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Seryl-tRNA synthetase inhibits Wnt signaling and breast cancer progression and metastasis

ABSTRACT: Seryl-tRNA synthetase inhibits Wnt signaling and breast cancer progression and metastasis

PROVIDER: PRJNA1103150 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28773211.fastq.gz	Fastqsanger.gz
	SRR28773212.fastq.gz	Fastqsanger.gz
	SRR28773213.fastq.gz	Fastqsanger.gz
	SRR28773214.fastq.gz	Fastqsanger.gz
	SRR28773215.fastq.gz	Fastqsanger.gz

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Seryl-tRNA synthetase inhibits Wnt signaling and breast cancer progression and metastasis

Project description:Tumors require ample protein synthesis to grow, and aminoacyl-tRNA synthetases, as critical translation factors, are expected to support cancer progression. Unexpectedly, overexpression of seryl-tRNA synthetase (SerRS) suppresses primary tumor growth of breast cancer. However, the effects of SerRS on metastasis have not been studied. We observe a decrease in SerRS expression in breast cancer patient metastases compared to matched primary tumors, suggesting an inhibitory role of SerRS in metastasis. Through mouse metastasis models using breast cancer cell lines overexpressing SerRS, we show that SerRS impedes both primary tumor growth and establishment of metastases. By inducing SerRS overexpression after primary tumor implantation, we demonstrate the potential of SerRS as an anticancer therapeutic. Through tumor RNA-Seq, we identify Wnt signaling among the top SerRS-regulated pathways. Using cell-based studies, we confirm SerRS suppresses Wnt signaling and metastatic processes in breast cancer cells. To our knowledge, this is the first study to show a translation factor can act as both a tumor and metastasis suppressor.

2025-02-19 | GSE264557 | GEO

Serine-Threonine Kinase Encoded by a Split hipA Homologous Gene of Escherichia coli Inhibits Tryptophanyl-tRNA Synthetase

Project description:Type II toxin – antitoxin modules encode a stable toxin that inhibits translation, replication or cell wall synthesis and an unstable protein antitoxin that neutralizes the toxin by direct protein – protein contact. The hipBA module of Escherichia coli K-12 codes for HipA, a eukaryote-like serine/threonine protein kinase that phosphorylates and inhibits glutamyl-tRNA synthetase. Induction of hipA leads to a reduced level of charged glutamyl tRNA that, in turn, inhibits translation, induces RelA-dependent (p)ppGpp synthesis and multidrug tolerance (persistence). Here, we describe the discovery of a three-component TA module hipBST of E. coli O127:H6 strain E2348/69 that encodes HipT, which exhibits sequence similarity with the C-terminal part of HipA. We show that HipT is a kinase that phosphorylates tryptophanyl-tRNA synthetase in vitro at conserved serine residue. Consistently, induction of hipT inhibits cell growth, stimulates production of stringent factor (p)ppGpp and induces persistence. Remarkably, the gene immediately upstream of hipT, called hipS, encodes a small protein that exhibits sequence similarity with the C-terminal part of HipA. Unexpectedly, HipT kinase is neutralized by HipS in vivo whereas the third component, HipB0127, encoded by the first gene of the operon, does not counteract HipT kinase. However, HipB contains a HTH DNA-binding domain and may function to autoregulate the hipBST operon. Thus, hipA has been split into two genes, hipS and hipT that function as a toxin – antitoxin pair.

2019-06-24 | PXD012023 | Pride

tRNA overexpression rescues peripheral neuropathy caused by mutations in tRNA synthetase

Project description:Heterozygous mutations in six tRNA synthetase genes cause Charcot-Marie-Tooth (CMT) peripheral neuropathy. CMT-mutant glycyl- or tyrosyl-tRNA synthetases inhibit global protein synthesis by an unknown mechanism, independent of aminoacylation activity. We report that tRNAGly overexpression rescues protein synthesis and peripheral neuropathy phenotypes in Drosophila and mouse models of CMT caused by glycyl-tRNA synthetase (GlyRS) mutations (CMT2D). Kinetic experiments revealed that CMT-mutant GlyRS bind tRNAGly, but display markedly slow release rates. This tRNAGly sequestration may deplete the cellular tRNAGly pool, leading to insufficient glycyl-tRNAGly supply to the ribosome and translation deficit.

2021-09-07 | GSE160584 | GEO

McFarland2020 - Synthetase sequestration Model:a combined translation and tRNA charging cycle

Project description:The Synthetase Sequestration Model (SSM) is a simplified translation model that considers explicitly two main steps in the process of tRNA aminoacylation: first, the tRNA is bound by the aminoacyl tRNA synthetase, and in a second step, the amino acid is attached to the tRNA. The tRNA then participates in the translation reaction, becoming deacylated as a result. The tRNA exists in states bound, charged and uncharged. In the bound state, the tRNA is bound to the synthetase but uncharged, i.e., the tRNA is sequestered by the synthetase. The model predicts how the balance between the three different tRNA states (empty, bound and charged) changes depending on aminoacyl tRNA synthetase availability.

