Translocation and deletion breakpoints in cancer genomes are associated with potential non-B DNA-forming sequences.
Translocation and deletion breakpoints in cancer genomes are associated with potential non-B DNA-forming sequences.
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DOI：
10.1093/nar/gkw261
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发表时间：
2016-07-08
影响因子：
14.9
通讯作者：
Cooper DN
中科院分区：
文献类型：
--
作者：
Bacolla A;Tainer JA;Vasquez KM;Cooper DN
总染色体重排（包括易位、缺失、插入和重复）是癌症基因组的标志，通常会产生致癌融合基因。产生这种总重排的一个必要步骤是形成DNA双链断裂（DSB）。由于重排断裂点的基因组分布是非随机的，内在细胞因素可能使某些基因组区域易于断裂。值得注意的是，某些具有折叠成二级结构潜力的DNA序列[潜在的非B DNA结构（PONDS）;例如三链体、四链体、发夹/十字形、Z-DNA和单链环出结构，其在DNA复制和转录中具有意义]可以刺激DNA DSB的形成。在这里，我们测试的假设，这些DNA序列可能会发现，或在附近，重排断点。通过分析癌症基因组中19 947个易位和46 365个序列特征性缺失断点±500个碱基范围内的PONDS形成序列的分布，发现PONDS形成重复序列与癌症断点之间存在显著相关性。具体而言，（AT）n，（GAA）n和（GAAA）n构成最常见的重复易位断点，而A-tracts发生优先删除断点。在不同的个体和患者肿瘤样本中，PONDS形成重复序列附近的易位断点也会复发。因此，PONDS形成序列代表了癌症基因组中基因组重排的内在风险因素。
Gross chromosomal rearrangements (including translocations, deletions, insertions and duplications) are a hallmark of cancer genomes and often create oncogenic fusion genes. An obligate step in the generation of such gross rearrangements is the formation of DNA double-strand breaks (DSBs). Since the genomic distribution of rearrangement breakpoints is non-random, intrinsic cellular factors may predispose certain genomic regions to breakage. Notably, certain DNA sequences with the potential to fold into secondary structures [potential non-B DNA structures (PONDS); e.g. triplexes, quadruplexes, hairpin/cruciforms, Z-DNA and single-stranded looped-out structures with implications in DNA replication and transcription] can stimulate the formation of DNA DSBs. Here, we tested the postulate that these DNA sequences might be found at, or in close proximity to, rearrangement breakpoints. By analyzing the distribution of PONDS-forming sequences within ±500 bases of 19 947 translocation and 46 365 sequence-characterized deletion breakpoints in cancer genomes, we find significant association between PONDS-forming repeats and cancer breakpoints. Specifically, (AT)n, (GAA)n and (GAAA)n constitute the most frequent repeats at translocation breakpoints, whereas A-tracts occur preferentially at deletion breakpoints. Translocation breakpoints near PONDS-forming repeats also recur in different individuals and patient tumor samples. Hence, PONDS-forming sequences represent an intrinsic risk factor for genomic rearrangements in cancer genomes.