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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.

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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

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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.

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