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Global Inhibition with Specific Activation: How p53 and MYC Redistribute the Transcriptome in the DNA Double-Strand

Joshua R Porter1, Brian E Fisher1, Laura Baranello1

  • 1Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.

Molecular Cell
|September 5, 2017
PubMed

Insights

Cells balance general transcription suppression with targeted gene activation during DNA damage responses. This involves p53-driven MYC reduction, crucial for regulating cell fate and stress adaptation.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • Cells halt normal processes under stress but require specific pathways for effective responses.
  • Understanding transcriptional regulation during DNA damage is crucial for cell fate.
  • p53 and MYC are key regulators of cellular processes and stress responses.

Purpose of the Study:

  • To investigate how cells redistribute global transcriptional activity in response to DNA damage.
  • To elucidate the role of p53 and MYC in regulating transcription during DNA damage.
  • To determine the impact of MYC suppression on cell-fate decisions.

Main Methods:

  • RNA sequencing (RNA-seq) of newly synthesized transcripts.
  • Analysis of p53 and MYC oscillations in response to double-strand breaks.
  • Experimental manipulation of MYC levels during DNA damage response.

Main Results:

  • p53 oscillations lead to counter-oscillatory MYC decrease.
  • p53-mediated MYC suppression reduces global transcription, particularly highly expressed genes.
  • Upregulation of p53 targets is largely independent of MYC suppression.
  • Counteracting MYC repression reduces cell-cycle arrest and increases apoptosis.

Conclusions:

  • Global transcriptional suppression coupled with specific pathway activation is vital for DNA damage response.
  • The p53-MYC axis plays a critical role in cell-fate regulation during DNA damage.
  • This regulatory mechanism may be a general principle in cellular stress responses.
Keywords:
DNA damageMYCapoptosiscell cyclep53transcriptome

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