Journal
SCIENCE
Volume 364, Issue 6443, Pages 849-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aaq1165
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Funding
- La Caixa Ph.D. fellowship
- Spanish Ramon y Cajal fellowship
- Spanish Ministry of Economy and Competitiveness
- European Regional Development Fund (ERDF-EU) [SAF2016-76598-R]
- National Institute of Health Carlos III
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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 radiationinduced GIS, whereas halving URI expression sensitizes mice to IR. URI specifically inhibits beta-catenin in stem cell-like label-retaining (LR) cells, which are essential for organ regeneration after IR. URI reduction activates beta-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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