High Temperature Drives Topoisomerase Mediated Chromosomal Break Repair Pathway Choice.

Mohamed E Ashour,Menattallah Elserafy,Sameh Magdeldin,Mohamed K Hassan,Waheba Elsayed,Walaa Allam,Reham Atteya,Sherif F El-Khamisy

doi:10.3390/cancers13102315

Abstract

Simple SummaryTargeting 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.

Highlights

IntroductionCancer is a leading cause of mortality with variable incidence among populations [1]
Cancer is a leading cause of mortality with variable incidence among populations [1].Analysis of epidemiological data has uncovered an inverse pattern of geographical cancer distribution and annual temperature
We uncover that hyperthermia suppresses the level of genomic instability induced by topoisomerase poisons by inhibiting nuclease activities, thereby channeling repair to the error-free TDP pathways. These findings identify a novel mechanism for the protective effect of hyperthermia from topoisomerase-induced genomic instability and could help in understanding the inverse relationship between cancer and environmental temperature

Summary

Introduction

Cancer is a leading cause of mortality with variable incidence among populations [1]. Analysis of epidemiological data has uncovered an inverse pattern of geographical cancer distribution and annual temperature. Countries with low average annual temperatures exhibit the highest incidence of cancer [1,2,3,4]. The two populations living in the coldest environments, Alaska Indians and Inuit, exhibit high cancer incidence [3,5]. Human thermoregulation systems sustain body core temperature at 37 ◦C, exposure to extreme or sustained temperatures overwhelms the body’s thermoregulatory capacity especially at old age, leading to hypothermia (40.5 ◦C) [6,7]. How the changes in environmental and body temperature affect cancer development remains unclear

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