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Tia1 dependent regulation of mRNA subcellular location and translation controls p53 expression in B cells

Manuel D Díaz-Muñoz1,2, Vladimir Yu Kiselev3,4, Nicolas Le Novère3

  • 1Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge, CB22 3AT, UK. manuel.diaz-munoz@babraham.ac.uk.

Nature Communications
|September 15, 2017
PubMed

Insights

Cellular mRNA regulation is vital for protein synthesis. This study reveals how p53 mRNA translation and stress granule localization are controlled during DNA damage and B lymphocyte activation.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Immunology

Background:

  • Post-transcriptional regulation of mRNA is crucial for protein synthesis.
  • mRNA translational repression and subcellular localization impact protein expression.
  • Cytoplasmic RNA granules, including stress granules, form upon cell activation.

Purpose of the Study:

  • To investigate the role of mRNA translational repression and subcellular localization in B lymphocyte activation and DNA damage response.
  • To elucidate the mechanism by which p53 mRNA translation is regulated.
  • To understand the function of the RNA-binding protein Tia1 in these processes.

Main Methods:

  • Analysis of mRNA abundance and translation.
  • Study of RNA-binding protein Tia1 interactions with p53 mRNA.
  • Investigation of stress granule formation and dynamics.
  • Assessment of ATM-dependent pathways.

Main Results:

  • Tia1 binds to p53 mRNA, controlling its translational silencing and localization in stress granules.
  • DNA damage causes dissociation of Tia1 from p53 mRNA, leading to its release from stress granules.
  • p53 mRNA associates with polyribosomes for CAP-independent translation upon DNA damage.
  • This is an ATM-dependent mechanism to enhance protein expression of DNA damage response modulators.

Conclusions:

  • Sequestering mRNA in cytoplasmic stress granules is a key mechanism for translational repression.
  • Upon DNA damage, p53 mRNA is released from stress granules and translated in a CAP-independent manner.
  • This process is part of an extended ATM-dependent pathway to boost protein synthesis of DNA damage response regulators.

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