Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, 852-8523, Japan.
Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
Biochem Biophys Res Commun. 2021 Oct 1;572:191-196. doi: 10.1016/j.bbrc.2021.08.001. Epub 2021 Aug 4.
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 (HO)-induced single-strand breaks gave rise to double-strand breaks in a replication-dependent manner. Additionally, HO 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 HO 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.
染色体重排是人类癌症中常见的结构性染色体异常，源于两个或多个在不同基因组区域产生的 DNA 双链断裂的错误连接。因此，染色体重排可以产生融合基因，促进肿瘤发生。已经使用外源双链断裂诱导剂（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。本研究旨在确定染色体重排的主要来源和抑制它们的 DNA 修复途径。使用癌症基因组图谱数据集筛选潜在抑制基因融合的 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。这些修复因子中有超过 60%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来源。本研究表明，过氧化氢（HO）诱导的单链断裂以复制依赖性方式产生双链断裂。此外，HO 诱导了 RPA 和 RAD51 焦点的形成，这表明源自单链断裂的双链断裂通过同源重组修复。此外，只有在下调同源重组因子（如 BRCA1 和 CtIP）时，HO 处理才会促进径向染色体（一种染色体重排类型）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。
