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

Andrea L. Bredemeyer, Beth A. Helmink, Cynthia L. Innes, Boris Calderon, Lisa M. McGinnis, Grace K. Mahowald, Eric J. Gapud, Laura M. Walker, Jennifer B. Collins, Brian K. Weaver, Laura Mandik-Nayak, Robert D. Schreiber, Paul M. Allen, Michael J. May, Richard S. Paules, Craig H. Bassing, Barry P. Sleckman

Research output: Contribution to journalArticlepeer-review

107 Scopus citations

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 survival. 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.

Original languageEnglish
Pages (from-to)819-824
Number of pages6
JournalNature
Volume456
Issue number7223
DOIs
StatePublished - Dec 11 2008

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