Abstract
BackgroundDouble 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.ResultsWe 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.ConclusionsComparing 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.
Highlights
Double strand 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
While it is known that genotoxic agents, such as ionizing radiation (IR), activate transcriptional programs involved in maintaining the integrity of the genome, we want to investigate whether or not the genotoxic breaks could affect lymphocyte-specific maturation transcriptional responses similar to those we observed following RAGinduced physiological double strand breaks (DSBs)
Ionizing radiation induces a broad transcriptional program in wild type murine pre-B cells Utilizing Affymetrix whole mouse genome gene expression microarrays, we collected gene expression data from viral (v)-Abelson tyrosine kinase (Abl) kinase-transformed pre-B cell lines that were generated from multiple WT mice expressing an Eμ-B cell leukemia/lymphoma 2 (Bcl2) transgene
Summary
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. In developing lymphocytes one source of physiological double strand breaks (DSBs) is the process of V(D)J recombination that is utilized to generate rearranged antigen receptor genes [1,2] This process is initiated by RAG endonucleases while the lymphocytes are in the G1 phase response to dsDNA breaks includes the activation of multiple transcriptional pathways that can lead to cell cycle arrest at specific checkpoints, DNA repair, or death of the affected cells [3,4]. These genome wide transcriptional responses are very tightly regulated and complex. Elucidation of the similarities and differences in these responses may lead to a greater understanding of the cellular mechanisms involved in lympho-proliferative cancer formation and lymphocyte maturation
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