Global genomic instability caused by reduced expression of DNA polymerase ε in yeast [DZP2-derived isolates]
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PROVIDER: PRJNA768823 | ENA |
REPOSITORIES: ENA
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Project description:Yeast Saccharomyces cerevisiae has been widely used as a model system for studying genome instability. Here, a heterozygous diploid S. cerevisiae strain DZP2 was generated to determine the genomic alterations induced by DNA polymerase ε. The expression of POL2 was regulated by the GAL1 promoter. In combination of a custom SNP microarray, the patterns of chromosomal instability induced by low Pol ε could be explored at a whole genome level in DZP2. Using this system, we found hundreds-fold higher rate of genomic alterations, including aneuploidy, loss of heterozygosity (LOH), and chromosomal rearrangement. DNA polymerase ε (Pol ε) is one of the three replicative eukaryotic DNA polymerases. Pol ε deficiency leads to genomic instability and multiple human diseases. Here, we explored global genomic alterations in yeast strains with reduced expression of POL2, the gene that encodes the catalytic subunit of Pol ε. Using whole-genome SNP microarray and sequencing, we found that low levels of Pol ε elevated the rates of mitotic recombination and chromosomal aneuploidy by two orders of magnitude. Strikingly, low levels of Pol ε resulted in a contraction of the number of repeats in the rDNA cluster and reduced the length of telomeres. These short telomeres led to an elevated frequency of break-induced replication, resulting in terminal loss of heterozygosity. In addition, low levels of Pol ε increased the rate of single-base mutations by 13-fold by a Pol ζ-dependent pathway. Finally, the patterns of genomic alterations caused by low levels of Pol ε were different from those observed in strains with low levels of the other replicative DNA polymerases Pol α and Pol δ, providing further insights into the different roles of the B-family DNA polymerases in maintaining genomic stability.
2021-10-07 | GSE185365 | GEO
Project description:Yeast Saccharomyces cerevisiae has been widely used as a model system for studying genome instability. Here, a heterozygous diploid S. cerevisiae strain DZP2 was generated to determine the genomic alterations induced by DNA polymerase ε. The expression of POL2 was regulated by the GAL1 promoter. In combination of a custom SNP microarray, the patterns of chromosomal instability induced by low Pol ε could be explored at a whole genome level in DZP2. Using this system, we found hundreds-fold higher rate of genomic alterations, including aneuploidy, loss of heterozygosity (LOH), and chromosomal rearrangement. DNA polymerase ε (Pol ε) is one of the three replicative eukaryotic DNA polymerases. Pol ε deficiency leads to genomic instability and multiple human diseases. Here, we explored global genomic alterations in yeast strains with reduced expression of POL2, the gene that encodes the catalytic subunit of Pol ε. Using whole-genome SNP microarray and sequencing, we found that low levels of Pol ε elevated the rates of mitotic recombination and chromosomal aneuploidy by two orders of magnitude. Strikingly, low levels of Pol ε resulted in a contraction of the number of repeats in the rDNA cluster and reduced the length of telomeres. These short telomeres led to an elevated frequency of break-induced replication, resulting in terminal loss of heterozygosity. In addition, low levels of Pol ε increased the rate of single-base mutations by 13-fold by a Pol ζ-dependent pathway. Finally, the patterns of genomic alterations caused by low levels of Pol ε were different from those observed in strains with low levels of the other replicative DNA polymerases Pol α and Pol δ, providing further insights into the different roles of the B-family DNA polymerases in maintaining genomic stability.
2021-10-07 | GSE185364 | GEO
Project description:Global genomic instability caused by reduced expression of DNA polymerase ε in yeast
| PRJNA768812 | ENA
Project description:Global genomic instability caused by reduced expression of DNA polymerase ε in yeast [DZP2-derived sectored colonies]
| PRJNA768822 | ENA
Project description:SignificanceAlthough most studies of the genetic regulation of genome stability involve an analysis of mutations within the coding sequences of genes required for DNA replication or DNA repair, recent studies in yeast show that reduced levels of wild-type enzymes can also produce a mutator phenotype. By whole-genome sequencing and other methods, we find that reduced levels of the wild-type DNA polymerase ε in yeast greatly increase the rates of mitotic recombination, aneuploidy, and single-base mutations. The observed pattern of genome instability is different from those observed in yeast strains with reduced levels of the other replicative DNA polymerases, Pol α and Pol δ. These observations are relevant to our understanding of cancer and other diseases associated with genetic instability.