2020-02-05 | MODEL2001080005 | BioModels

Growth Optimized Aminoacyl-tRNA Synthetase Levels Prevent Maximal tRNA Charging

Project description:Growth Optimized Aminoacyl-tRNA Synthetase Levels Prevent Maximal tRNA Charging

| PRJNA593256 | ENA

Induction of proteasomal activity in mammalian cells by lifespan-extending tRNA synthetase inhibitors

Project description:ATF4-dependent differential transcription in response to tRNA synthetase inhibitor treatment in mouse embryonic fibroblasts We performed RNAseq on wild type and ATF4 KO mouse embryonic fibroblasts with and without tRNA synthetase inhibitor as our block design described in JAAA-D-23-00283R1 by Geroscience

2023-09-05 | GSE217634 | GEO

Transcriptional responses to glutaminyl tRNA synthetase Gln4p depletion in Saccharomyces cerevisiae

Project description:A tet-off strain of Saccharomyces cerevisiae was constructed in which the GLN4 glutamine tRNA synthetase gene was placed under control of a doxycycline-regulated promoter. The transcriptional responses to Gln4p tRNA synthetase depletion were assessed by growth of the strain in the presence, or absence, of doxycycline (1 µg/ml). A control, wild-type strain was similarly treated with doxycycline or left untreated as a reference. Each strain/condition RNA isolation was performed using triplicate independent biological samples A, B and C.

2019-04-01 | GSE126435 | GEO

Chimeric design of Pyrrolysyl-tRNA synthetase/tRNA pairs and canonical synthetase/tRNA pairs for genetic code expansion

Project description:An orthogonal aminoacyl-tRNA synthetase/tRNA pair is a key prerequisite for site-specific incorporation of unnatural amino acids. Due to its high codon suppression efficiency and full orthogonality, the pyrrolysyl-tRNA synthetase/pyrrolysyl-tRNA pair is currently the ideal system for genetic code expansion in both eukaryotes and prokaryotes. There is a pressing need to discover or engineer other fully orthogonal translation systems that allow unnatural amino acids with distinct scaffolds and functionalities to be incorporated into a wide range of living organisms efficiently. Here, through rational chimera design by transplanting the key orthogonal components from the pyrrolysine system, we create multiple chimeric tRNA synthetase/chimeric tRNA pairs, including chimera histidine, phenylalanine, and alanine systems. We further show that these engineered chimeric systems are orthogonal and highly efficient with comparable flexibility to the pyrrolysine system. In addition, the chimera phenylalanine system can incorporate a group of phenylalanine, tyrosine and tryptophan analogues efficiently in both E. coli and mammalian cells. These aromatic amino acids analogous exhibit unique properties and characteristics, including fluorescence, post-translation modification. To our knowledge, most of these molecules have never been shown to be incorporated with fully orthogonal pairs. Therefore, these chimera pairs offer the potential for incorporation of de novo unnatural amino acids into target proteins for a variety of applications.

2020-05-25 | PXD018660 | Pride

tRNA overexpression rescues peripheral neuropathy caused by mutations in tRNA synthetase

Project description:tRNA overexpression rescues peripheral neuropathy caused by mutations in tRNA synthetase

| PRJNA673697 | ENA

Nuclear translocation of an aminoacyl-tRNA synthetase may mediate a chronic "integrated stress response"

Project description:Various stress conditions are signaled through phosphorylation of translation initiation factor eukaryotic initiation factor 2α (eIF2α) to inhibit global translation while selectively activating transcription factor ATF4 to aid cell survival and recovery. However, this integrated stress response is acute and cannot resolve lasting stress. Here, we report that tyrosyl-tRNA synthetase (TyrRS), a member of the aminoacyl-tRNA synthetase family that responds to diverse stress conditions through cytosol-nucleus translocation to activate stress-response genes, also inhibits global translation. However, it occurs at a later stage than eIF2α/ATF4 and mammalian target of rapamycin (mTOR) responses. Excluding TyrRS from the nucleus over-activates translation and increases apoptosis in cells under prolonged oxidative stress. Nuclear TyrRS transcriptionally represses translation genes by recruiting TRIM28 and/or NuRD complex. We propose that TyrRS, possibly along with other family members, can sense a variety of stress signals through intrinsic properties of this enzyme and strategically located nuclear localization signal and integrate them by nucleus translocation to effect protective responses against chronic stress.

2023-06-09 | GSE155309 | GEO

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