Abstract
Exposure to genotoxic stress by environmental agents or treatments, such as radiation therapy, can diminish healthspan and accelerate aging. We have developed a Drosophila melanogaster model to study the molecular effects of radiation-induced damage and repair. Utilizing a quantitative intestinal permeability assay, we performed an unbiased GWAS screen (using 156 strains from the Drosophila Genetic Reference Panel) to search for natural genetic variants that regulate radiation-induced gut permeability in adult D. melanogaster. From this screen, we identified an RNA binding protein, Musashi (msi), as one of the possible genes associated with changes in intestinal permeability upon radiation. The overexpression of msi promoted intestinal stem cell proliferation, which increased survival after irradiation and rescued radiation-induced intestinal permeability. In summary, we have established D. melanogaster as an expedient model system to study the effects of radiation-induced damage to the intestine in adults and have identified msi as a potential therapeutic target.
Highlights
A typical mammalian cell encounters approximately 2 × 105 DNA lesions per day[1]
Even though ionizing radiation (IR) is extensively studied in the context of mutagenesis e xperiments[41,42] and embryonic development signals[43] in D. melanogaster, not much is known regarding its effects in adult flies
Understanding the mechanisms involved in tissue homeostasis and repair in response to age-related genotoxic stress is critical for developing therapeutics against the side effects of chemotherapeutic agents
Summary
A typical mammalian cell encounters approximately 2 × 105 DNA lesions per day[1] External stressors, both chemical and radioactive, and internal factors such as oxidative stress, are the primary sources of DNA damage[2]. DNA damaging agents, such as radiation, are the only available treatments for certain pathologies These therapies can lead to complications due to cellular and tissue damage caused by genotoxic stress. Cells undergo one of the following fates: apoptosis, replicative arrest, such as senescence, or clearance by phagocytosis or autophagy[20] These fates often involve the cell nonautonomous interactions, which cannot be recapitulated by in vitro models of genotoxic stress. They fail to represent the complexities of tissue microenvironments and the cell non-autonomous consequences of radiation damage. We have taken advantage of the flies’ genetic malleability, short lifespan, and complex tissue microenvironments to develop a whole-animal model to study therapeutic targets for radiation damage to the intestine
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