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Yeast As a Chassis for Developing Functional Assays to Study Human P53
14:57

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

Published on: August 4, 2019

Novel dyskerin-mediated mechanism of p53 inactivation through defective mRNA translation

Lorenzo Montanaro1, Maria Calienni, Sara Bertoni

  • 1Dipartimento di Patologia Sperimentale, Università di Bologna, via San Giacomo 14, 40126 Bologna, Italy. lorenzo.montanaro@unibo.it

Cancer Research
|May 27, 2010
PubMed

Insights

Dyskerin impairment hinders p53 translation, impacting tumor suppressor function. This mechanism of p53 inactivation, independent of telomerase, may occur in human cancers.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genetics

Background:

  • p53 gene mutations inactivate tumor suppressor functions in up to 60% of human cancers.
  • Alternative p53 inactivation mechanisms primarily affect its posttranslational regulation.
  • Dyskerin (DKC1) mutations in X-linked dyskeratosis congenita impair translation of internal ribosome entry site (IRES)-containing mRNAs.

Purpose of the Study:

  • To investigate if dyskerin impairment causes p53 inactivation through defective mRNA translation.
  • To explore the role of dyskerin in p53 mRNA translation initiation and functional activity.
  • To determine if dyskerin levels correlate with p53 activity in human breast cancers.

Main Methods:

  • siRNA-mediated reduction of dyskerin levels in human breast cancer and primary mammary epithelial progenitor cells.
  • Assessment of p53 mRNA translation, protein levels, and functional activity.
  • Analysis of dyskerin expression and p53 target gene expression in human primary breast cancers.

Main Results:

  • Reduced dyskerin levels decreased p53 mRNA translation, protein levels, and functional activity.
  • Impairment of translation initiation via IRES elements in p53 mRNA was observed.
  • Low dyskerin expression in primary breast cancers correlated with reduced expression of p53 target genes.
  • Effects were independent of dyskerin's known role in telomerase function.

Conclusions:

  • Dyskerin impairment can lead to p53 inactivation by disrupting p53 mRNA translation.
  • This dyskerin-mediated mechanism of p53 inactivation may occur in a subset of human tumors.
  • Targeting dyskerin could be a potential strategy for cancer therapy.

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