Genome-wide TOP2A DNA cleavage is biased toward translocated and highly transcribed loci

TOP2A cleavage in genes involved in oncogenic translocations. (A, left) Larger proportions of genes containing CCRs in KMT2A recombinome compared with all coding genes. (**) P < 1 × 10⁻⁵ for DMSO, VP16, mitoxantrone; (*) P < 1 × 10⁻⁴ for pBQ, genistein; χ² test. (A, middle) Larger proportions of genes containing TOP2A DSBs in KMT2A recombinome compared with all coding genes. (*) P < 0.05 for DMSO, mitoxantrone, pBQ, genistein; (**) P = 0.00027375 for VP16; χ² test. (A, right) Larger proportions of cancer fusion genes (Mitelman et al. 2016) containing CCRs compared with all coding genes. (***) P < 2.2 × 10⁻¹⁶; χ² test. Amplified samples; same treatments merged where applicable (Supplemental Table S1). (B–E) CCR signals (HP10M) in individual amplified samples along regions of genes involved in leukemia-associated translocations linked to TOP2 poisons (bars). Panels show sonicated input and different treatments (top in panels). Gene models from GRCh38/hg38 in the UCSC Genome Browser (bottom) (Kent et al. 2002; http://genome.ucsc.edu/) correspond to tracks shown. (B) KMT2A. Bar, 8.3-kb bcr spanning exon 7 through exon 13 positions 118,481,830–118,490,167; NC_000011.10. (C) PML. Left bar, 1.45-kb intron 3 bcr, positions 74,023,409–74,024,856; right bar, 1.06-kb intron 6 bcr, positions 74,033,415–74,034,477; NC_000015.10. (D) RARA. Bar, 16.9-kb intron 2 bcr, positions 40,332,397–40,348,315; NC_000017.11. (E) RUNX1. Left bar, 25-kb intron 6 bcr, positions 34,859,473–34,834,602; right bar, 35-kb intron 7 bcr, positions 34,834,409–34,799,463; NC_000021.9.