| S-EPMC8944251 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-10-07 | GSE185366 | GEO
Project description:Chronic lymphocytic leukemia (CLL) is a consequence of pathological B cell accumulation in blood and lymphoid organs. Due to high refractoriness, CLL is considered incurable which calls for novel therapeutic options. Previously, we showed casein kinase 1δ/ε (CK1δ/ε) inhibition prolonged survival of Eµ-TCL1 mice with CLL-like disease. Herein, we elucidate mechanisms mediating CK1δ/ε inhibition efficacy in CLL suppression. Using in vivo Eµ-TCL1 adoptive transfer (AT) model, we showed CK1δ/ε inhibition mediated cell cycle slowdown and CLL cell accumulation at S/G2 interface. This observation was validated using multiple CLL cell lines and EdU/Click-iT reaction applied in vivo. Furthermore, we showed CK1δ/ε inhibition led to T cell decrease in lymph nodes (LN). Using system mimicking LN microenvironment in vitro, we observed CK1δ/ε inhibition triggered downregulation of nuclear factor κ B (NFκB) pathway that acts downstream of T-cell-mediated CD40L:CD40 stimulus, inducing CLL cell proliferation. Finally, we showed CK1δ/ε inhibition counteracted proliferation of CLL cells from wide range of patients, with lower efficacy only in patients bearing TP53 defects.
2026-03-31 | GSE304722 | GEO
Project description:Chronic lymphocytic leukemia (CLL) is a consequence of pathological B cell accumulation in blood and lymphoid organs. Due to high refractoriness, CLL is considered incurable which calls for novel therapeutic options. Previously, we showed casein kinase 1δ/ε (CK1δ/ε) inhibition prolonged survival of Eµ-TCL1 mice with CLL-like disease. Herein, we elucidate mechanisms mediating CK1δ/ε inhibition efficacy in CLL suppression. Using in vivo Eµ-TCL1 adoptive transfer (AT) model, we showed CK1δ/ε inhibition mediated cell cycle slowdown and CLL cell accumulation at S/G2 interface. This observation was validated using multiple CLL cell lines and EdU/Click-iT reaction applied in vivo. Furthermore, we showed CK1δ/ε inhibition led to T cell decrease in lymph nodes (LN). Using system mimicking LN microenvironment in vitro, we observed CK1δ/ε inhibition triggered downregulation of nuclear factor κ B (NFκB) pathway that acts downstream of T-cell-mediated CD40L:CD40 stimulus, inducing CLL cell proliferation. Finally, we showed CK1δ/ε inhibition counteracted proliferation of CLL cells from wide range of patients, with lower efficacy only in patients bearing TP53 defects.
2026-03-31 | GSE305855 | GEO
Project description:The female reproductive tract (FRT) is vulnerable to sexually transmitted infections and therefore a well-tuned immune surveillance system is crucial for maintaining a healthy FRT. However, our understanding of the factors that impact viral infection of the FRT and the host response are not well understood. In this work, we investigate the role of a hormonally regulated type I interferon, IFN epsilon, in control of Zika virus (ZIKV) infection of the FRT. We demonstrate that IFN epsilon has anti-ZIKV properties using a combination of IFN epsilon KO mice, blockade of endogenous IFN epsilon by neutralising Abs and rescue of IFN epsilon KO mice by recombinant IFN epsilon administered directly to the FRT.
2023-02-14 | GSE223635 | GEO
Project description:Salmonella Typhimurium is one of the major foodborne pathogens due to its biofilm formation on food contact surfaces. A polymer of positively charged lysine, ε-Polylysine has been demonstrated to inhibit biofilm formation of both Gram-positive and -negative bacteria. To elucidate the mechanism for inhibition of biofilm formation by ε-Polylysine, transcriptional profiles were compared between the cells before and after treatment with ε-Polylysine in Salmonella Typhimurium. A genome-wide DNA microarray analysis was performed after cultivation in 0.1% bacto soytone in the presence of 0.001% ε-Polylysine at 30°C for 2 h. Genes involved in curli and cellulose production, quorum sensing, and flagellar motility were down-regulated, whereas genes associated with colanic acid synthesis were up-regulated. The data from microarray was validated by RT-qPCR. Furthermore, production of colanic acid in S. Typhimurium decreased in the presence of ε-Polylysine. The outcome of this study provides a basic understanding of the anti-biofilm mechanisms of ε-Polylysine and may contributes to develop new disinfectant to control biofilm during food manufacturing and storage.
2019-11-14 | GSE140300 | GEO