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RNA polymerase stalling-derived genome instability underlies ribosomal antibiotic efficacy and resistance evolution

ABSTRACT: RNA polymerase stalling-derived genome instability underlies ribosomal antibiotic efficacy and resistance evolution

PROVIDER: PRJNA1003865 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25583200_1.fastq.gz	Fastqsanger.gz
	SRR25583200_2.fastq.gz	Fastqsanger.gz
	SRR25583201_1.fastq.gz	Fastqsanger.gz
	SRR25583201_2.fastq.gz	Fastqsanger.gz
	SRR25583202_1.fastq.gz	Fastqsanger.gz

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RNA polymerase stalling-derived genome instability underlies ribosomal antibiotic efficacy and resistance evolution

Project description:RNA polymerase stalling-derived genome instability underlies ribosomal antibiotic efficacy and resistance evolution

| PRJNA980634 | ENA

RNA polymerase stalling-derived genome instability underlies ribosomal antibiotic efficacy and resistance evolution

Project description:Bacteria often evolve antibiotic resistance through mutagenesis. However, the processes causing the mutagenesis have not been fully resolved. Here we found that a broad range of ribosome-targeting antibiotics caused mutations through an underexplored pathway. Focusing on the clinically important aminoglycoside gentamicin, we found that the translation inhibitor caused genome-wide premature stalling of RNA polymerase (RNAP) in a loci-dependent manner. Further analysis showed that the stalling was caused by disruption of transcription-translation coupling. Anti-intuitively, the stalled RNAPs subsequently induced lesions to the DNA via transcription-coupled repair. While most of the bacteria were killed by genotoxicity, a small subpopulation acquired mutations via SOS-induced mutagenesis. Given that these processes were triggered shortly after antibiotic addition, resistance rapidly emerged in the population. Our work revealed a new mechanism of action of ribosomal antibiotics, illustrates the importance of dissecting the complex interplay between multiple molecular processes in understanding antibiotic efficacy, and suggests new strategies for countering the development of resistance.

2024-06-24 | GSE240474 | GEO

RNA polymerase stalling-derived genome instability underlies ribosomal antibiotic efficacy and resistance evolution

Project description:In bacteria, the precise coordination of DNA replication, transcription and translation is mediated by dynamic interactions among the corresponding macromolecular machineries, playing a pivotal role in maintaining cellular homeostasis. Here we showed that such coordination could be hijacked by ribosome antibiotics to trigger secondary damage predominantly contributing to their efficacy, via a yet overlooked reverse-central-dogma pathway. Through the utilization of a self-establishing transcription dynamics profiling method, complemented by genetic and biochemical approaches, we unveil that the disruption of transcription-translation coupling leads to premature stalling of RNA polymerase (RNAP) at genome scale, subsequently triggering extensive genomic instability. Moreover, a distinct subpopulation exhibits hyperactivation of the SOS response, facilitating an inducible evolutionary path towards genetic resistance characterized by a unique mutation spectrum. Our findings reveal the emergence of secondary drug damage resulting from network disorder, and establish a framework to understand antibiotic efficacy and induced mutagenesis from a systems biology perspective.

2023-12-24 | GSE234254 | GEO

RNAP stalling-derived genome instability underlies ribosomal antibiotics efficacy and resistance evolution (ChIP-seq data)

Project description:RNAP stalling-derived genome instability underlies ribosomal antibiotics efficacy and resistance evolution (ChIP-seq data)

| PRJNA1110738 | ENA

RNAP stalling-derived genome instability underlies ribosomal antibiotics efficacy and resistance evolution (ChIP-seq data)

2024-05-15 | GSE267245 | GEO

RNA polymerase stalling-derived genome instability underlies ribosomal antibiotic efficacy and resistance evolution.

Project description:Bacteria often evolve antibiotic resistance through mutagenesis. However, the processes causing the mutagenesis have not been fully resolved. Here, we find that a broad range of ribosome-targeting antibiotics cause mutations through an underexplored pathway. Focusing on the clinically important aminoglycoside gentamicin, we find that the translation inhibitor causes genome-wide premature stalling of RNA polymerase (RNAP) in a loci-dependent manner. Further analysis shows that the stalling is caused by the disruption of transcription-translation coupling. Anti-intuitively, the stalled RNAPs subsequently induce lesions to the DNA via transcription-coupled repair. While most of the bacteria are killed by genotoxicity, a small subpopulation acquires mutations via SOS-induced mutagenesis. Given that these processes are triggered shortly after antibiotic addition, resistance rapidly emerges in the population. Our work reveals a mechanism of action of ribosomal antibiotics, illustrates the importance of dissecting the complex interplay between multiple molecular processes in understanding antibiotic efficacy, and suggests new strategies for countering the development of resistance.

