URI is required to maintain intestinal architecture during ionizing radiation
URI is required to maintain intestinal architecture during ionizing radiation
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DOI：
10.1126/science.aaq1165
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发表时间：
2019-05-31
期刊：
影响因子：
56.9
通讯作者：
Djouder, Nabil
中科院分区：
文献类型：
--
作者：
Chaves-Perez, Almudena;Yilmaz, Mahmut;Djouder, Nabil
电离辐射（IR）可引起胃肠综合征（GIS），这是一种致死性疾病，其机制尚不清楚。我们发现，高剂量辐射增加非常规的prefoldin RPB 5相互作用（URI）在小鼠肠隐窝的水平，但器官再生与URI减少。肠中URI过表达保护小鼠免受辐射诱导的GIS，而URI表达减半使小鼠对IR敏感。URI特异性抑制干细胞样标记保留（LR）细胞中的β-连环蛋白，这是IR后器官再生所必需的。URI减少激活β-连环蛋白诱导的c-MYC表达，导致LR细胞增殖和DNA损伤，使其对辐射敏感。因此，URI标记LR细胞，其促进组织再生以响应高剂量辐射，而c-MYC抑制剂可能是处于发展GIS风险的人类的对策。
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.