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Purification of Ubiquitinated p53 Proteins from Mammalian Cells
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Purification of Ubiquitinated p53 Proteins from Mammalian Cells

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Drosophila p53 directs nonapoptotic programs in postmitotic tissue

Paula Kurtz1, Amanda E Jones1, Bhavana Tiwari1

  • 1Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.

Molecular Biology of the Cell
|March 21, 2019
PubMed

Insights

The tumor suppressor p53 (TP53) has distinct functions in adult tissues. In adult fruit fly heads, p53 regulates DNA repair and metabolism, not apoptosis, despite its role in embryonic development.

Area of Science:

  • Genetics
  • Molecular Biology
  • Developmental Biology

Background:

  • TP53 is the most frequently mutated gene in human cancers.
  • Genome-scale studies of p53 function in whole animal models are rare.
  • Unappreciated p53 functions may contribute to cancer prevention.

Purpose of the Study:

  • To interrogate p53 function in a postmitotic context using the Drosophila system.
  • To investigate the mechanisms underlying differential p53 activity in developing versus adult tissues.

Main Methods:

  • Comparative RNA-sequencing (RNA-seq) of developing and adult tissues.
  • Chromatin immunoprecipitation followed by sequencing (ChIP-seq) to map p53 binding sites.
  • Analysis of p53 enhancer activity and chromatin contacts.

Main Results:

  • In developing Drosophila embryos, p53 activates apoptotic genes in response to DNA damage via long-range enhancers.
  • In adult Drosophila heads, the canonical p53 apoptotic program fails to activate.
  • p53 does not bind to the apoptotic enhancer in adult heads but regulates distinct genes involved in DNA repair, metabolism, and proteolysis.
  • p53 binding landscapes in adult heads showed poor correlation with nearby transcriptional effects, suggesting long-range enhancer action.

Conclusions:

  • p53 exhibits context-dependent functions, regulating apoptosis in developing tissues and distinct pathways in postmitotic adult tissues.
  • The differential regulation of p53 targets in adult tissues is not due to altered chromatin contacts but rather p53 occupancy at enhancers.
  • p53 enhancers may generally act over long distances, with binding landscapes poorly correlated with proximal gene expression in postmitotic cells.

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