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URI is required to maintain intestinal architecture during ionizing radiation.

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URIREQUIREDTOMAINTAIN_2019.pdf (15.7 MB)
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URI: http://hdl.handle.net/20.500.12105/17555
DOI: 10.1126/science.aaq1165
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2019-05-31
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American Association for the Advancement of Science (AAAS)
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Ionizing radiation (IR) can cause gastrointestinal syndrome (GIS), a lethal disorder, by means of unknown mechanisms. We show that high-dose irradiation increases unconventional prefoldin RPB5 interactor (URI) levels in mouse intestinal crypt, but organ regeneration correlates with URI reductions. URI overexpression in intestine protects mice from radiation-induced GIS, whereas halving URI expression sensitizes mice to IR. URI specifically inhibits β-catenin in stem cell-like label-retaining (LR) cells, which are essential for organ regeneration after IR. URI reduction activates β-catenin-induced c-MYC expression, causing proliferation of and DNA damage to LR cells, rendering them radiosensitive. Therefore, URI labels LR cells which promote tissue regeneration in response to high-dose irradiation, and c-MYC inhibitors could be countermeasures for humans at risk of developing GIS.
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Radiation Tolerance Regeneration Animals Gastrointestinal Diseases Gene Knock-In Techniques Intestinal Mucosa Mice Mice, Inbred C57BL Mice, Mutant Strains Radiation Injuries Radiation, Ionizing Receptors, G-Protein-Coupled Repressor Proteins beta Catenin
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Science . 2019 ;364(6443):eaaq1165.
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https://doi.org/10.1126/science.aaq1165.
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journal article