| S-EPMC11297953 | biostudies-literature

ROS-induced ribosome stalling and collision underlies ZAKalpha-mediated metabolic decline in obesity and aging

Project description:The ribotoxic stress response (RSR) denotes a signaling pathway in which the p38 and JNK-activating MAP3 kinase ZAKalpha senses stalling and/or collision of ribosomes with unknown physiological implications. Here, we show that reactive oxygen species (ROS)-generating agents robustly trigger translational impairment and ZAKalpha activation. Underscoring the physiological importance of this signaling pathway, zebrafish larvae deficient for the ZAKalpha kinase are protected from ROS-induced pathology and death. Furthermore, livers of mice fed a ROS-generating and obesogenic diet exhibit ZAKalpha-activating changes in ribosomal elongation dynamics. Highlighting a role for the RSR in metabolic regulation, ZAK knockout (KO) mice are protected from developing high-fat diet-induced blood glucose intolerance and liver steatosis under these conditions. Finally, ZAK ablation slows animals from developing hallmarks of metabolic aging. In sum, our work highlights ROS-induced translational impairment as a physiological activation signal for ZAKalpha that underlies metabolic adaptation in obesity and aging.

2024-02-01 | PXD043071 | Pride

Bump-finder: identification of causal codons to the stalling of ribosomes

Project description:Stalling of the ribosomes on the mRNA has been linked to myriad of molecular and biological functions. While a multitude of algorithms predict codon-usage in ribosome profiling data, no tool exists to predict the context-specific stalling of ribosomes on transcripts. Combining these two features can reveal unprecedented insights in the ribosomal function and their usage across cells and conditions. To overcome this lack of tools to comprehensively analyze these features, we created Bumpfinder, a web-server, that provides comprehensive analytical details on differences in total ribosome occupancy on transcripts, ribosomal occupancy across codons, ribosome-stalling and the underlying causal amino-acids/codons, as well as collisions. Employing Bumpfinder on generated and publicly available ribosome-profiling datasets, we studied the response of various cell types to amino-acid starvation conditions. We observed interesting patterns in response to the biological effects, suggesting the impact of quality control mechanisms of protein synthesis. Complimentary analysis of collided ribosomes demonstrated phased ribosome stalling on the identified sites. Thus, by deciphering context-specific ribosome distribution, Bumpfinder provides unprecedented molecular insights in the ribosome function and mRNA translation during stress response conditions.

2023-12-31 | GSE156443 | GEO

Replication stress underlies genomic instability at CTCF/cohesin-binding sites in cancer

Project description:Replication stress underlies genomic instability at CTCF/cohesin-binding sites in cancer

| PRJNA1237290 | ENA

Ribosome stalling induced by mutation of a CNS-specific tRNA causes neurodegeneration

Project description:In higher eukaryotes, the large numbers of nuclear-encoded tRNA genes partially ensure the robustness of cytoplasmic protein translation. Here we discover that a loss-of-function in n-Tr20, a member of the nuclear-encoded tRNA Arg UCU family that is expressed specifically in the central nervous systems leads to low but detectable levels of ribosome stalling. In the absence of GTPBP2, a novel binding partner of the ribosome recycling protein Pelota, ribosome stalling increases, leading to widespread neurodegeneration. Our results not only define GTPBP2 as a ribosome rescue factor, but also unmask the disease potential of mutations in nuclear-encoded tRNA genes. In this submission we provide ribosome footprinting data from the cerebella of four strains derived from the C57BL/6J strain with combinations of n-Tr20 and GTPBP2 mutations. Examination of ribosome stalling in cerebella from 4 mouse strains derived from the: C57BL/6J (B6J) strain. The nmf205-/- strain has a homozygous mutation in the gene GTPBP2 while the B6J strain has normal GTPBP2. The n-Tr20 J/J strain has a defect in the n-Tr20 tRNA while the n-Tr20 N/N strain has a functional n-Tr20 tRNA. The 4 strains are the 2x2 combinations of these defects and correctly functioning sequences. 2 replicates for each strain. Please note that only BAM files are included in the records since they form the basis of the study's conclusions. The raw data ribosomal RNA have been filtered and then unique reads mapping to mm10 were computed using tophat and igenome annotations.

2014-07-28 | E-GEOD-56127 | biostudies-arrayexpress

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