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Yeast As a Chassis for Developing Functional Assays to Study Human P53
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Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

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Global analysis of p53-regulated transcription identifies its direct targets and unexpected regulatory mechanisms

Mary Ann Allen1, Zdenek Andrysik2, Veronica L Dengler2

  • 1Howard Hughes Medical Institute, University of Colorado, Boulder, Boulder, United States Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Boulder, United States BioFrontiers Institute, Boulder, United States Computational Biosciences Program, University of Colorado, Denver-Anschutz Medical Campus, Aurora, United States.

Elife
|May 29, 2014
PubMed

Insights

The p53 tumor suppressor rapidly activates hundreds of genes, including many novel targets, upon MDM2 inhibition. This study reveals new regulatory mechanisms and uncharacterized p53 target genes using Global Run-On sequencing (GRO-seq).

Area of Science:

  • Molecular Biology
  • Genomics
  • Cancer Research

Background:

  • The p53 transcription factor is a critical tumor suppressor.
  • Understanding its direct transcriptional targets is key to cancer therapy.

Purpose of the Study:

  • To analyze the direct transcriptional program of p53 using Global Run-On sequencing (GRO-seq).
  • To identify novel p53 target genes and regulatory mechanisms.

Main Methods:

  • Global Run-On sequencing (GRO-seq) to analyze RNA synthesis.
  • MDM2 inhibition using Nutlin-3 to activate p53.
  • Comparative analysis of RNA synthesis versus steady-state levels.

Main Results:

  • p53 rapidly activates approximately 200 genes upon MDM2 inhibition, many previously unknown.
  • Microarray profiling misses low-abundance p53-activated transcripts.
  • p53 regulates enhancer-derived RNAs and represses some targets before activation.
  • Direct p53 targets show pre-activated enhancers, even in p53-null cells.

Conclusions:

  • GRO-seq reveals a complex p53 transcriptional network with novel targets and regulatory features.
  • This work expands the understanding of p53's role in tumor suppression and identifies new avenues for research.
Keywords:
PIG3PUMAeRNAgenomicsp21tumor supressor

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