Spatial Chromosome Folding and Active Transcription Drive DNA Fragility and Formation of Oncogenic MLL Translocations.

How spatial chromosome organization influences genome integrity is still poorly understood. Here, we show that DNA double-strand breaks (DSBs) mediated by topoisomerase 2 (TOP2) activities are enriched at chromatin loop anchors with high transcriptional activity. Recurrent DSBs occur at CCCTC-binding factor (CTCF) and cohesin-bound sites at the bases of chromatin loops, and their frequency positively correlates with transcriptional output and directionality. The physiological relevance of this preferential positioning is indicated by the finding that genes recurrently translocating to drive leukemias are highly transcribed and are enriched at loop anchors. These genes accumulate DSBs at recurrent hotspots that give rise to chromosomal fusions relying on the activity of both TOP2 isoforms and on transcriptional elongation. We propose that transcription and 3D chromosome folding jointly pose a threat to genomic stability and are key contributors to the occurrence of genome rearrangements that drive cancer. • TOP2-mediated DNA fragility is linked to transcription and proximity to loop anchors • Loop-anchor DNA fragility correlates with transcriptional activity and directionality • Genes forming oncogenic fusions are highly transcribed and enriched at loop anchors • Formation of MLL fusions relies on the activities of both TOP2 isoforms Gothe et al. show that DNA double-strand breaks (DSBs) mediated by incomplete topoisomerase 2 activities are enriched within highly transcribed genes located proximal to chromatin loop anchors. Genes recurrently translocating to drive leukemias are highly transcribed, are localized proximal to loop boundaries, and form chromosome fusions in a transcription-dependent manner. [ABSTRACT FROM AUTHOR]