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High Temperature Drives Topoisomerase Mediated Chromosomal Break Repair Pathway Choice.

Ashour, M.E.
; 
Allam, W.
; 
Elsayed, W.
; 
Atteya, R.
; 
Elserafy, M.
; 
Magdeldin, S.
; 
Hassan, M.K.
; 
Publication Date
2021-05
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Keywords
Topoisomerase, TDP1, TDP2, Cancer, Ageing, Hyperthermia, Genomic instability
Rights
© 2021 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 (https://creativecommons.org/licenses/by/4.0/).
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Yes
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openAccess
Accepted for publication
2021-05-07
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Life Sciences Publications
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Abstract
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.
URI
http://hdl.handle.net/10454/19678
Version
Published version
Citation
Ashour ME, Allam W, Elsayed W, et al. (2021) High Temperature Drives Topoisomerase Mediated Chromosomal Break Repair Pathway Choice. Cancers. 13 (10): 2315.
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https://doi.org/10.3390/cancers13102315
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Article
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