High Temperature Drives Topoisomerase Mediated Chromosomal Break Repair Pathway Choice

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 noncancerou...

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Bibliographic Details
Published in:Cancers 2021-05, Vol.13 (10), p.2315
Main Authors: Ashour, Mohamed E., Allam, Walaa, Elsayed, Waheba, Atteya, Reham, Elserafy, Menattallah, Magdeldin, Sameh, Hassan, Mohamed K., El-Khamisy, Sherif F.
Format: Article
Language:English
Subjects:
Androgens
Cancer
Cancer therapies
Cell cycle
Chemotherapy
Chromosome translocations
Cytotoxicity
Deoxyribonucleic acid
DNA
DNA damage
DNA repair
Fever
Genomes
Genomic instability
Heat
High temperature
Hyperthermia
Nuclease
Proteins
Radiation
Radiation therapy
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Summary: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.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers13102315