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

Mol Cell. 2019 Jul 25;75(2):267-283.e12. doi: 10.1016/j.molcel.2019.05.015. Epub 2019 Jun 12.


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.

Keywords: DNA topology; MLL; TOP2; cancer; chromosome breaks; chromosome organization; chromosome translocations; supercoiling; topoisomerases; torsional stress; transcription.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CCCTC-Binding Factor / genetics
  • Carcinogenesis / genetics
  • Cell Line, Tumor
  • Chromatin / chemistry
  • Chromatin / genetics
  • Chromosomes / chemistry
  • Chromosomes / genetics
  • DNA / genetics
  • DNA Breaks, Double-Stranded
  • DNA Topoisomerases, Type II / genetics*
  • Genomic Instability / genetics*
  • Histone-Lysine N-Methyltransferase / genetics*
  • Humans
  • Leukemia / genetics
  • Leukemia / pathology
  • Myeloid-Lymphoid Leukemia Protein / genetics*
  • Poly-ADP-Ribose Binding Proteins / genetics*
  • Translocation, Genetic / genetics*


  • CCCTC-Binding Factor
  • CTCF protein, human
  • Chromatin
  • KMT2A protein, human
  • Poly-ADP-Ribose Binding Proteins
  • Myeloid-Lymphoid Leukemia Protein
  • DNA
  • Histone-Lysine N-Methyltransferase
  • DNA Topoisomerases, Type II
  • TOP2A protein, human