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P-body proteins regulate transcriptional rewiring to promote DNA replication stress resistance

Raphael Loll-Krippleber1, Grant W Brown2

  • 1Department of Biochemistry and Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON, Canada, M5S 3E1.

Nature Communications
|September 17, 2017
PubMed

Insights

Cytoplasmic mRNA-processing bodies (P-bodies) store and degrade mRNAs during cellular stress. This study identifies P-body mRNA targets during DNA replication stress, revealing how they prevent toxic transcript accumulation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • mRNA-processing bodies (P-bodies) are dynamic cytoplasmic granules involved in mRNA regulation.
  • P-bodies play a crucial role in cellular stress responses, including DNA replication stress.
  • The specific mRNA targets and regulatory mechanisms of P-bodies during replication stress remain largely uncharacterized.

Purpose of the Study:

  • To identify the complete set of mRNA targets regulated by P-bodies during hydroxyurea-induced DNA replication stress.
  • To elucidate the role of P-body proteins, specifically Lsm1, in controlling the abundance of specific mRNAs.
  • To investigate the functional consequences of aberrant mRNA accumulation during replication stress.

Main Methods:

  • Hydroxyurea treatment to induce DNA replication stress in yeast.
  • Identification of P-body mRNA targets using quantitative molecular biology techniques.
  • Analysis of gene expression changes and cellular phenotypes.

Main Results:

  • The study identified a comprehensive list of P-body mRNA targets during replication stress.
  • The P-body protein Lsm1 was found to regulate the abundance of HHT1, ACF4, ARL3, TMA16, RRS1, and YOX1 mRNAs.
  • Accumulation of YOX1 mRNA led to the downregulation of critical DNA replication stress resistance genes and toxic acetaldehyde accumulation.

Conclusions:

  • P-bodies actively regulate mRNA populations during DNA replication stress.
  • Specific P-body proteins like Lsm1 are essential for preventing the accumulation of potentially toxic mRNAs.
  • Dysregulation of P-body targets can impair cellular stress resistance and lead to detrimental metabolic consequences.

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