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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| Format: | Article |
| Language: | English |
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MDPI AG
2021-05-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/10/2315 |
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| author | Mohamed E. Ashour Walaa Allam Waheba Elsayed Reham Atteya Menattallah Elserafy Sameh Magdeldin Mohamed K. Hassan Sherif F. El-Khamisy |
| author_facet | Mohamed E. Ashour Walaa Allam Waheba Elsayed Reham Atteya Menattallah Elserafy Sameh Magdeldin Mohamed K. Hassan Sherif F. El-Khamisy |
| author_sort | Mohamed E. Ashour |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T11:30:10Z |
| format | Article |
| id | doaj.art-e056fd134b8a4cb59546fb4a4dd60759 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T11:30:10Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-e056fd134b8a4cb59546fb4a4dd607592023-11-21T19:20:10ZengMDPI AGCancers2072-66942021-05-011310231510.3390/cancers13102315High Temperature Drives Topoisomerase Mediated Chromosomal Break Repair Pathway ChoiceMohamed E. Ashour0Walaa Allam1Waheba Elsayed2Reham Atteya3Menattallah Elserafy4Sameh Magdeldin5Mohamed K. Hassan6Sherif F. El-Khamisy7Center for Genomics, Helmy Institute for Medical Science, Zewail City of Science and Technology, Giza 12578, EgyptCenter for Genomics, Helmy Institute for Medical Science, Zewail City of Science and Technology, Giza 12578, EgyptCenter for Genomics, Helmy Institute for Medical Science, Zewail City of Science and Technology, Giza 12578, EgyptCenter for Genomics, Helmy Institute for Medical Science, Zewail City of Science and Technology, Giza 12578, EgyptCenter for Genomics, Helmy Institute for Medical Science, Zewail City of Science and Technology, Giza 12578, EgyptProteomics and Metabolomics Research Program, Children Cancer Hospital (CCHE 57357), Cairo 11441, EgyptCenter for Genomics, Helmy Institute for Medical Science, Zewail City of Science and Technology, Giza 12578, EgyptThe Healthy Lifespan and the Neuroscience Institutes, University of Sheffield, South Yorkshire, Sheffield S10 2TN, UKCancer-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.https://www.mdpi.com/2072-6694/13/10/2315topoisomeraseTDP1TDP2cancerageinghyperthermia |
| spellingShingle | Mohamed E. Ashour Walaa Allam Waheba Elsayed Reham Atteya Menattallah Elserafy Sameh Magdeldin Mohamed K. Hassan Sherif F. El-Khamisy High Temperature Drives Topoisomerase Mediated Chromosomal Break Repair Pathway Choice Cancers topoisomerase TDP1 TDP2 cancer ageing hyperthermia |
| title | High Temperature Drives Topoisomerase Mediated Chromosomal Break Repair Pathway Choice |
| title_full | High Temperature Drives Topoisomerase Mediated Chromosomal Break Repair Pathway Choice |
| title_fullStr | High Temperature Drives Topoisomerase Mediated Chromosomal Break Repair Pathway Choice |
| title_full_unstemmed | High Temperature Drives Topoisomerase Mediated Chromosomal Break Repair Pathway Choice |
| title_short | High Temperature Drives Topoisomerase Mediated Chromosomal Break Repair Pathway Choice |
| title_sort | high temperature drives topoisomerase mediated chromosomal break repair pathway choice |
| topic | topoisomerase TDP1 TDP2 cancer ageing hyperthermia |
| url | https://www.mdpi.com/2072-6694/13/10/2315 |
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