Rpd3L Contributes to the DNA Damage Sensitivity of Saccharomyces cerevisiae Checkpoint Mutants
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ABSTRACT:
PROVIDER: PRJNA454307 | ENA |
REPOSITORIES: ENA
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Project description:DNA replication forks that are stalled by DNA damage activate an S phase checkpoint that prevents irreversible fork arrest and cell death. The increased cell death caused by DNA damage in budding yeast cells lacking the Rad53 checkpoint protein kinase is partially suppressed by deletion of the EXO1 gene. Here,we identified that loss of the histone deacetylase complex Rpd3L promotes survival of rad53∆ cells exposed to DNA damaging agents. From epistasis analysis, we show that this suppression operates in a separate pathway from the previously described suppression by deletion of EXO1.
2019-02-27 | GSE113869 | GEO
Project description: Not available
| S-EPMC6366903 | biostudies-literature
Project description:DNA damage results in the activation of checkpoint kinases, which phosphorylate downstream effectors that inhibit the cell cycle, activate DNA repair, and cause widespread changes in transcription. However, the specific connections between the checkpoint kinases and downstream transcription factors (TFs) are not well understood. Here, we introduce a strategy for mapping regulatory networks between kinases and TFs involving integration of kinase mutant expression profiles, transcriptional regulatory interactions, and phosphoproteomics. We use this approach to investigate the role of the Saccharomyces cerevisiae checkpoint kinases (Mec1, Tel1, Chk1, Rad53, and Dun1) in the transcriptional response to DNA damage caused by methyl methanesulfonate (MMS). The result is a global kinase-TF regulatory network in which Mec1 and Tel1 signal through Rad53 to synergistically regulate the expression of more than 600 genes. This network implicates at least nine TFs, including Msn4, Gcn4, SBF (Swi4/Swi6), MBF (Swi6/Mbp1), and Fkh2/Ndd1/Mcm1, nearly all of which have sites of Rad53-dependent phosphorylation, as downstream regulators of checkpoint kinase-dependent genes. We also identify a major DNA damage-induced transcriptional network acting independently of Rad53 and other checkpoint kinases to regulate expression of genes involved in general and oxidative stress responses. Expression was profiled with and without MMS treatment in several genetic backgrounds (gene deletion strains).
2013-03-31 | E-GEOD-40351 | biostudies-arrayexpress
Project description:Regulation of the DNA damage response and cell cycle progression is critical for maintaining genome integrity. Here we report that in response to DNA damage, COPS5 deubiquitinates and stabilizes PEA15 in an ATM kinase-dependent manner. PEA15 expression oscillates throughout the cell cycle, and the loss of PEA15 accelerates cell cycle progression by activating CDK6 expression via the c-JUN transcription factor. Cells lacking PEA15 exhibit a DNA damage-induced G2/M checkpoint defect due to increased CDC25C activity and consequentially higher CDK1/Cyclin B activity and accordingly have an increased rate of spontaneous mutagenesis. We find that oncogenic RAS inhibits PEA15 expression and ectopic PEA15 expression blocks RAS-mediated transformation, which can be partially rescued by ectopic expression of CDK6. Finally, we show that PEA15 expression is down regulated in colon, breast and lung cancer samples. Collectively, our results demonstrate that tumor suppressor PEA15 is a regulator of genome integrity and is an integral component of the DNA damage response pathway that regulates cell cycle progression, the DNA-damage-induced G2/M checkpoint and cellular transformation. HCT116 cells stably expressing a non-silencing shRNA or two individual shRNAs against PEA15 were used to prepare the total RNA, which was then used to analyze for gene expression using Illumina expression array.
2014-04-07 | E-GEOD-39297 | biostudies-arrayexpress
Project description:To investigate the importance of DNA damage checkpoint regulation in mammalian preimplantation embryos, we overexpressed wild type and mutant form of CHK1 kinase in mouse zygotes and performed high-throughput RNA-sequencing of zygotes, late 2-cell embryos and blastocysts. Transcriptome analysis revealed that zygotes are particular sensitive to the perturbation of Chk1 governed DNA damage checkpoint. However, once zygotes can overcome DNA damage checkpoint induced cell cycle arrest, they can still have normal development.
2021-05-04 | GSE163765 | GEO
Project description:iTRAQ-based quantitative proteomics and phosphoproteomics analyses of induced pluripotent stem cells (iPSC) from patients with longstanding type 1 diabetes. "Preserved DNA Damage Checkpoint Pathway Protects From Complications in Long-standing Type 1 Diabetes", Cell Metabolism, in press.
2015-07-08 | MSV000079185 | MassIVE
Project description:DNA damage results in the activation of checkpoint kinases, which phosphorylate downstream effectors that inhibit the cell cycle, activate DNA repair, and cause widespread changes in transcription. However, the specific connections between the checkpoint kinases and downstream transcription factors (TFs) are not well understood. Here, we introduce a strategy for mapping regulatory networks between kinases and TFs involving integration of kinase mutant expression profiles, transcriptional regulatory interactions, and phosphoproteomics. We use this approach to investigate the role of the Saccharomyces cerevisiae checkpoint kinases (Mec1, Tel1, Chk1, Rad53, and Dun1) in the transcriptional response to DNA damage caused by methyl methanesulfonate (MMS). The result is a global kinase-TF regulatory network in which Mec1 and Tel1 signal through Rad53 to synergistically regulate the expression of more than 600 genes. This network implicates at least nine TFs, including Msn4, Gcn4, SBF (Swi4/Swi6), MBF (Swi6/Mbp1), and Fkh2/Ndd1/Mcm1, nearly all of which have sites of Rad53-dependent phosphorylation, as downstream regulators of checkpoint kinase-dependent genes. We also identify a major DNA damage-induced transcriptional network acting independently of Rad53 and other checkpoint kinases to regulate expression of genes involved in general and oxidative stress responses.
2013-03-31 | GSE40351 | GEO
Project description:PBRM1 is a subunit of the PBAF (SWI/SNF) chromatin remodelling complex that is mutated in approximately 40% of clear cell renal cell carcinomas (ccRCC). PBRM1 loss has been implicated in the response to immune checkpoint inhibitor (ICI) therapy in ccRCC. However, it is unclear how PBRM1 influences this. DNA damage-induced inflammatory signalling is an important factor determining ICI therapy response. This response is kept in check by the G2/M checkpoint, which prevents progression through mitosis with unrepaired damage. Here, we show that PBRM1 is required for p53-dependent maintenance of the G2/M checkpoint. In its absence, p53-dependent transcriptional upregulation of p21 is delayed, leading to defective repression of DREAM complex targets and premature entry into mitosis. Consequently, DNA damage induced inflammatory signalling pathways are activated by cytosolic DNA. Notably, p53 is infrequently mutated in ccRCC, so PBRM1 mutational status is critical to G2/M checkpoint maintenance following DNA damage in this cancer. These findings have implications for ICI therapy responses in ccRCC.
2022-10-13 | PXD028336 | Pride
Project description:This study aimed to investigate the role of DNA damage contributes in STING pathway activation and its implication in colorectal cancer.
2021-01-14 | GSE164730 | GEO
Project description:Comparative genomic hybridization was performed to compare amplification gradients of stage 13 follicle cells from several DNA damage checkpoint and double-strand break repair mutants to wild-type (OrR) gradients. Two-three replicates were done for each genotype.
2015-06-18 | GSE66690 | GEO