Spatial chromosome folding and active transcription drive DNA fragility and formation of oncogenic MLL translocations
Henrike Johanna Gothe,
Britta Annika Maria Bouwman,
Eduardo Gade Gusmao,
Christian Friberg Nielsen,
Damien Francis Hudson,
Posted 03 Dec 2018
bioRxiv DOI: 10.1101/485763 (published DOI: 10.1016/j.molcel.2019.05.015)
Posted 03 Dec 2018
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 CTCF/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 hot spots 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.
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