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Updated: May 13, 2026
Measuring DNA Damage and Repair in Mouse Splenocytes After Chronic In Vivo Exposure to Very Low Doses of Beta- and Gamma-Radiation
Published on: July 3, 2015
DNA damage activates a complex transcriptional response in murine lymphocytes that includes both physiological and
Cynthia L Innes1, Jill E Hesse, Stela S Palii
1Environmental Stress and Cancer Group, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Background:
Double strand (ds) DNA breaks are a form of DNA damage that can be generated from both genotoxic exposures and physiologic processes, can disrupt cellular functions and can be lethal if not repaired properly. Physiologic dsDNA breaks are generated in a variety of normal cellular functions, including the RAG endonuclease-mediated rearrangement of antigen receptor genes during the normal development of lymphocytes. We previously showed that physiologic breaks initiate lymphocyte development-specific transcriptional programs. Here we compare transcriptional responses to physiological DNA breaks with responses to genotoxic DNA damage induced by ionizing radiation.
Results:
We identified a central lymphocyte-specific transcriptional response common to both physiologic and genotoxic breaks, which includes many lymphocyte developmental processes. Genotoxic damage causes robust alterations to pathways associated with B cell activation and increased proliferation, suggesting that genotoxic damage initiates not only the normal B cell maturation processes but also mimics activated B cell response to antigenic agents. Notably, changes including elevated levels of expression of Kras and mmu-miR-155 and the repression of Socs1 were observed following genotoxic damage, reflecting induction of a cancer-prone phenotype.
Conclusions:
Comparing these transcriptional responses provides a greater understanding of the mechanisms cells use in the differentiation between types of DNA damage and the potential consequences of different sources of damage. These results suggest genotoxic damage may induce a unique cancer-prone phenotype and processes mimicking activated B cell response to antigenic agents, as well as the normal B cell maturation processes.
Insights
Physiological and genotoxic DNA breaks trigger common lymphocyte-specific gene expression. Genotoxic damage uniquely promotes B cell activation and a cancer-prone phenotype, mimicking immune responses.
Area of Science:
- Molecular Biology
- Immunology
- Genetics
Background:
- Double-strand (ds) DNA breaks are critical DNA damage, arising from genotoxic or physiological sources.
- Physiological dsDNA breaks occur during normal lymphocyte development (e.g., RAG endonuclease activity).
- Previous work demonstrated physiological breaks initiate lymphocyte development-specific transcription.
Purpose of the Study:
- To compare transcriptional responses to physiological DNA breaks with those induced by genotoxic DNA damage (ionizing radiation).
Main Methods:
- Transcriptional profiling of lymphocytes subjected to physiological vs. genotoxic DNA breaks.
- Comparative analysis of gene expression patterns.
Main Results:
- A common lymphocyte-specific transcriptional response was identified for both damage types, involving developmental processes.
- Genotoxic damage induced robust alterations in B cell activation and proliferation pathways.
- Genotoxic damage elevated Kras and mmu-miR-155 expression and repressed Socs1, indicating a cancer-prone phenotype.
Conclusions:
- Cells differentiate between DNA damage types through distinct transcriptional responses.
- Genotoxic damage may induce a unique cancer-prone phenotype and mimic activated B cell responses.
- Understanding these responses aids in evaluating the consequences of different DNA damage sources.
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