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

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 fac...

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Autores principales: Atkin, Naomi D., Raimer, Heather M., Wang, Yuh-Hwa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826763/
https://www.ncbi.nlm.nih.gov/pubmed/31614754
http://dx.doi.org/10.3390/genes10100791
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author Atkin, Naomi D.
Raimer, Heather M.
Wang, Yuh-Hwa
author_facet Atkin, Naomi D.
Raimer, Heather M.
Wang, Yuh-Hwa
author_sort Atkin, Naomi D.
collection PubMed
description 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.
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spelling pubmed-68267632019-11-18 Broken by the Cut: A Journey into the Role of Topoisomerase II in DNA Fragility Atkin, Naomi D. Raimer, Heather M. Wang, Yuh-Hwa Genes (Basel) Review 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. MDPI 2019-10-12 /pmc/articles/PMC6826763/ /pubmed/31614754 http://dx.doi.org/10.3390/genes10100791 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Atkin, Naomi D.
Raimer, Heather M.
Wang, Yuh-Hwa
Broken by the Cut: A Journey into the Role of Topoisomerase II in DNA Fragility
title Broken by the Cut: A Journey into the Role of Topoisomerase II in DNA Fragility
title_full Broken by the Cut: A Journey into the Role of Topoisomerase II in DNA Fragility
title_fullStr Broken by the Cut: A Journey into the Role of Topoisomerase II in DNA Fragility
title_full_unstemmed Broken by the Cut: A Journey into the Role of Topoisomerase II in DNA Fragility
title_short Broken by the Cut: A Journey into the Role of Topoisomerase II in DNA Fragility
title_sort broken by the cut: a journey into the role of topoisomerase ii in dna fragility
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826763/
https://www.ncbi.nlm.nih.gov/pubmed/31614754
http://dx.doi.org/10.3390/genes10100791
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