Genome-wide TOP2A DNA cleavage is biased toward translocated and highly transcribed loci.
Genome-wide TOP2A DNA cleavage is biased toward translocated and highly transcribed loci.
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DOI：
10.1101/gr.211615.116
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发表时间：
2017-07
期刊：
影响因子：
7
通讯作者：
Felix CA
中科院分区：
文献类型：
--
作者：
Yu X;Davenport JW;Urtishak KA;Carillo ML;Gosai SJ;Kolaris CP;Byl JAW;Rappaport EF;Osheroff N;Gregory BD;Felix CA
II型拓扑异构酶协调适当的DNA拓扑结构，并且它们是抗癌药物的靶点，这些抗癌药物导致具有平衡易位的治疗相关的白血病。在这里，我们开发了一种高通量测序技术，以单碱基精度定义TOP2切割位点，并使用该技术来表征人K562白血病细胞系中的TOP2A切割全基因组。我们发现，TOP2A切割具有功能保守的局部序列偏好，发生在切割簇区域（CCR），并富含内含子和lincRNA位点。TOP2A CCR偏向于基因体的远端区域，TOP2毒物导致其分布的近端移位。我们在TOP2中毒相关白血病中发现了参与易位的基因中的高TOP2A切割水平。此外，我们发现大部分参与致癌易位的基因都含有TOP2A CCR。编码和lincRNA基因的TOP2A切割独立地与长度和转录物丰度两者相关。与ENCODE数据的比较揭示了与转录标记、开放染色质和增强子重叠的不同TOP2A CCR簇。我们的研究结果表明，TOP2A切割作为一个广泛的DNA损伤机制，在致癌易位，以及功能作用的TOP2A切割调节转录延伸和基因激活。
Type II topoisomerases orchestrate proper DNA topology, and they are the targets of anti-cancer drugs that cause treatment-related leukemias with balanced translocations. Here, we develop a high-throughput sequencing technology to define TOP2 cleavage sites at single-base precision, and use the technology to characterize TOP2A cleavage genome-wide in the human K562 leukemia cell line. We find that TOP2A cleavage has functionally conserved local sequence preferences, occurs in cleavage cluster regions (CCRs), and is enriched in introns and lincRNA loci. TOP2A CCRs are biased toward the distal regions of gene bodies, and TOP2 poisons cause a proximal shift in their distribution. We find high TOP2A cleavage levels in genes involved in translocations in TOP2 poison–related leukemia. In addition, we find that a large proportion of genes involved in oncogenic translocations overall contain TOP2A CCRs. The TOP2A cleavage of coding and lincRNA genes is independently associated with both length and transcript abundance. Comparisons to ENCODE data reveal distinct TOP2A CCR clusters that overlap with marks of transcription, open chromatin, and enhancers. Our findings implicate TOP2A cleavage as a broad DNA damage mechanism in oncogenic translocations as well as a functional role of TOP2A cleavage in regulating transcription elongation and gene activation.