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Article

High Temperature Drives Topoisomerase Mediated Chromosomal Break Repair Pathway Choice

1
Center for Genomics, Helmy Institute for Medical Science, Zewail City of Science and Technology, Giza 12578, Egypt
2
Proteomics and Metabolomics Research Program, Children Cancer Hospital (CCHE 57357), Cairo 11441, Egypt
3
Physiology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt
4
Biotechnology Program, Biology Department, Faculty of Science, Port Said University, Port Said 42522, Egypt
5
The Healthy Lifespan and the Neuroscience Institutes, University of Sheffield, South Yorkshire, Sheffield S10 2TN, UK
6
The Institute of Cancer Therapeutics, University of Bradford, West Yorkshire BD7 1DP, UK
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Godefridus J. Peters
Cancers 2021, 13(10), 2315; https://doi.org/10.3390/cancers13102315
Received: 21 March 2021 / Revised: 5 May 2021 / Accepted: 7 May 2021 / Published: 12 May 2021
(This article belongs to the Collection Genome Maintenance in Cancer Biology and Therapy)
Targeting topoisomerases has been widely used as anticancer therapeutics. Exposure to high temperature (hyperthermia) protects cells from the cytotoxic effect of topoisomerase-targeting therapeutics, yet the mechanism remains unknown. Here, we report that hyperthermia inhibits the nucleolytic processing of topoisomerase-induced DNA damage and drives repair to a more faithful pathway mediated by TDP1 and TDP2. We further show that hyperthermia suppresses topoisomerase-induced chromosomal translocation and hallmarks of inflammation, which has broad implications in cancer development and therapy.
Cancer-causing mutations often arise from inappropriate DNA repair, yet acute exposure to DNA damage is widely used to treat cancer. The challenge remains in how to specifically induce excessive DNA damage in cancer cells while minimizing the undesirable effects of genomic instability in noncancerous cells. One approach is the acute exposure to hyperthermia, which suppresses DNA repair and synergizes with radiotherapy and chemotherapy. An exception, however, is the protective effect of hyperthermia on topoisomerase targeting therapeutics. The molecular explanation for this conundrum remains unclear. Here, we show that hyperthermia suppresses the level of topoisomerase mediated single- and double-strand breaks induced by exposure to topoisomerase poisons. We further uncover that, hyperthermia suppresses hallmarks of genomic instability induced by topoisomerase targeting therapeutics by inhibiting nuclease activities, thereby channeling repair to error-free pathways driven by tyrosyl-DNA phosphodiesterases. These findings provide an explanation for the protective effect of hyperthermia from topoisomerase-induced DNA damage and may help to explain the inverse relationship between cancer incidence and temperature. They also pave the way for the use of controlled heat as a therapeutic adjunct to topoisomerase targeting therapeutics. View Full-Text
Keywords: topoisomerase; TDP1; TDP2; cancer; ageing; hyperthermia; genomic instability topoisomerase; TDP1; TDP2; cancer; ageing; hyperthermia; genomic instability
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MDPI and ACS Style

Ashour, M.E.; Allam, W.; Elsayed, W.; Atteya, R.; Elserafy, M.; Magdeldin, S.; Hassan, M.K.; El-Khamisy, S.F. High Temperature Drives Topoisomerase Mediated Chromosomal Break Repair Pathway Choice. Cancers 2021, 13, 2315. https://doi.org/10.3390/cancers13102315

AMA Style

Ashour ME, Allam W, Elsayed W, Atteya R, Elserafy M, Magdeldin S, Hassan MK, El-Khamisy SF. High Temperature Drives Topoisomerase Mediated Chromosomal Break Repair Pathway Choice. Cancers. 2021; 13(10):2315. https://doi.org/10.3390/cancers13102315

Chicago/Turabian Style

Ashour, Mohamed E., Walaa Allam, Waheba Elsayed, Reham Atteya, Menattallah Elserafy, Sameh Magdeldin, Mohamed K. Hassan, and Sherif F. El-Khamisy 2021. "High Temperature Drives Topoisomerase Mediated Chromosomal Break Repair Pathway Choice" Cancers 13, no. 10: 2315. https://doi.org/10.3390/cancers13102315

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