4.8 Article

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

Journal

NATURE
Volume 456, Issue 7223, Pages 819-U113

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/nature07392

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Funding

  1. National Institutes of Health [AI47829]
  2. Washington University Department of Pathology and Immunology
  3. Department of Pathology and Center for Childhood Cancer Research of the Children's Hospital of Philadelphia
  4. Abramson Family Cancer Research Institute
  5. National Institute of Environmental Health Sciences
  6. Research Scholar Award from the American Cancer Society

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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 survival(1-5). 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.

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