DNA double-strand breaks activate a multi-functional genetic program in developing lymphocytes

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Abstract
As part of the response to exogenous DNA damage, the transcription of certain genes involved in cell cycle checkpoints and survival is affected; these changes help the cell to maintain its genomic integrity. There are also situations in which endogenous, physiological DNA double-strand breaks occur. In this work, Bredemeyer et al. show that the breaks which initiate the rearrangement of antigen receptor genes also activate a transcriptional program — but with a difference. Many of the regulated genes are involved in lymphocyte development. Thus, DNA breaks can regulate cell-type-specific processes and not just functions that will allow the cell to repair and survive a DNA break. As part of the response to exogenous DNA damage, the transcription of certain genes involved in cell cycle checkpoints and survival is affected; these changes help the cell to maintain its genomic integrity. There are also situations in which endogenous, physiological DNA double-strand breaks occur. This paper shows that the breaks which initiate the rearrangement of antigen receptor genes also activate a transcriptional program, but with a difference. Many of the regulated genes are involved in lymphocyte development. DNA double-strand breaks are generated by genotoxic agents and by cellular endonucleases as intermediates of several important physiological processes. The cellular response to genotoxic DNA breaks includes the activation of transcriptional programs known primarily to regulate cell-cycle checkpoints and cell survival1,2,3,4,5. DNA double-strand breaks are generated in all developing lymphocytes during the assembly of antigen receptor genes, a process that is essential for normal lymphocyte development. Here we show that in murine lymphocytes these physiological DNA breaks activate a broad transcriptional program. This program transcends the canonical DNA double-strand break response and includes many genes that regulate diverse cellular processes important for lymphocyte development. Moreover, the expression of several of these genes is regulated similarly in response to genotoxic DNA damage. Thus, physiological DNA double-strand breaks provide cues that can regulate cell-type-specific processes not directly involved in maintaining the integrity of the genome, and genotoxic DNA breaks could disrupt normal cellular functions by corrupting these processes.