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Published on: July 3, 2015
Sag/Rbx2 Partial Inactivation Sensitizes Mice to Radiation and Radiation-Induced Tumorigenesis1
Yi Sun1,2,3, Hua Li4, Mingjia Tan4
1Cancer Institute of the 2nd Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China, 310009.
Abstract:
SAG (sensitive to apoptosis gene)/RBX2 (RING box-2), is the second family member of RING component of cullin-RING ligase (CRL) complex required for its enzymatic activity. Using total or conditional Sag knockout mouse models, we previously showed that Sag plays an essential role in embryonic development, apoptosis, vasculogenesis, angiogenesis and tumorigenesis. We also found that Sag-null ES cells are more sensitive to radiation. In this study, we generated the SagΔ/flneo mice with partial Sag inactivation due to deletion in one allele (Δ allele), and disrupted expression in the another (by a neo cassette). Compared to wild-type, SagΔ/fl-neo mice are more sensitive to a lethal dose of radiation with significantly shortened life span, resulting from an increased tissue damage with reduced proliferation and increased apoptosis in the intestines. Similar observations were made when SagΔ/fl-neo mice received a high dose of radiation directly delivered to the abdomen with reduced proliferation and prolonged DNA damage repair. Mechanistically, we found accumulations of Sag substrates, p21 and p27, explaining the proliferation defect. Finally, we found that SagΔ/fl-neo mice are more prone to tumorigenesis induced by a low dose of radiation with shortened life-span and increased incidence of lymphoma. Collectively, our study demonstrates that Sag protects mice from radiation-induced tissue damages and tumorigenesis.
Insights
Sensitive to apoptosis gene (SAG) protects mice from radiation damage. Partial SAG inactivation increases sensitivity to radiation, leading to tissue damage, impaired proliferation, and higher cancer risk.
Area of Science:
- Molecular Biology
- Genetics
- Radiation Biology
Background:
- Sensitive to apoptosis gene (SAG)/RING box-2 (RBX2) is crucial for cullin-RING ligase (CRL) complex activity.
- Previous studies established SAG's role in development, apoptosis, and tumorigenesis.
- SAG-null cells exhibit increased sensitivity to radiation.
Purpose of the Study:
- To investigate the role of partial SAG inactivation in radiation sensitivity and tumorigenesis.
- To elucidate the mechanisms underlying SAG's protective effects against radiation damage.
Main Methods:
- Generation of SagΔ/flneo mice with partial SAG inactivation.
- Exposure of mice to lethal and low doses of radiation.
- Assessment of tissue damage, proliferation, apoptosis, DNA repair, and tumor incidence.
Main Results:
- SagΔ/flneo mice showed increased sensitivity to lethal radiation, with shortened lifespan, intestinal damage, reduced proliferation, and increased apoptosis.
- Partial SAG inactivation led to accumulation of p21 and p27, explaining proliferation defects.
- SagΔ/flneo mice were more prone to radiation-induced tumorigenesis, particularly lymphoma.
Conclusions:
- SAG plays a protective role against radiation-induced tissue damage.
- SAG is a critical factor in preventing radiation-induced tumorigenesis.
