Chromosome Loop Anchors Are Susceptible to DNA Double-Strand Breaks

The type II topoisomerase TOP2B is expressed throughout the cell cycle and induces transient DNA double-strand breaks (DSB) to dissipate torsional stress especially at sites of transcription, but when these DSBs are not faithfully re-ligated, genomic rearrangements can occur. Further, treatment with the TOP2 inhibitor etoposide is associated with development of therapy-related acute myeloid leukemia (t-AML), which often harbors genomic rearrangements associated with translocations in breakpoint cluster regions (BCR). Thus, Canela, Maman, and colleagues sought to uncover the link between TOP2B and oncogenic translocations. Etoposide treatment induced DNA breaks at common BCRs, including MLL, NUP98, and TMPRSS2, and these sites showed DNase I hypersensitivity and were enriched for occupancy of TOP2B and CTCF, which binds to chromosome “loop anchors” in long-distance DNA loops. Moreover, spontaneous DSBs occurred at many of the same BCRs, albeit at a lower frequency than after etoposide treatment. TOP2B was required for etoposide-induced double-strand breaks, and its activity was higher at active promoters and enhancers and largely independent of transcription. DSBs were enriched at loop anchors, and TOP2B-associated DSBs were able to predict the positions of CTCF-anchored loops. Introduction of single-nucleotide variations in the CTCF binding sites disrupted DSBs and resulted in DSBs at different sites. Collectively, these findings demonstrate that CTCF-bound loop anchors are more susceptible to TOP2B-induced DSBs, thereby creating fragile sites that become hotspots for chromosomal translocations in cancer. Further, these findings shed light on the origin of etoposide-induced secondary cancers.

Canela A, Maman Y, Jung S, Wong N, Callen E, Day A, et al. Genome organization drives chromosome fragility. Cell 2017;170:507–21.e18.

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