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

Nature volume 456, pages 819–823 (2008)Cite this article

Abstract

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.

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Figure 1: Rag DSBs activate a broad genetic program.
Figure 2: Rag DSB-dependent gene expression changes in developing B cells in vivo.
Figure 3: NF-κB activation in response to transient Rag DSBs.
Figure 4: Genotoxic DSBs promote changes in expression of lymphocyte-specific genes.

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Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

The microarray gene expression data have been deposited in NCBI’s Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) under accession number GSE9024.

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Acknowledgements

We thank J. Bednarski, B. Van Honten and M. Diaz for critical review of the manuscript, F. W. Alt for providing us with the Artemis-/- mice and D. Ballard for providing us with the IκBα-ΔN construct. This research is supported by the National Institutes of Health (NIH, grant AI47829) and the Washington University Department of Pathology and Immunology (to B.P.S.); the Department of Pathology and Center for Childhood Cancer Research of the Children’s Hospital of Philadelphia, and the Abramson Family Cancer Research Institute (to C.H.B.); and the intramural research program of the NIH, National Institute of Environmental Health Sciences (to R.S.P.). B.P.S. is a recipient of a Research Scholar Award from the American Cancer Society. C.H.B. is a Pew Scholar in the Biomedical Sciences. A.L.B. is supported by a post-doctoral training grant from the NIH.

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Author notes

  1. Andrea L. Bredemeyer and Beth A. Helmink: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA,

    Andrea L. Bredemeyer, Beth A. Helmink, Boris Calderon, Lisa M. McGinnis, Grace K. Mahowald, Eric J. Gapud, Laura M. Walker, Brian K. Weaver, Laura Mandik-Nayak, Robert D. Schreiber, Paul M. Allen & Barry P. Sleckman

  2. Environmental Stress and Cancer Group, and NIEHS Microarray Group, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA,

    Cynthia L. Innes, Jennifer B. Collins & Richard S. Paules

  3. School of Veterinary Medicine, and,,

    Michael J. May

  4. Department of Pathology and Laboratory Medicine, Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia 19104, USA,

    Craig H. Bassing

  5. Abramson Family Cancer Research Institute, Philadelphia, Philadelphia 19104, USA,

    Craig H. Bassing

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Correspondence to Barry P. Sleckman.

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Bredemeyer, A., Helmink, B., Innes, C. et al. DNA double-strand breaks activate a multi-functional genetic program in developing lymphocytes. Nature 456, 819–823 (2008). https://doi.org/10.1038/nature07392

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