Mechanism of chromosome rearrangement arising from single-strand breaks
Mechanism of chromosome rearrangement arising from single-strand breaks
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DOI：
10.1016/j.bbrc.2021.08.001
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发表时间：
2021-08-07
影响因子：
3.1
通讯作者：
Matsuda, Naoki
中科院分区：
文献类型：
--
作者：
Kot, Palina;Yasuhara, Takaaki;Matsuda, Naoki
染色体重排是人类癌症中常见的染色体结构异常，是由不同基因组区域发生的两个或多个 DNA 双链断裂之间的错误重新连接引起的。因此，染色体重排可以产生促进肿瘤发生的融合基因。已经使用外源双链断裂诱导剂（例如辐射和核酸酶）研究了染色体重排的机制。然而，在没有外源双链断裂诱导刺激的情况下染色体重排发生的机制尚不清楚。这项研究旨在确定染色体重排的主要来源以及抑制它们的 DNA 修复途径。使用癌症基因组图谱数据集筛选了可能抑制基因融合的 DNA 修复因子。总共鉴定出 22 个表达水平与基因融合频率呈负相关的修复因子。超过 60% 的这些修复因子参与同源重组，这是一种主要的双链断裂修复途径。我们假设DNA单链断裂是导致染色体重排的双链断裂的根源。这项研究表明，过氧化氢（H2O2）诱导的单链断裂以复制依赖性方式引起双链断裂。此外，H2O2诱导RPA和RAD51焦点的形成，这表明单链断裂衍生的双链断裂通过同源重组得到修复。此外，只有在同源重组因子（例如 BRCA1 和 CtIP）下调的情况下，H2O2 处理才能促进放射状染色体（一种染色体重排）的形成。因此，当同源重组因子的表达下调时，单链断裂是染色体重排的主要来源。 (C) 2021 Elsevier Inc. 保留所有权利。
Chromosome rearrangements, which are structural chromosomal abnormalities commonly found in human cancer, result from the misrejoining between two or more DNA double-strand breaks arising at different genomic regions. Consequently, chromosome rearrangements can generate fusion genes that promote tumorigenesis. The mechanisms of chromosome rearrangement have been studied using exogenous double-strand break inducers, such as radiation and nucleases. However, the mechanism underlying the occurrence of chromosome rearrangements in the absence of exogenous double-strand break-inducing stimuli is unclear. This study aimed to identify the major source of chromosome rearrangements and the DNA repair pathway that suppresses them. DNA repair factors that potentially suppress gene fusion were screened using The Cancer Genome Atlas dataset. In total, 22 repair factors whose expression levels were negatively correlated with the frequency of gene fusion were identified. More than 60% of these repair factors are involved in homologous recombination, a major double-strand break repair pathway. We hypothesized that DNA single-strand breaks are the source of double-strand breaks that lead to chromosome rearrangements. This study demonstrated that hydrogen peroxide (H2O2)-induced single-strand breaks gave rise to double-strand breaks in a replication-dependent manner. Additionally, H2O2 induced the formation of RPA and RAD51 foci, which indicated that double-strand breaks derived from single-strand breaks were repaired through homologous recombination. Moreover, treatment with H2O2 promoted the formation of radial chromosomes, a type of chromosome rearrangements, only upon the downregulation of homologous recombination factors, such as BRCA1 and CtIP. Thus, single-strand breaks are the major source of chromosome rearrangements when the expression of homologous recombination factors is downregulated. (C) 2021 Elsevier Inc. All rights reserved.