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Identification of primary transcriptional regulation of cell cycle-regulated genes upon DNA damage

Tong Zhou1, Jeff Chou, Thomas E Mullen

  • 1Department of Pathology and Laboratory Medicine, Center for Environmental Health and Susceptibility, and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.

Cell Cycle (Georgetown, Tex.)
|April 4, 2007
PubMed

Insights

DNA damage alters gene expression through direct regulation or cell cycle shifts. A new model distinguishes direct transcriptional targets from indirect effects, identifying 150 genes directly affected by ionizing radiation in human fibroblasts.

Area of Science:

  • Molecular Biology
  • Genomics
  • Cell Biology

Background:

  • DNA damage triggers complex cellular responses affecting gene expression.
  • Gene expression changes can result from direct transcriptional regulation or cell cycle redistribution.
  • Distinguishing these mechanisms is crucial for understanding DNA damage response pathways.

Purpose of the Study:

  • To develop a model to differentiate direct transcriptional targets from indirect gene expression changes after DNA damage.
  • To identify direct transcriptional targets of ionizing radiation (IR)-induced DNA damage in human fibroblasts.

Main Methods:

  • Developed a computational model to estimate gene expression based on cell cycle phase proportions.
  • Applied the model to normal human fibroblasts treated with genotoxins.
  • Isolated the effects of cell cycle phase redistribution to identify direct transcriptional targets.

Main Results:

  • The model accurately estimated expression levels of over 400 cell cycle-regulated genes.
  • Identified 150 out of 406 cell cycle-regulated genes as putative direct transcriptional targets of IR.
  • Demonstrated that IR-induced gene expression changes result from both direct regulation and cell cycle synchronization.

Conclusions:

  • The developed model effectively distinguishes direct transcriptional targets from indirect effects of DNA damage.
  • Ionizing radiation directly impacts a significant subset of cell cycle-regulated genes.
  • Understanding these dual mechanisms provides deeper insights into cellular responses to genotoxic stress.

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