Elucidating regulatory mechanisms of RAG2 in response to DNA damage
| Autor: | Jennifer Byrum, William Rodgers, Karla Rodgers |
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| Rok vydání: | 2016 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 196:204.10-204.10 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | V(D)J recombination of lymphocyte antigen receptor genes occurs via the formation of DNA double strand breaks (DSBs) through the activity of RAG1 and RAG2. The co-existence of RAG-independent DNA DSBs generated by genotoxic stressors potentially increases the risk of incorrect repair and chromosomal abnormalities. However, it is not known whether cellular responses to DSBs by genotoxic stressors affect the RAG complex. Using cellular imaging and subcellular fractionation approaches, we show that formation of DSBs by treating cells with DNA damaging agents causes export of nuclear RAG2. Within the cytoplasm, RAG2 exhibited substantial enrichment at the centrosome. Further, RAG2 export was sensitive to inhibition of ATM, and was reversed following DNA repair. Live cell imaging reveals export of RAG2 within minutes of DNA damage, demonstrating a rapid response to genotoxic stress. Intriguingly, dose response assessment exhibited RAG2 export following the generation of very few DNA DSBs, indicating that DNA damage-triggered export of RAG2 can occur under normal physiological conditions. The core region of RAG2 was sufficient for export, but not centrosome targeting, and RAG2 export was blocked by mutation of Thr490. In summary, DNA damage triggers relocalization of RAG2 from the nucleus to centrosomes, suggesting a novel mechanism for modulation of cellular responses to DSBs in developing lymphocytes. |
| Databáze: | OpenAIRE |
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