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Negative control of CSL gene transcription by stress/DNA damage response and p53

Elena Menietti1, Xiaoying Xu1, Paola Ostano2

  • 1a Department of Biochemistry , University of Lausanne , Epalinges , Switzerland.

Cell Cycle (Georgetown, Tex.)
|May 11, 2016
PubMed

Insights

Cancer, Susceptibility, Locus (CSL) expression is reduced by DNA damage and stress. This regulation by p53 enhances cellular DNA damage response, impacting cancer development.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • The CSL (Cancer, Susceptibility, Locus) protein is a crucial transcriptional repressor in Notch signaling.
  • Mechanisms regulating CSL itself are not well understood.
  • CSL downregulation in human dermal fibroblasts (HDFs) induces a cancer-associated fibroblast (CAF) phenotype, promoting keratinocyte tumors.

Purpose of the Study:

  • To investigate the regulation of CSL expression.
  • To explore the relationship between CSL, DNA damage, and the p53 pathway.

Main Methods:

  • Analysis of CSL transcript levels in HDF strains.
  • Assessment of CSL expression under various stress conditions (UVA, ROS, smoke extract, doxorubicin).
  • Investigation of p53's role in regulating CSL transcription and promoter activity.

Main Results:

  • CSL transcript levels varied among HDF strains and negatively correlated with DNA damage/repair genes.
  • CSL expression was downregulated by UVA, ROS, smoke extract, and doxorubicin.
  • p53 negatively controlled CSL transcription, partly via p21 induction.
  • p53 suppresses CSL promoter activity.

Conclusions:

  • CSL expression is negatively regulated by DNA damage and stress.
  • p53 directly and indirectly suppresses CSL gene transcription.
  • This reciprocal regulation enhances p53 activity during acute DNA damage response.
Keywords:
CSL/RBPJκUVA/DNA damage responsedermal fibroblastsindividual variations in gene transcriptionp53

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