Abstract

Purpose

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.

Conclusions

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.

中文翻译：

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同源重组在响应电离辐射诱导的 DNA 损伤中的作用

摘要

目的

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 是最具细胞毒性的损伤之一，错误修复会导致小规模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”致癌物。DSB 在照射后立即出现，称为“坦率 DSB”，以及几个小时后以复制依赖的方式出现，称为“次级”或“复制依赖的 DSB”。复制叉崩溃导致的 DSB 是单端的，因此与两端的直接 DSB 相比会产生明显的问题。DSB 通过容易出错的非同源末端连接 (NHEJ) 或通常无差错的同源重组 (HR) 修复，每个都有子路径。

结论

NHEJ 和 HR 之间的选择在细胞周期和其他因素中受到调节。DSB 修复途径是电离辐射后细胞存活的主要贡献者，包括肿瘤对放射治疗的抗性。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很重要。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。三种结构特异性核酸酶在非常不同的时间进化，表明随着基因组在进化过程中大小的增加，复制叉重新启动的增量加速以限制有毒的 HR 中间体和基因组不稳定性，包括获得大量 HR 倾向的重复元素。电离辐射还会引起延迟效应，在暴露数天至数周后观察到，包括延迟细胞死亡和延迟 HR。在这篇综述中，我们强调了 HR 在细胞对电离辐射的反应中的作用，并讨论了 HR 作为癌症放射治疗可开发靶点的重要性。