Date of this Version
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.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
Yu, X., Davenport, J. W., Urtishak, K. A., Carillo, M. L., Gosai, S. J., Kolaris, C. P., Byl, J. W., Rappaport, E. F., Osheroff, N., Gregory, B. D., & Felix, C. A. (2017). Genome-Wide TOP2A DNA Cleavage is Biased Toward Translocated and Highly Transcribed Loci. Genome Research, 27 (7), 1238-1249. http://dx.doi.org/10.1101/gr.211615.116
Additional FilesSupplemental_Methods_Genome-wide TOP2A DNA cleavage.docx (127 kB)
Supplemental_Table_S1_Genome-wide TOP2A DNA cleavage.docx (34 kB)
Supplemental_Table_S2_Genome-wide TOP2A DNA cleavage.docx (42 kB)
Supplemental_Table_S3_Genome-wide TOP2A DNA cleavage.docx (38 kB)
Supplemental_Table_S4_Genome-wide TOP2A DNA cleavage.docx (33 kB)
Supplemental_Fig_S1_Genome-wide TOP2A DNA cleavage.pdf (717 kB)
Supplemental_Fig_S2_Genome-wide TOP2A DNa cleavage.pdf (2111 kB)
Supplemental_Fig_S3_Genome-wide TOP2A DNA cleavage.pdf (8595 kB)
Supplemental_Fig_S4_Genome-wide TOP2A DNA cleavage.pdf (10372 kB)
Supplemental_Fig_S5_Genome-wide TOP2A DNA cleavage.pdf (417 kB)
Supplemental_Fig_S6_Genome-wide TOP2A DNA cleavage.pdf (406 kB)
Supplemental_Fig_S7_Genome-wide TOP2A DNA cleavage.pdf (451 kB)
Supplemental_Fig_S8_Genome-wide TOP2A DNA cleavage.pdf (373 kB)
Supplemental_Fig_S9_Genome-wide TOP2A DNA cleavage.pdf (1340 kB)
Supplemental_Fig_S10_Genome-wide TOP2A DNA cleavage.pdf (392 kB)
Date Posted: 14 July 2017
This document has been peer reviewed.