Roles of homologous recombination in response to ionizing radiation-induced DNA damage.
Roles of homologous recombination in response to ionizing radiation-induced DNA damage.
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DOI：
10.1080/09553002.2021.1956001
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发表时间：
2023
影响因子：
2.6
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中科院分区：
文献类型：
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电离辐射会引起大量 DNA 损伤，包括碱基损伤以及单链和双链断裂（SSB、DSB）。 DSB 是最具细胞毒性的病变之一，错误修复会导致小范围和大规模的基因组改变，从而导致癌变。事实上，电离辐射是一种“完全”的致癌物质。 DSB 在辐射后立即出现，称为“直接 DSB”，以及几个小时后以复制依赖性方式出现，称为“次级”或“复制依赖性 DSB”。复制叉崩溃产生的 DSB 是单端的，因此与双端的直接 DSB 相比，存在明显的问题。 DSB 通过易出错的非同源末端连接 (NHEJ) 或通常无错误的同源重组 (HR) 进行修复，每个重组都有子路径。阐明这些途径如何在正常细胞和肿瘤细胞中发挥作用对于增强肿瘤控制并最大限度地减少放射治疗期间的副作用至关重要。 NHEJ 和 HR 之间的选择受到细胞周期和其他因素的调节。 DSB 修复途径是电离辐射后细胞存活的主要因素，包括肿瘤对放疗的抵抗力。几种核酸酶对于 HR 介导的复制依赖性 DSB 修复以及复制叉重启非常重要。其中包括三种结构特异性核酸酶（3'MUS81 核酸酶）和两种 5' 核酸酶（EEPD1 和 Metnase），以及三种末端切除核酸酶（MRE11、EXO1 和 DNA2）。这三种结构特异性核酸酶在非常不同的时间进化，表明复制叉重新启动的加速逐渐加速，以限制有毒的HR中间体和基因组不稳定性，因为在进化过程中基因组大小增加，包括获得大量HR倾向的重复元件。电离辐射还会引起延迟效应，在暴露后数天至数周内观察到，包括延迟细胞死亡和延迟 HR。在这篇综述中，我们强调了 HR 在细胞对电离辐射反应中的作用，并讨论了 HR 作为癌症放射治疗可利用靶点的重要性。
Ionizing radiation induces a vast array of DNA lesions including base damage, and single- and double-strand breaks (SSB, DSB). DSBs are among the most cytotoxic lesions, and mis-repair causes small- and large-scale genome alterations that can contribute to carcinogenesis. Indeed, ionizing radiation is a ‘complete’ carcinogen. DSBs arise immediately after irradiation, termed ‘frank DSBs,’ as well as several hours later in a replication-dependent manner, termed ‘secondary’ or ‘replication-dependent DSBs. DSBs resulting from replication fork collapse are single-ended and thus pose a distinct problem from two-ended, frank DSBs. DSBs are repaired by error-prone non-homologous end-joining (NHEJ), or generally error-free homologous recombination (HR), each with sub-pathways. Clarifying how these pathways operate in normal and tumor cells is critical to increasing tumor control and minimizing side effects during radiotherapy. The choice between NHEJ and HR is regulated during the cell cycle and by other factors. DSB repair pathways are major contributors to cell survival after ionizing radiation, including tumor-resistance to radiotherapy. Several nucleases are important for HR-mediated repair of replication-dependent DSBs and thus replication fork restart. These include three structure-specific nucleases, the 3’ MUS81 nuclease, and two 5’ nucleases, EEPD1 and Metnase, as well as three end-resection nucleases, MRE11, EXO1, and DNA2. The three structure-specific nucleases evolved at very different times, suggesting incremental acceleration of replication fork restart to limit toxic HR intermediates and genome instability as genomes increased in size during evolution, including the gain of large numbers of HR-prone repetitive elements. Ionizing radiation also induces delayed effects, observed days to weeks after exposure, including delayed cell death and delayed HR. In this review we highlight the roles of HR in cellular responses to ionizing radiation, and discuss the importance of HR as an exploitable target for cancer radiotherapy.
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