed2/41598_2021_82917_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f105/7876102/98a6e916728d/41598_2021_82917_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f105/7876102/87b93c358379/41598_2021_82917_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f105/7876102/d37fe24d92f7/41598_2021_82917_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f105/7876102/f060f07ddb51/41598_2021_82917_Fig5_HTML.jpg

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