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Landscape of TOP2A-mediated DNA cleavage across the human genome

ABSTRACT: Type II topoisomerases orchestrate proper DNA topology and they also are the targets of anticancer drugs that cause leukemias with balanced translocations as secondary cancers. Here, we develop a novel high-throughput sequencing technology to define TOP2 cleavage sites at single base precision in human cells and use the technology to characterize TOP2A cleavage genome-wide in the K562 leukemia cell line. We find that TOP2A cleavage has functionally conserved local sequence predilections, occurs in cleavage cluster regions (CCRs) and is enriched in introns and lincRNA loci. In coding genes we discover a bias of TOP2A CCRs towards the distal regions of gene bodies and proximal shifts in TOP2A CCRs with TOP2 poisons. We find high TOP2A cleavage levels in the genes involved in translocations associated with TOP2 poisons in leukemia. In addition, we find that large a 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. By making comparisons to ENCODE data, we uncover distinct TOP2A CCR clusters that overlap with marks of gene transcription, open chromatin and enhancers. Our findings implicate TOP2A as the DNA damage mediator in oncogenic translocations more broadly than was previously appreciated. They also identify TOP2A as a functional DNA element that contributes to the regulation of transcription elongation and gene activation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE79593 | GEO | 2017/03/08

SECONDARY ACCESSION(S): PRJNA316335

REPOSITORIES: GEO

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