Research Article

URI is required to maintain intestinal architecture during ionizing radiation

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Science  31 May 2019:
Vol. 364, Issue 6443, eaaq1165
DOI: 10.1126/science.aaq1165

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Illuminating intestine irradiation

High-dose radiation exposure affects multiple body systems, including the blood and the neurovascular system. Radiation can also cause severe intestinal toxicity, known as gastrointestinal syndrome (GIS). Working in mice, Chaves-Pérez et al. focused on the mechanisms underlying GIS. The molecular chaperone URI (unconventional prefoldin RPB5 interactor) labeled slow-cycling label-retaining (LR) cells, which are essential for organ regeneration following ionizing radiation. Reduced URI levels rendered LR cells highly proliferative via the activation of the β-catenin/c-MYC axis. Consequently, LR cells became radiosensitive, increasing GIS severity. Thus, URI protects LR cells to promote tissue regeneration in response to high-dose irradiation.

Science, this issue p. eaaq1165

Structured Abstract

INTRODUCTION

Exposure to high-dose irradiation (>10 gray) from the uncontrolled release of radioactive materials or intensive radiotherapy for cancer treatment can cause gastrointestinal syndrome (GIS), a lethal disorder affecting the intestinal structure. Symptoms and signs include nausea, diarrhea, vomiting, bleeding, and intestinal perforation, leading to the death of the patient through bacterial infection and septic shock. Treatments are very limited and generally focused on reducing GIS symptoms. Natural products, dietary interventions, and antioxidants have also been tested preclinically but have shown very modest effects in mitigating GIS. To assess medical countermeasures, it is essential to develop specific and robust animal models in which the relationship between radiation doses, GIS incidence, and severity can be correlated with the histopathology of the intestine. Here, we aim to understand cell biology and molecular events of GIS after radiation exposure by using a genetic GIS mouse model generated in our laboratory. This information will help in identifying biomarkers that can predict degrees of intestinal toxicity after severe ionizing radiation and assist in developing procedures to protect against GIS.

RATIONALE

High levels of DNA damage and cell death are well-known clinical features of intestinal radiation toxicity. The molecular chaperone unconventional prefoldin RPB5 interactor (URI) reportedly controls and protects genome integrity in response to environmental insults. Therefore, we hypothesized that URI may play an important role in ensuring genome stability in the highly proliferative intestinal epithelium after exposure to ionizing radiation. By using genetically engineered mouse models for URI gain- and loss-of-function specifically in the intestinal epithelium, we studied the role of URI in GIS.

RESULTS

URI levels fluctuate in intestinal crypts dose- and time-dependently after different doses of ionizing radiation. Specifically, URI increases at early postirradiation stages (24 to 48 hours), correlating with activation of the DNA damage response, whereas URI levels decrease during the regenerative response (72 to 96 hours postirradiation). We altered the level of URI and found that overexpression in mouse intestinal epithelium protects against intensive ionizing radiation and GIS, whereas halving URI expression sensitizes to ionizing radiation. Moreover, genetic URI ablation in the intestine caused mouse death, mimicking features of human GIS. We show that URI labels the slow-dividing stem cell–like label-retaining (LR) cells and is essential for protecting them from death, allowing the regeneration of the injured organ after high-dose irradiation. Mechanistically, we demonstrate that URI loss activates the β−catenin–c-MYC axis specifically in LR cells. Reducing URI expression renders LR cells proliferative, thereby accumulating c-MYC–dependent replicative stress and hence making them radiosensitive. In line with these findings, complete URI deletion causes LR cell death and disruption of intestinal architecture, leading to GIS. Therefore, URI-positive (URIhigh) slow-cycling cells within the crypts constitute the facultative stem cell pool capable of repopulating the organ after ionizing radiation.

CONCLUSION

URI labels LR cells, which are essential for intestinal regeneration after high-dose irradiation. Reducing URI levels before ionizing radiation increases β−catenin–c-MYC–dependent proliferation and replicative stress-induced DNA damage, thereby rendering LR cells radiosensitive. On the basis of this work, selective c-MYC inhibition could be used as a countermeasure for humans at risk of developing radiation-induced GIS.

Schematic summarizing the role of URI in GIS.

(Top) URI is a marker of the slow-cycling LR cells. URI-positive (URIhigh) slow-cycling cells are radioresistant. URIhigh slow-cycling cells within the crypts represent the facultative stem cell pool essential for organ regeneration after high-dose irradiation. (Bottom) Reduced URI levels (URIlow) increase proliferation and DNA damage in LR cells, rendering them radiosensitive.

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.

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