Chromatin Trapping of Factors Involved in DNA Replication and Repair Underlies Heat-Induced Radio- and Chemosensitization
Open Access
- 8 June 2020
- Vol. 9 (6), 1423
- https://doi.org/10.3390/cells9061423
Abstract
Hyperthermia has been used as an adjuvant treatment for radio- and chemotherapy for decades. In addition to its effects on perfusion and oxygenation of cancer tissues, hyperthermia can enhance the efficacy of DNA-damaging treatments such as radiotherapy and chemotherapy. Although it is believed that the adjuvant effects are based on hyperthermia-induced dysfunction of DNA repair systems, the mechanisms of these dysfunctions remain elusive. Here, we propose that elevated temperatures can induce chromatin trapping (c-trapping) of essential factors, particularly those involved in DNA repair, and thus enhance the sensitization of cancer cells to DNA-damaging therapeutics. Using mass spectrometry-based proteomics, we identified proteins that could potentially undergo c-trapping in response to hyperthermia. Functional analyses of several identified factors involved in DNA repair demonstrated that c-trapping could indeed be a mechanism of hyperthermia-induced transient deficiency of DNA repair systems. Based on our proteomics data, we showed for the first time that hyperthermia could inhibit maturation of Okazaki fragments and activate a corresponding poly(ADP-ribose) polymerase-dependent DNA damage response. Together, our data suggest that chromatin trapping of factors involved in DNA repair and replication contributes to heat-induced radio- and chemosensitization.Funding Information
- Russian Foundation for Basic Research (17-00-00098)
- Russian Science Foundation (19-75-10123)
This publication has 32 references indexed in Scilit:
- Heat exposure enhances radiosensitivity by depressing DNA-PK kinase activity during double strand break repairInternational Journal of Hyperthermia, 2014
- Mechanisms of heat shock response in mammalsCellular and Molecular Life Sciences, 2013
- Dual effect of heat shock on DNA replication and genome integrityMolecular Biology of the Cell, 2012
- Mild hyperthermia inhibits homologous recombination, induces BRCA2 degradation, and sensitizes cancer cells to poly (ADP-ribose) polymerase-1 inhibitionProceedings of the National Academy of Sciences of the United States of America, 2011
- ATM protein kinase: the linchpin of cellular defenses to stressCellular and Molecular Life Sciences, 2011
- 53BP1 nuclear bodies form around DNA lesions generated by mitotic transmission of chromosomes under replication stressNature, 2011
- Alterations in heat-induced radiosensitization accompanied by nuclear structure alterations in Chinese hamster cellsInternational Journal of Hyperthermia, 2006
- Mechanism of radiosensitization by hyperthermia (43°C) as derived from studies with DNA repair defective mutant cell linesInternational Journal of Hyperthermia, 2004
- Role of nuclear protein denaturation and aggregation in thermal radiosensitizationInternational Journal of Hyperthermia, 2004
- Intracellular redistribution and modification of proteins of the Mre11/Rad50/Nbs1 DNA repair complex following irradiation and heat‐shockJournal of Cellular Physiology, 2004