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Evolution of drug resistance enabled by replicative RNAs carrying MEK1

ABSTRACT: Evolution of drug resistance enabled by replicative RNAs carrying MEK1

PROVIDER: PRJNA1133793 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29759400.fastq.gz	Fastqsanger.gz
	SRR29759401.fastq.gz	Fastqsanger.gz
	SRR29759402.fastq.gz	Fastqsanger.gz
	SRR29759403.fastq.gz	Fastqsanger.gz
	SRR29759404.fastq.gz	Fastqsanger.gz

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Tracing the lineage of replicative RNAs carrying MEK1 in the evolution of drug resistance

Project description:Drug resistance poses a significant clinical challenge, and comprehending the mechanisms underlying this resistance can facilitate the design of novel inhibitors and advance cancer treatment. The REPLACE system was employed to examine resistance mutations in MEK1 during the administration of 3 allosteric inhibitors. To explore the accumulation of mutations in various RNAs during the MEK1 evolution experiment, we established a barcoded library and conducted lineage tracing of replicative RNAs carrying MEK1 throughout the drug resistance evolution process.

2024-09-30 | GSE271875 | GEO

Evolution of drug resistance enabled by replicative RNAs carrying MEK1

Project description:Drug resistance poses a significant clinical challenge, and comprehending the mechanisms underlying this resistance can facilitate the design of novel inhibitors and advance cancer treatment. The REPLACE system was employed to examine resistance mutations in MEK1 during the administration of 3 allosteric inhibitors (i.e., cobimetinib, trametinib, and selumetinib). These experiments represent a category of experiments that utilize REPLACE to achieve continuous evolution (or adaptation) by linking the activity of evolutionary targets with the survival of mammalian cells.

2024-09-30 | GSE271878 | GEO

Tracing the lineage of replicative RNAs carrying MEK1 in the evolution of drug resistance

Project description:Tracing the lineage of replicative RNAs carrying MEK1 in the evolution of drug resistance

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Tracing the lineage of replicative RNAs in the process of KRAS (S17N) evolution

Project description:A dominant-negative gene therapy approach has been proposed and tested on proto-oncogene KRAS, wherein the oncogenic activity (and cell proliferation) of KRAS can be suppressed by introducing a dominant-negative KRAS allele (S17N). We employed REPLACE to conduct continuous evolution on KRAS (S17N) and examined its potential pathways for conferring resistance in this gene therapy methodology.To explore the accumulation of mutations in various RNAs during the KRAS (S17N) evolution experiment, we established a barcoded library and conducted lineage tracing of replicative RNAs carrying KRAS (S17N) throughout the evolution process.

2024-09-30 | GSE271874 | GEO

Histone H3 threonine 11 phosphorylation is catalyzed directly by the meiosis-specific kinase Mek1 and provides a molecular readout of Mek1 activity in vivo

Project description:Saccharomyces cerevisiae Mek1 is a CHK2/Rad53-family kinase that regulates meiotic recombination and progression upon its activation in response to DNA double-strand breaks (DSBs). The full catalog of direct Mek1 phosphorylation targets remains unknown. Here, we show that phosphorylation of histone H3 on threonine 11 (H3 T11ph) is induced by meiotic DSBs in S. cerevisiae and Schizosaccharomyces pombe. Molecular genetic experiments in S. cerevisiae confirmed that Mek1 is required for H3 T11ph and revealed that phosphorylation is rapidly reversed when Mek1 kinase is no longer active. Reconstituting histone phosphorylation in vitro with recombinant proteins demonstrated that Mek1 directly catalyzes H3 T11 phosphorylation. Mutating H3 T11 to nonphosphorylatable residues conferred no detectable meiotic defects, indicating that H3 T11ph is dispensable for Mek1 functions in controlling recombination. However, H3 T11ph provides an excellent marker of ongoing Mek1 kinase activity in vivo. Anti-H3 T11ph chromatin immunoprecipitation followed by deep sequencing demonstrated that H3 T11ph was highly enriched at presumed sites of attachment of chromatin to chromosome axes, gave a more modest signal along chromatin loops, and was present at still lower levels immediately adjacent to DSB hotspots. These localization patterns closely tracked the distribution of Red1 and Hop1, axis proteins required for Mek1 activation. These findings provide insight into the spatial disposition of Mek1 kinase activity and the higher order organization of recombining meiotic chromosomes.

