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Open Access Research article

DNA damage activates a complex transcriptional response in murine lymphocytes that includes both physiological and cancer-predisposition programs

Cynthia L Innes1, Jill E Hesse1, Stela S Palii1, Beth A Helmink2, Abigail J Holub2, Barry P Sleckman2 and Richard S Paules1*

Author Affiliations

1 Environmental Stress and Cancer Group, National Institute of Environmental Health Sciences, Research Triangle Park, , NC, 27709, USA

2 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA

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BMC Genomics 2013, 14:163  doi:10.1186/1471-2164-14-163

Published: 12 March 2013

Abstract

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.

Keywords:
miR-155; B cells; Ionizing radiation; DNA damage; Double strand breaks; Transcriptome profiles