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Science. 2019 May 31;364(6443). pii: eaaq1165. doi: 10.1126/science.aaq1165.

URI is required to maintain intestinal architecture during ionizing radiation.

Author information

1
Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional Investigaciones Oncológicas, CNIO, Madrid 28029, Spain.
2
Department of Pathology, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid 28034, Spain.
3
Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional Investigaciones Oncológicas, CNIO, Madrid 28029, Spain. ndjouder@cnio.es.

Abstract

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.

PMID:
31147493
DOI:
10.1126/science.aaq1165

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