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RPA and ATR link transcriptional stress to p53

Frederick A Derheimer1, Heather M O'Hagan, Heather M Krueger

  • 1Department of Radiation Oncology, Division of Radiation and Cancer Biology, University of Michigan Comprehensive Cancer Center, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA.

Proceedings of the National Academy of Sciences of the United States of America
|July 10, 2007
PubMed

Insights

DNA damage response is activated by transcription blockage, leading to p53 protein accumulation. This process involves mRNA export inhibition and replication protein A (RPA)- and ATM and Rad3-related (ATR)-dependent phosphorylation of p53.

Area of Science:

  • Molecular Biology
  • Cellular Stress Response
  • DNA Damage Signaling

Background:

  • The precise mechanisms linking DNA-damaging agents to the activation of the stress response protein p53 remain unclear.
  • Potential pathways include chromatin alterations, transcription blockage, or replication interference.

Purpose of the Study:

  • To elucidate how transcription-blocking agents induce the stress response protein p53.
  • To investigate the role of transcription and replication in p53 induction.

Main Methods:

  • Utilized transcription-blocking agents to assess p53 phosphorylation at Ser-15.
  • Employed microinjection of anti-RNA polymerase II antibodies to study transcription blockage effects.
  • Investigated p53 accumulation mechanisms, including mRNA nuclear export and RPA/ATR involvement.

Main Results:

  • Transcription-blocking agents induce Ser-15 phosphorylation of p53 independently of replication.
  • Blockage of transcription alone is sufficient for p53 accumulation, even without DNA damage.
  • p53 induction involves diminished mRNA nuclear export and RPA/ATR-dependent Ser-15 phosphorylation.

Conclusions:

  • Transcription-based stress response pathways involving RPA, ATR, and p53 act as a DNA damage-sensing mechanism.
  • This mechanism safeguards cells against DNA damage-induced mutagenesis.
  • Transcription inhibition is a key trigger for p53-mediated cellular protection.

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