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Published on: August 4, 2019

p53 activates transcription by directing structural shifts in Mediator

Krista D Meyer1, Shih-Chieh Lin, Carrie Bernecky

  • 1Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado, USA.

Nature Structural & Molecular Biology
|May 11, 2010
PubMed

Insights

The p53 protein's interaction with the Mediator complex causes structural changes that activate RNA polymerase II (Pol II) transcription. These Mediator structural shifts are crucial for initiating gene expression by releasing stalled Pol II.

Area of Science:

  • Molecular Biology
  • Gene Regulation
  • Biochemistry

Background:

  • The precise mechanisms of transcription initiation involving the Mediator complex, transcription factor IIH (TFIIH), and RNA polymerase II (Pol II) remain unclear.
  • Activator binding to Mediator induces structural changes, but their functional impact on transcription is not well understood.

Purpose of the Study:

  • To elucidate how the p53 protein interacts with the Mediator complex to regulate transcription initiation.
  • To investigate the structural consequences of p53 binding to Mediator and their effect on Pol II activity.

Main Methods:

  • Studied p53 C-terminus and activation domain interactions with Mediator subunits.
  • Analyzed structural changes in the Mediator complex upon p53 binding using structural biology techniques.
  • Assessed the impact of these structural changes on Pol II activity and C-terminal domain phosphorylation.

Main Results:

  • Distinct p53-Mediator interactions lead to differential Mediator structures.
  • The p53 activation domain induces a pocket at the Mediator-Pol II interface, activating stalled Pol II.
  • Mediator is required for TFIIH-dependent Pol II C-terminal domain phosphorylation, with distinct p53-Mediator structures correlating with different Pol II processing.

Conclusions:

  • p53 binding induces specific Mediator structural shifts that are critical for activating transcription.
  • Mediator structural rearrangements are a key mechanism for releasing stalled Pol II and promoting productive elongation.
  • These findings reveal a fundamental pathway for p53-mediated transcriptional activation.

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