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Broken by the Cut: A Journey into the Role of Topoisomerase II in DNA Fragility

Department of Biochemistry and Molecular Genetics, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA
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Genes 2019, 10(10), 791; https://doi.org/10.3390/genes10100791
Received: 14 September 2019 / Revised: 5 October 2019 / Accepted: 10 October 2019 / Published: 12 October 2019
(This article belongs to the Special Issue DNA Topoisomerases in Biology and Medicine)
DNA topoisomerase II (TOP2) plays a critical role in many processes such as replication and transcription, where it resolves DNA structures and relieves torsional stress. Recent evidence demonstrated the association of TOP2 with topologically associated domains (TAD) boundaries and CCCTC-binding factor (CTCF) binding sites. At these sites, TOP2 promotes interactions between enhancers and gene promoters, and relieves torsional stress that accumulates at these physical barriers. Interestingly, in executing its enzymatic function, TOP2 contributes to DNA fragility through re-ligation failure, which results in persistent DNA breaks when unrepaired or illegitimately repaired. Here, we discuss the biological processes for which TOP2 is required and the steps at which it can introduce DNA breaks. We describe the repair processes that follow removal of TOP2 adducts and the resultant broken DNA ends, and present how these processes can contribute to disease-associated mutations. Furthermore, we examine the involvement of TOP2-induced breaks in the formation of oncogenic translocations of leukemia and papillary thyroid cancer, as well as the role of TOP2 and proteins which repair TOP2 adducts in other diseases. The participation of TOP2 in generating persistent DNA breaks and leading to diseases such as cancer, could have an impact on disease treatment and prevention. View Full-Text
Keywords: DNA topoisomerases; DNA fragility; chromatin organization; TOP2 cleavage complex; topoisomerases and disease; DNA repair DNA topoisomerases; DNA fragility; chromatin organization; TOP2 cleavage complex; topoisomerases and disease; DNA repair
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Atkin, N.D.; Raimer, H.M.; Wang, Y.-H. Broken by the Cut: A Journey into the Role of Topoisomerase II in DNA Fragility. Genes 2019, 10, 791.

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