title: Controlled DNA double-strand break induction in mice reveals post-damage transcriptome stability.
abstract: DNA double-strand breaks (DSBs) and their repair can cause extensive epigenetic changes. As a result, DSBs have been proposed to promote transcriptional and, ultimately, physiological dysfunction via both cell-intrinsic and cell-non-autonomous pathways. Studying the consequences of DSBs in higher organisms has, however, been hindered by a scarcity of tools for controlled DSB induction. Here, we describe a mouse model that allows for both tissue-specific and temporally controlled DSB formation at ∼140 defined genomic loci. Using this model, we show that DSBs promote a DNA damage signaling-dependent decrease in gene expression in primary cells specifically at break-bearing genes, which is reversed upon DSB repair. Importantly, we demonstrate that restoration of gene expression can occur independently of cell cycle progression, underlining its relevance for normal tissue maintenance. Consistent with this, we observe no evidence for persistent transcriptional repression in response to a multi-day course of continuous DSB formation and repair in mouse lymphocytes in vivo Together, our findings reveal an unexpected capacity of primary cells to maintain transcriptome integrity in response to DSBs, pointing to a limited role for DNA damage as a mediator of cell-autonomous epigenetic dysfunction.
authors.affiliation: Laboratory for Receptor Biology and Gene Expression, National Cancer Institute, 41 Library Drive, Bethesda, MD 20892, USA.
authors.forename: Jeongkyu
authors.initials: J
authors.lastname: Kim
authors.affiliation: Laboratory for Receptor Biology and Gene Expression, National Cancer Institute, 41 Library Drive, Bethesda, MD 20892, USA.
authors.forename: David
authors.initials: D
authors.lastname: Sturgill
authors.affiliation: Laboratory for Receptor Biology and Gene Expression, National Cancer Institute, 41 Library Drive, Bethesda, MD 20892, USA.
authors.forename: Andy D
authors.initials: AD
authors.lastname: Tran
authors.affiliation: The Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Sinclair
authors.affiliation: Laboratory for Receptor Biology and Gene Expression, National Cancer Institute, 41 Library Drive, Bethesda, MD 20892, USA Philipp.Oberdoerffer@nih.gov.
authors.forename: Philipp
authors.initials: P
authors.lastname: Oberdoerffer
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D053903:DNA Breaks, Double-Stranded; D004706:Endodeoxyribonucleases; D056426:Genetic Loci; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D004706:Endodeoxyribonucleases