2017-10-17 | GSE103823 | GEO

Analyzing the process of mutation accumulation in MEK1 evolution experiment using amplicon sequencing

Project description:Directed evolution in mammalian cells can facilitate the engineering of mammalian-compatible biomolecules and can enable synthetic evolvability for mammalian cells. We engineered an orthogonal alphaviral RNA replication system to evolve synthetic RNA-based devices, enabling RNA replicase-assisted continuous evolution (REPLACE) in live mammalian cells. we employed REPLACE to drive the continuous intracellular evolution of the cancer-related protein MEK1 with the aim of conferring resistance to Cobimetinib. To investigate the accumulation of mutations during this evolutionary process, we conducted amplicon sequencing on experimental materials collected at different stages. The results revealed intricate relationships among different mutations, highlighting the complex nature of the evolutionary landscape.

2024-07-07 | GSE235328 | GEO

Spo11-oligo mapping in S. cerevisiae red1, hop1, mek1 mutants

Project description:Meiotic recombination starts with the formation of DNA double-strand breaks (DSBs) made by Spo11. In Saccharomyces cerevisiae, the nonrandom distribution of meiotic DSBs along the genome can be attributed to the combined influence of multiple factors on Spo11 cleavage. One factor is higher-order chromatin structure, particularly the loop-axis organization of meiotic chromosomes. Axial element proteins Red1 and Hop1 provide the basis for meiotic loop-axis organization and are implicated in diverse aspects of meiotic recombination. Mek1 is a meiotic-specific kinase associated with Red1 and Hop1. Red1, Hop1, and Mek1 are required for normal DSB levels, but their effects on the DSB distribution has not been examined, and exactly how these proteins influence DSB levels and distribution is unknown. Here, we examined the contributions of Red1, Hop1, and Mek1 to the DSB distribution by deep sequencing and mapping Spo11-associated oligonucleotides from red1, hop1, and mek1 mutant strains, thereby generating genome-wide meiotic DSB maps.

2018-09-01 | GSE84859 | GEO

MEK1/2 inhibitors unlock the constrained interferon response in macrophages through IRF1 signaling

Project description:Analysis of bone-marrow derived macrophages (BMDMs) stimulated with single or combinatorial TLR agonist and MEK1/2 inhibitor in wild-type and Irf1-/- macrophages. Results provide insights into the versatile but yet uncharacterized roles of IRF1 in TLR-MEK1/2-ERK MAPK signaling.

2018-12-28 | GSE123512 | GEO

Analyzing the process of mutation accumulation in MEK1 evolution experiment using amplicon sequencing

Project description:Analyzing the process of mutation accumulation in MEK1 evolution experiment using amplicon sequencing

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Extended suppression of Mek1/2 impairs the developmental potential of mouse embryonic stem cells

Project description:Simultaneous inhibition of Gsk3α/β and Mek1/2 activity in the presence of LIF (2i/L) induces a naïve state in mouse embryonic stem cells (ESCs) that resembles the inner cell mass (ICM) of the pre-implantation embryo. Since the ICM exists only transiently in vivo, it remains unclear how extended propagation of naïve ESCs in vitro affects their stability and functionality. Here we show that extended culture of male ESCs in 2i/L results in the progressive erosion of genomic imprints, loss of H2A.X binding, and accumulation of chromosomal aberrations. Consistent with these observations, we find that the developmental potential of ESCs cultured in 2i/L is impaired. Mechanistically, we demonstrate that Mek1/2 inhibition is predominantly responsible for these effects, in part through downregulation of DNA methyltransferases. Additionally, we demonstrate that female ESCs cultured in conventional serum/LIF media phenocopy male ESCs cultured in 2i/L, including the aforementioned epigenetic and developmental abnormalities. Finally, we show that replacement of the Mek1/2 inhibitor with a Src inhibitor preserves the epigenetic and genomic integrity as well as developmental potential of ESCs. Taken together, our data suggest that, while short-term suppression of Mek1/2 in ESCs maintains an ICM-like epigenetic state, prolonged suppression results in irreversible changes that compromise their developmental potential.

2017-07-27 | GSE97954 | GEO

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