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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Replication stress induces tumor-like microdeletions in FH/T/FRA3B
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Replication stress induces tumor-like microdeletions in FH/T/FRA3B

机译：复制应激在FH / T / FRA3B中诱导肿瘤样微缺失

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摘要

Common fragile sites (CFSs) are loci that preferentially exhibit meta-phase chromosome gaps and breaks after partial inhibition of DNA synthesis. The fragile site FRA3B, which lies within the FHIT tumor-suppressor gene, is a site of frequent heterozygous and homozygous deletions in many cancer cells and precancerous lesions. The great majority of FHIT and other CFS-associated gene rearrangements in tumors are submicroscopic, intralocus deletions of hundreds of kilo-bases that often result in inactivation of associated genes. Although CFS instability leads to chromosome gaps and breaks and transloca-tions, there has been no direct evidence showing that CFS instability or replication stress can generate large submicroscopic deletions of the type seen in cancer cells. Here, we have produced FHIT/FRA3B deletions closely resembling those in tumors by exposing human-mouse chromosome 3 somatic hybrid cells to aphidicolin-mediated replication stress. Clonal cell populations were analyzed for deletions by using PCR, array comparative genomic hybridization (aCGH), and FISH. Thirteen percent to 23% of clones exhibited submicroscopic FHIT deletions spanning =200-600 kb within FRA3B. Chromosomes with FRA3B deletions exhibited significantly decreased fragility of this locus, with a 2- to 12-fold reduction in metaphase gaps and breaks compared with controls. Sequence analysis showed no regions of homology at breakpoints and suggests involvement of NHEJ in generating the deletions. Our results demonstrate that replication stress induces a remarkably high frequency of tumor-like microdeletions that reduce fragility at a CFS in cultured cells and suggests that similar conditions during tumor formation lead to intralocus deletion and inactivation of genes at CFSs and perhaps elsewhere in the genome.
机译：常见的脆弱位点（CFS）是在局部抑制DNA合成后优先显示中期染色体缺口和断裂的位点。位于FHIT肿瘤抑制基因内的脆弱位点FRA3B是许多癌细胞和癌前病变中频繁杂合和纯合缺失的位点。肿瘤中绝大多数FHIT和其他与CFS相关的基因重排是亚显微的，成百上千个碱基的基因座内缺失，通常会导致相关基因失活。尽管CFS的不稳定性会导致染色体缺口，断裂和易位，但尚无直接证据表明CFS的不稳定性或复制压力会产生癌细胞中见到的亚显微缺失。在这里，我们通过将人类小鼠3号染色体的体细胞杂交细胞暴露于蚜虫素介导的复制压力下，产生了与肿瘤中的FHIT / FRA3B缺失非常相似的缺失。通过使用PCR，阵列比较基因组杂交（aCGH）和FISH分析克隆细胞群体的缺失。 13％到23％的克隆在FRA3B内显示了亚显微FHIT缺失，跨度= 200-600 kb。与对照相比，具有FRA3B缺失的染色体显示出该基因座的脆性显着降低，中期缺口和断裂减少了2到12倍。序列分析显示在断点处没有同源性区域，并提示NHEJ参与产生缺失。我们的研究结果表明，复制应激诱导了高频率的肿瘤样微缺失，降低了培养细胞在CFS处的脆弱性，并表明在肿瘤形成过程中类似的条件导致了位点内缺失以及CFS处以及基因组其他地方基因的失活。

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