Ontology highlight
ABSTRACT:
PROVIDER: PRJNA508952 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8197260.fastq.gz | Fastqsanger.gz | |||
| SRR8197270.fastq.gz | Fastqsanger.gz | |||
| SRR8197261.fastq.gz | Fastqsanger.gz | |||
| SRR8197271.fastq.gz | Fastqsanger.gz | |||
| SRR8197262.fastq.gz | Fastqsanger.gz |
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Project description:dsDNA Breaks and Genome Editing Trigger Ribosome Remodeling and Translational Shutdown
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Project description:DNA damage activates a robust transcriptional stress response, but much less is known about how DNA damage impacts translation. The advent of genome editing with Cas9 has intensified interest in understanding cellular responses to DNA damage. Here, we find that DNA double-strand breaks (DSBs), including those induced by Cas9, trigger the loss of ribosomal protein RPS27A from ribosomes via p53-independent proteasomal degradation. Comparisons of Cas9 and dCas9 ribosome profiling and mRNA-seq experiments reveal a global translational response to DSBs that precedes changes in transcript abundance. Our results demonstrate that even a single DSB can lead to altered translational output and ribosome remodeling, suggesting caution in interpreting cellular phenotypes measured immediately after genome editing.
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Project description:In Saccharomyces cerevisiae, glucose depletion induces metabolic reprogramming through widespread transcriptional and translational reorganization. We report that initial very rapid translational silencing is driven by a specialized metabolic mechanism. Following glucose withdrawal, intracellular NTP levels drop drastically over 30 sec, before stabilizing at a regulated, post-stress set-point. Programmed translational control results from the differential NTP affinities of key enzymes; ATP falls below the (high) binding constants for DEAD-box helicase initiation factors, including eIF4A, driving mRNA release and blocking 80S assembly. Contrastingly, GTP levels always greatly exceed the (low) binding constants for elongation factors, allowing ribosome run-off and orderly translation shutdown. Translation initiation is immediately lost on all pre-existing mRNAs, before being selectively re-established on newly synthesized, upregulated stress-response transcripts. This response is unique to, and potentially de-risks, rapid glycolytic growth. We conclude that enzymatic constants are tuned for metabolic remodeling, allowing hierarchical inhibition of energy-consuming processes on very rapid timescales.
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Project description:Ribosomal stress was evaluated in melanoma cell line CHL-1 after CRISPR editing genomic locus containing SNORD50A/B We have used CRISPR genome editing tool to KD snoRNAs SNORD50A/B from CHL-1 genome and assessed ribosomal binding genome-wide using ribosome profiling
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Project description:The WEE1 kinase negatively regulates the CDK1/2 kinases to control DNA replication and prevent premature entry into mitosis. Pharmacological inhibition of WEE1 (WEE1i) causes hyperactivation of CDK1 and CDK2, leading to premature mitosis in the presence of DNA lesions. WEE1i treatment is particularly cytotoxic in cells with oncogene-induced or treatment-induced replication stress. To uncover genetic factors that sensitize cancer cells to WEE1i, a genome-wide insertional mutagenesis screen was performed and identified that mutation of the alternative translation initiation factor EIF2A sensitized cells to WEE1i. WEE1i sensitivity of EIF2AKO cells was not explained by altered replication kinetics. Rather, WEE1i leads to a translational shut-down which is lethal in combination with the reduced translation in EIF2AKO cells. A genome-wide CRISPR-Cas9 screen in WEE1i-treated cells revealed that inactivation of the integrated stress response (ISR) kinase GCN2 rescued WEE1i-mediated cytotoxicity. In line with these findings, WEE1i resulted in GCN2 activation, ATF4 upregulation and a translational shutdown. Moreover, WEE1 inhibition leads to altered ribosome dynamics and increased ribosome collisions. Accordingly, cells lacking the collided ribosome sensor ZNF598 show increased sensitivity to WEE1i. This response was not restricted to cancer cells, but was also observed in peripheral blood monocytic cells. The GCN2-mediated ISR was not required for WEE1i to induce DNA damage in S-phase, premature mitotic entry nor the sensitizing effects to DNA damaging chemotherapeutics. Conversely, ISR activation and translational shut-down are independent on WEE1i-mediated activation of CDK1/2. WEE1i-mediated ISR activation was independent of the presence of WEE1, pointing at an off-target effect, which is shared by multiple chemically distinct WEE1 inhibitors. Importantly, WEE1 inhibition at doses that do not induce the ISR can still synergize with PKMYT1 inhibition. Taken together, pharmacological WEE1 inhibition triggers cytotoxic ISR activation and translational shutdown, which can be prevented by low-dose treatments, while retaining the cell cycle checkpoint-perturbing effects.
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Project description:The WEE1 kinase negatively regulates the CDK1/2 kinases to control DNA replication and prevent premature entry into mitosis. Pharmacological inhibition of WEE1 (WEE1i) causes hyperactivation of CDK1 and CDK2, leading to premature mitosis in the presence of DNA lesions. WEE1i treatment is particularly cytotoxic in cells with oncogene-induced or treatment-induced replication stress. To uncover genetic factors that sensitize cancer cells to WEE1i, a genome-wide insertional mutagenesis screen was performed and identified that mutation of the alternative translation initiation factor EIF2A sensitized cells to WEE1i. WEE1i sensitivity of EIF2AKO cells was not explained by altered replication kinetics. Rather, WEE1i leads to a translational shut-down which is lethal in combination with the reduced translation in EIF2AKO cells. A genome-wide CRISPR-Cas9 screen in WEE1i-treated cells revealed that inactivation of the integrated stress response (ISR) kinase GCN2 rescued WEE1i-mediated cytotoxicity. In line with these findings, WEE1i resulted in GCN2 activation, ATF4 upregulation and a translational shutdown. Moreover, WEE1 inhibition leads to altered ribosome dynamics and increased ribosome collisions. Accordingly, cells lacking the collided ribosome sensor ZNF598 show increased sensitivity to WEE1i. This response was not restricted to cancer cells, but was also observed in peripheral blood monocytic cells. The GCN2-mediated ISR was not required for WEE1i to induce DNA damage in S-phase, premature mitotic entry nor the sensitizing effects to DNA damaging chemotherapeutics. Conversely, ISR activation and translational shut-down are independent on WEE1i-mediated activation of CDK1/2. WEE1i-mediated ISR activation was independent of the presence of WEE1, pointing at an off-target effect, which is shared by multiple chemically distinct WEE1 inhibitors. Importantly, WEE1 inhibition at doses that do not induce the ISR can still synergize with PKMYT1 inhibition. Taken together, pharmacological WEE1 inhibition triggers cytotoxic ISR activation and translational shutdown, which can be prevented by low-dose treatments, while retaining the cell cycle checkpoint-perturbing effects.
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