依赖于 RAD18 和 BRCA1 的途径可促进细胞对核苷类似物更昔洛韦的耐受性。

IF 16.4 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Tasnim Ahmad, Ryotaro Kawasumi, Kouji Hirota
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引用次数: 0

摘要

更昔洛韦(GCV)是一种重要的临床药物,用于治疗病毒感染。GCV 在复制过程中被整合到 DNA 中,干扰整合了 GCV 的模板的后续复制。然而,GCV 对宿主基因组的影响以及细胞耐受 GCV 的机制仍不清楚。在本研究中,我们利用一系列突变的 DT40 细胞探索了这些机制。我们发现 RAD17/-、BRCA1-/- 和 RAD18-/- 细胞对 GCV 高度敏感。RAD17是替代检查点钳夹加载器RAD17-RFC的一个组成部分,它是GCV处理后激活S内检查点所必需的。BRCA1是促进同源重组(HR)的关键因子,需要它来抑制DNA双链断裂(DSB)。此外,参与 DNA 修复的 E3 连接酶 RAD18 在抑制 GCV 引起的断裂染色体异常连接方面也至关重要。我们发现,BRCA1 通过 HR 介导的修复和模板转换(TS)介导的损伤旁路来抑制 DSB。此外,尽管作为 HR 标志的姐妹染色单体交换事件仅部分恢复,但 53BP1 的缺失可挽救 BRCA1-/- 细胞对 GCV 的强烈敏感性。这些结果表明,BRCA1 通过两种机制(TS 和 HR 介导的修复)促进细胞对 GCV 的耐受性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
RAD18- and BRCA1-dependent pathways promote cellular tolerance to the nucleoside analog ganciclovir

Ganciclovir (GCV) is a clinically important drug as it is used to treat viral infections. GCV is incorporated into the DNA during replication, where it interferes with subsequent replication on GCV-incorporated templates. However, the effects of GCV on the host genome and the mechanisms underlying cellular tolerance to GCV remain unclear. In this study, we explored these mechanisms using a collection of mutant DT40 cells. We identified RAD17/−, BRCA1−/−, and RAD18−/− cells as highly GCV-sensitive. RAD17, a component of the alternative checkpoint-clamp loader RAD17-RFC, was required for the activation of the intra-S checkpoint following GCV treatment. BRCA1, a critical factor for promoting homologous recombination (HR), was required for suppressing DNA double-strand breaks (DSBs). Moreover, RAD18, an E3-ligase involved in DNA repair, was critical in suppressing the aberrant ligation of broken chromosomes caused by GCV. We found that BRCA1 suppresses DSBs through HR-mediated repair and template switching (TS)-mediated damage bypass. Moreover, the strong GCV sensitivity of BRCA1−/− cells was rescued by the loss of 53BP1, despite the only partial restoration in the sister chromatid exchange events which are hallmarks of HR. These results indicate that BRCA1 promotes cellular tolerance to GCV through two mechanisms, TS and HR-mediated repair.

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来源期刊
Accounts of Chemical Research
Accounts of Chemical Research 化学-化学综合
CiteScore
31.40
自引率
1.10%
发文量
312
审稿时长
2 months
期刊介绍: Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.
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