Abstract
mRNA-processing (P-) bodies are cytoplasmic granules that form in eukaryotic cells in response to numerous stresses to serve as sites of degradation and storage of mRNAs. Functional P-bodies are critical for the DNA replication stress response in yeast, yet the repertoire of P-body targets and the mechanisms by which P-bodies promote replication stress resistance are unknown. In this study we identify the complete complement of mRNA targets of P-bodies during replication stress induced by hydroxyurea treatment. The key P-body protein Lsm1 controls the abundance of HHT1, ACF4, ARL3, TMA16, RRS1 and YOX1 mRNAs to prevent their toxic accumulation during replication stress. Accumulation of YOX1 mRNA causes aberrant downregulation of a network of genes critical for DNA replication stress resistance and leads to toxic acetaldehyde accumulation. Our data reveal the scope and the targets of regulation by P-body proteins during the DNA replication stress response.
Highlights
MRNA-processing (P-) bodies are cytoplasmic granules that form in eukaryotic cells in response to numerous stresses to serve as sites of degradation and storage of mRNAs
As available data indicate that P-body regulation of mRNA targets is relevant to DNA replication stress resistance, we sought to identify the network of P-body targets to understand how they contribute to cellular fitness during DNA replication stress
In order to identify the complement of mRNA targets of P-body regulation, we used RNA-seq to profile the transcriptomes of wild-type (WT) and lsm1Δ cells, in the presence and absence of the replication stress inducing drug hydroxyurea (HU) (Fig. 1a)
Summary
MRNA-processing (P-) bodies are cytoplasmic granules that form in eukaryotic cells in response to numerous stresses to serve as sites of degradation and storage of mRNAs. Accumulation of YOX1 mRNA causes aberrant downregulation of a network of genes critical for DNA replication stress resistance and leads to toxic acetaldehyde accumulation. Our data reveal the scope and the targets of regulation by P-body proteins during the DNA replication stress response. In the model eukaryote Saccharomyces cerevisiae, the DNA replication stress response has been extensively studied at both the single-gene/protein level and at the genome/proteome scale[3,4,5,6,7,8,9,10]. Our genomic analyses converge on the transcription factor Yox[1], whose accumulation is toxic in cells experiencing replication stress, and whose mRNA localizes to P-bodies. We identify a key DNA replication stress resistance pathway regulated by the P-body target YOX1
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