Genome organization drives chromosome fragility
Jul. 9, 2018 16:00 - 17:00
DB Bldg. SeminarRoom A7F
National Cancer Institute, USA National Institutes of Health Laboratory of Genome Integrity Research Fellow in the group of Dr. Andre Nussenzweig
The folding and organization of DNA within the nucleus produces torsional stress resulting in DNA entanglements. Using a methodology to map in the genome DNA double strand breaks (DSBs) generated by the activity of Topoisomerase 2, we find that Topoisomerase 2B (TOP2B) releases torsional stress specifically at chromosome loop anchors, bound by CCCTC-binding factor (CTCF) and cohesin. We also observe that TOP2-induced DSBs occurred in the same DNA regions that typically undergo chromosomal translocations in cancer. Thus, TOP2B activity relieves torsional stress in the DNA during genome organization, but paradoxically makes chromatin loop anchors vulnerable target regions in oncogenic translocations. Additionally, these Top2B-mediated DSBs are largely transcription-, replication and cell-type-independent. Our studies demonstrate that polymorphisms between two different mice species that change CTCF, cohesin occupancy and loop formation also re-localize TOP2B-induced DSBs. In conclusion, loop anchors serve as fragile sites that generate DSBs and chromosomal rearrangements.