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Controlled DNA double-strand break induction in mice reveals post-damage transcriptome stability

Jeongkyu Kim1, David Sturgill1, Andy D Tran1

  • 1Laboratory for Receptor Biology and Gene Expression, National Cancer Institute, 41 Library Drive, Bethesda, MD 20892, USA.

Nucleic Acids Research
|December 22, 2015
PubMed

Insights

DNA double-strand breaks (DSBs) can alter gene expression, but primary cells can maintain transcriptome integrity. DSB repair reverses expression changes, independent of cell cycle, suggesting limited cell-autonomous dysfunction.

Area of Science:

  • Genetics
  • Epigenetics
  • Molecular Biology

Background:

  • DNA double-strand breaks (DSBs) and their repair are linked to epigenetic alterations.
  • DSBs are hypothesized to cause physiological dysfunction through cell-intrinsic and non-autonomous pathways.
  • Controlled DSB induction in vivo has been a significant challenge.

Purpose of the Study:

  • To develop a mouse model for spatiotemporal control of DSB induction at specific genomic loci.
  • To investigate the impact of DSBs on gene expression and epigenetic regulation in primary cells.
  • To determine the role of DSBs in cell-autonomous dysfunction and tissue maintenance.

Main Methods:

  • Development of a novel mouse model for inducible and tissue-specific DSB formation at targeted genomic sites.
  • Analysis of gene expression changes in primary cells following DSB induction and repair.
  • Assessment of the relationship between gene expression restoration, cell cycle progression, and DNA damage signaling.

Main Results:

  • DSBs induce a DNA damage signaling-dependent decrease in gene expression at break sites, which is reversible upon repair.
  • Gene expression restoration after DSB repair is independent of cell cycle progression.
  • Continuous DSB formation and repair in vivo did not lead to persistent transcriptional repression in lymphocytes.

Conclusions:

  • Primary cells possess a robust capacity to maintain transcriptome integrity despite DSBs.
  • DSB-induced transcriptional changes are transient and repair-dependent.
  • DNA damage plays a limited role in mediating cell-autonomous epigenetic dysfunction.

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