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V(D)J Recombination Exploits DNA Damage Responses to Promote Immunity
1Division of Cancer Pathobiology, Department of Pathology and Laboratory Medicine, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Trends in Genetics : TIG
|May 24, 2017
Summary
Variable (diversity) joining [V(D)J] recombination is crucial for adaptive immunity but can lead to autoimmunity. New findings show that recombination-activating gene (RAG) endonuclease-induced DNA double-strand breaks regulate immune cell development and function.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- Variable (diversity) joining [V(D)J] recombination assembles antigen receptor genes, essential for adaptive immunity.
- This process carries risks for autoimmunity and lymphoid malignancies.
- Recombination-activating gene (RAG) endonuclease-induced DNA double-strand breaks (DSBs) were previously considered hazardous intermediates.
Purpose of the Study:
- To investigate the broader role of RAG-induced DSBs beyond V(D)J recombination.
- To understand how RAG cleavage regulates gene expression in immune cells.
- To explore the implications for immune cell differentiation and function.
Main Methods:
- Analysis of RAG endonuclease activity in lymphocyte progenitors.
- Gene expression profiling in response to RAG cleavage.
- Functional assays for immune cell differentiation and lineage commitment.
Main Results:
- RAG-induced DSBs are not merely hazardous intermediates but actively regulate gene expression.
- RAG cleavage controls the expression of both ubiquitous and lymphocyte-specific genes.
- This regulation impacts the differentiation and function of adaptive and innate immune cells.
Conclusions:
- RAG-induced DNA breaks have a critical regulatory role in immune cell development.
- These findings expand our understanding of adaptive and innate immunity.
- New avenues for diagnosing and treating immunological diseases are suggested.
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