P-bodies regulate transcriptional rewiring to promote DNA replication stress resistance
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA326238 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3696510.fastq.gz | Fastqsanger.gz | |||
| SRR3696520.fastq.gz | Fastqsanger.gz | |||
| SRR3696511.fastq.gz | Fastqsanger.gz | |||
| SRR3696521.fastq.gz | Fastqsanger.gz | |||
| SRR3696512.fastq.gz | Fastqsanger.gz |
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Project description:mRNA processing bodies (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 down-regulation of a network of genes critical for DNA replication stress resistance. Among these genes we identify ALD6, whose de-repression is critical to prevent accumulation of acetaldehyde, a strongly toxic molecule during DNA replication stress. This SuperSeries is composed of the SubSeries listed below.
2017-06-26 | GSE83515 | GEO
Project description:FBXL12 degrades FANCD2 to regulate replication recovery and promote cancer cell survival under conditions of replication stress
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Project description: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.P-bodies form in response to stress and act as sites of mRNA storage and degradation. Here the authors identify the mRNA targets of P-bodies during DNA replication stress, and show that P-body proteins act to prevent toxic accumulation of these target transcripts.
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Project description:Transcription bodies regulate gene expression by sequestering CDK9
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Project description:Oncogene-induced replication stress constitutes an early obstacle for pre-cancerous cells to overcome to progress towards malignancy. Fanconi anaemia signalling represents a major genomic maintenance pathway that is activated in response to replication stress, impinging on stalled replication fork stability and recovery. Here, we report that upon replication stress, phosphorylation of the FANCD2 N-terminus by CHK1 triggers FBXL12-dependent proteasomal degradation of FANCD2, facilitating clearance of FANCD2 at stalled replication forks. This mechanism is required to promote efficient and faithful DNA replication under conditions of CYCLIN E- and drug-induced replication stress. Notably, reconstitution of FANCD2 with mutations in the N-terminal phosphodegron fail to re-establish fork progression in FANCD2-deficient human fibroblasts in response to replication stress. In the absence of FBXL12, FANCD2 becomes trapped on chromatin leading to replication stress, excessive DNA damage, and cell death. In human cancers, FBXL12, CYCLIN E, and Fanconi anaemia signalling are positively correlated and upregulation or amplification of FBXL12 is linked to reduced survival in patients with high CYCLIN E expressing breast tumours. Finally, depletion of FBXL12 exacerbated oncogene-induced replication stress and sensitised breast cancer cells to drug-induced replication stress by WEE1 inhibition. Collectively, our results indicate that FBXL12 constitutes a vulnerability of CYCLIN E-overexpressing cancer cells and may represent a novel target for cancer therapy.
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Project description:Oncogene-induced replication stress constitutes an early obstacle for pre-cancerous cells to
overcome to progress towards malignancy. Fanconi anaemia signalling represents a major
genomic maintenance pathway that is activated in response to replication stress, impinging on
stalled replication fork stability and recovery. Here, we report that FBXL12 ubiquitinates the
central Fanconi anaemia protein FANCD2 at stalled replication forks upon CHK1-mediated
phosphorylation, resulting in FANCD2 degradation. This mechanism is required to promote
efficient and faithful DNA replication under conditions of cyclin E- and drug-induced
replication stress. In the absence of FBXL12, FANCD2 becomes trapped on chromatin leading
to replication stress, excessive DNA damage, and cell death. In human cancers, FBXL12, cyclin
E, and Fanconi anaemia signalling are positively correlated and upregulation or amplification
of FBXL12 is linked to reduced survival in patients with high cyclin E expressing breast
tumours. Finally, depletion of FBXL12 exacerbated oncogene-induced replication stress and
sensitised breast cancer cells to drug-induced replication stress by WEE1 inhibition.
Collectively, our results indicate that FBXL12 constitutes a vulnerability of cyclin E-
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Project description:The localization of transcriptional activity in specialized transcription bodies is a hallmark of gene expression in eukaryotic cells. It remains unclear, however, if and how they affect gene expression. Here, we disrupted the formation of two prominent endogenous transcription bodies that mark the onset of zygotic transcription in zebrafish embryos and analysed the effect on gene expression using enriched SLAM-Seq and live-cell imaging. We find that the disruption of transcription bodies results in downregulation of hundreds of genes, providing experimental support for a model in which transcription bodies increase the efficiency of transcription. We also find that a significant number of genes are upregulated, counter to the suggested stimulatory effect of transcription bodies. These upregulated genes have accessible chromatin and are poised to be transcribed in the presence of the two transcription bodies, but they do not go into elongation. Live-cell imaging shows that the disruption of the two large transcription bodies enables these poised genes to be transcribed in ectopic transcription bodies, suggesting that the large transcription bodies sequester a pause release factor. Supporting this hypothesis, we find that CDK9, the kinase that releases paused polymerase II, is highly enriched in the two large transcription bodies. Importantly, overexpression of CDK9 in wild type embryos results in the formation of ectopic transcription bodies and thus phenocopies the removal of the two large transcription bodies. Taken together, our results show that transcription bodies regulate transcription genome-wide: the accumulation of transcriptional machinery creates a favourable environment for transcription locally, while depriving genes elsewhere in the nucleus from the same machinery.
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Project description:The localization of transcriptional activity in specialized transcription bodies is a hallmark of gene expression in eukaryotic cells. It remains unclear, however, if and how they affect gene expression. Here, we disrupted the formation of two prominent endogenous transcription bodies that mark the onset of zygotic transcription in zebrafish embryos and analysed the effect on gene expression using enriched SLAM-Seq and live-cell imaging. We find that the disruption of transcription bodies results in downregulation of hundreds of genes, providing experimental support for a model in which transcription bodies increase the efficiency of transcription. We also find that a significant number of genes are upregulated, counter to the suggested stimulatory effect of transcription bodies. These upregulated genes have accessible chromatin and are poised to be transcribed in the presence of the two transcription bodies, but they do not go into elongation. Live-cell imaging shows that the disruption of the two large transcription bodies enables these poised genes to be transcribed in ectopic transcription bodies, suggesting that the large transcription bodies sequester a pause release factor. Supporting this hypothesis, we find that CDK9, the kinase that releases paused polymerase II, is highly enriched in the two large transcription bodies. Importantly, overexpression of CDK9 in wild type embryos results in the formation of ectopic transcription bodies and thus phenocopies the removal of the two large transcription bodies. Taken together, our results show that transcription bodies regulate transcription genome-wide: the accumulation of transcriptional machinery creates a favourable environment for transcription locally, while depriving genes elsewhere in the nucleus from the same machinery.
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Project description:Transcription bodies regulate gene expression by sequestering CDK9 [SLAM-seq I]
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