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An Integrated Approach Reveals DNA Damage and Proteotoxic Stress as Main Effects of Proton Radiation in S. cerevisiae
Authors:Laura Vanderwaeren,Rü  veyda Dok,Karin Voordeckers,Laura Vandemaele,Kevin J. Verstrepen,Sandra Nuyts
Affiliation:1.Laboratory of Experimental Radiotherapy, Department of Oncology, KU Leuven, 3000 Leuven, Belgium; (L.V.); (R.D.); (L.V.);2.Laboratory of Genetics and Genomics, Centre for Microbial and Plant Genetics, KU Leuven, 3000 Leuven, Belgium;3.Laboratory for Systems Biology, VIB-KU Leuven Center for Microbiology, 3000 Leuven, Belgium;4.Department of Radiation Oncology, Leuven Cancer Institute, University Hospitals Leuven, 3000 Leuven, Belgium
Abstract:Proton radiotherapy (PRT) has the potential to reduce the normal tissue toxicity associated with conventional photon-based radiotherapy (X-ray therapy, XRT) because the active dose can be more directly targeted to a tumor. Although this dosimetric advantage of PRT is well known, the molecular mechanisms affected by PRT remain largely elusive. Here, we combined the molecular toolbox of the eukaryotic model Saccharomyces cerevisiae with a systems biology approach to investigate the physiological effects of PRT compared to XRT. Our data show that the DNA damage response and protein stress response are the major molecular mechanisms activated after both PRT and XRT. However, RNA-Seq revealed that PRT treatment evoked a stronger activation of genes involved in the response to proteotoxic stress, highlighting the molecular differences between PRT and XRT. Moreover, inhibition of the proteasome resulted in decreased survival in combination with PRT compared to XRT, not only further confirming that protons induced a stronger proteotoxic stress response, but also hinting at the potential of using proteasome inhibitors in combination with proton radiotherapy in clinical settings.
Keywords:DNA damage response   proteotoxic stress   proton radiation   radiobiology   radiotherapy
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