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Regulation of the error-prone DNA polymerase polκ by oncogenic signaling and its contribution to drug resistance

ABSTRACT: Regulation of the error-prone DNA polymerase polκ by oncogenic signaling and its contribution to drug resistance

PROVIDER: PRJNA606746 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11088700_1.fastq.gz	Fastqsanger.gz
	SRR11088700_2.fastq.gz	Fastqsanger.gz
	SRR11088701_1.fastq.gz	Fastqsanger.gz
	SRR11088701_2.fastq.gz	Fastqsanger.gz
	SRR11088702_1.fastq.gz	Fastqsanger.gz

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Regulation of the error-prone DNA polymerase Pol? by oncogenic signaling and its contribution to drug resistance.

Project description:The DNA polymerase Pol? plays a key role in translesion synthesis, an error-prone replication mechanism. Pol? is overexpressed in various tumor types. Here, we found that melanoma and lung and breast cancer cells experiencing stress from oncogene inhibition up-regulated the expression of Pol? and shifted its localization from the cytoplasm to the nucleus. This effect was phenocopied by inhibition of the kinase mTOR, by induction of ER stress, or by glucose deprivation. In unstressed cells, Pol? is continually transported out of the nucleus by exportin-1. Inhibiting exportin-1 or overexpressing Pol? increased the abundance of nuclear-localized Pol?, particularly in response to the BRAFV600E-targeted inhibitor vemurafenib, which decreased the cytotoxicity of the drug in BRAFV600E melanoma cells. These observations were analogous to how Escherichia coli encountering cell stress and nutrient deprivation can up-regulate and activate DinB/pol IV, the bacterial ortholog of Pol?, to induce mutagenesis that enables stress tolerance or escape. However, we found that the increased expression of Pol? was not excessively mutagenic, indicating that noncatalytic or other functions of Pol? could mediate its role in stress responses in mammalian cells. Repressing the expression or nuclear localization of Pol? might prevent drug resistance in some cancer cells.

| S-EPMC7428051 | biostudies-literature

Error-free and error-prone DNA repair gene expression through reprogramming and passage in human iPS cells

Project description:Medical applications of human iPS cells(hiPSC) are evolving, but detailed elucidation of the mechanisms of reprogramming remains to be elucidated. Reprogramming is accompanied by an increase in the expression of related genes that maintain pluripotency, such as OCT3 /4 and NANOG. Also, through reprogramming, many CNVs and point mutation arise in genomes, which constitute a major barrier to the use of hiPSC for regenerative medicine. On the other hand, we recently found that DNA repair-related genes expression are altered through reprogramming, elevated expression of genes that accurately convey genomic information, such as homologous recombination (HR) and mismatch repair(MMR), and decreased expression of error-prone translesion Synthesis polymerase(TLS). Here, we confirmed this expression change in another cell-line, and further found that this expression change was maintained by overlapping passages as well as OCT3 /4 and NANOG. This suggests that changes in the expression of DNA repair-related genes associated with reprogramming and their maintenance may be new indicators of the quality control of cells exhibiting pluripotency.

2019-07-21 | GSE134441 | GEO

Regulation of the error-prone DNA polymerase polκ by oncogenic signaling and its contribution to drug resistance

Project description:We report how the A375 melanoma cell line changes following CRISPR-Cas9 inactivation of POLK

2020-02-15 | GSE145313 | GEO

Error-free and error-prone DNA repair gene expression through reprogramming and passage in human iPS cells

Project description:Error-free and error-prone DNA repair gene expression through reprogramming and passage in human iPS cells

| PRJNA555421 | ENA

Polymerase Error Rates by PacBio Sequencing

Project description:Polymerase Specific Error Rates and Profiles Identified by PacBio Single Molecule Sequencing

| PRJEB12175 | ENA

ESPRESSO: Robust discovery and quantification of transcript isoforms from error-prone long-read RNA-seq data

Project description:Long-read RNA sequencing (RNA-seq) holds great potential for characterizing transcriptome variation and full-length transcript isoforms, but the relatively high error rate of current long-read sequencing platforms poses a major challenge. We present ESPRESSO, a computational tool for robust discovery and quantification of transcript isoforms from error-prone long reads. ESPRESSO jointly considers alignments of all long reads aligned to a gene and uses error profiles of individual reads to improve the identification of splice junctions and the discovery of their corresponding transcript isoforms. On both a synthetic spike-in RNA sample and human RNA samples, ESPRESSO outperforms multiple contemporary tools in not only transcript isoform discovery but also transcript isoform quantification. In total, we generated and analyzed ~1.1 billion nanopore RNA-seq reads covering 30 human tissue samples and three human cell lines. ESPRESSO and its companion dataset provide a useful resource for studying the RNA repertoire of eukaryotic transcriptomes.

2022-10-14 | GSE192955 | GEO

Taq Polymerase Error Rate by PacBio Sequencing

Project description:Taq Polymerase Error Rate and Profile Determined by High Coverage Single Molecule Amplicon Sequencing

| PRJEB12157 | ENA

Error-prone protein synthesis recapitulates early symptoms of Alzheimer disease in aging mice

Project description:Error-prone protein synthesis recapitulates early symptoms of Alzheimer disease in aging mice

| PRJNA796296 | ENA

Error-prone protein synthesis recapitulates early symptoms of Alzheimer disease in aging mice

Project description:Age-related neurodegenerative diseases (NDDs) and neuronal dysfunction are associated with the aggregation and propagation of specific pathogenic protein species (e.g. Aβ, α-synuclein, tau). However, whether the disruption of synaptic homeostasis results from protein misfolding per se rather than accumulation of a specific rogue protein is an unexplored question. Here, we show that error-prone translation with its frequent outcome of random protein misfolding is sufficient to recapitulate many early features of NDDs, including proteostasis dysregulation, perturbed Ca2+ signalling, neuronal hyperexcitability, and mitochondrial dysfunction. Mice expressing the ribosomal ambiguity mutation Rps9 D95N exhibited disrupted synaptic homeostasis resulting in abnormal behavioral changes reminiscent of early Alzheimer's disease (AD), such as learning and memory deficits, maladaptive responses to novel stimuli, spontaneous epileptiform discharges, suppressed circadian rhythmicity, and sleep fragmentation. Ectopic hippocampal NPY expression and cerebral glucose hypometabolism (18F-fluorodeoxyglucose PET) were further signs of neuronal hyperexcitability. Collectively, our findings strongly suggest that random protein misfolding may contribute to the pathogenesis of age-related NDDs providing an alternative framework for understanding the initiation of Alzheimer’s disease.

2022-09-19 | GSE193459 | GEO

TENT4A non-canonical poly(A) polymerase regulates DNA-damage tolerance via multiple pathways which are mutated in endometrial cancer

Project description:TENT4A (PAPD7) is a non-canonical poly(A) polymerase, of which little is known. Here we show that TENT4A is involved in the regulation of multiple biological pathways, and focus on translesion DNA synthesis (TLS), a DNA-damage tolerance process in which unrepaired lesions are bypassed by error-prone DNA polymerases. We show that TENT4A regulates mRNA stability and/or translation of DNA polymerase η, and of the RAD18 E3 ligase that monoubiquitinates PCNA, the latter being a key step in TLS which enables recruitment of error-prone DNA polymerases to damaged DNA sites. Remarkably, in addition to the effect on RAD18 mRNA stability via controlling its poly(A) tail, TENT4A indirectly regulates RAD18 via the tumor suppressor CYLD, and via the long non-coding antisense RNA PAXIP1-AS2, which had no known function. Knocking down the expression of TENT4A or CYLD, or over-expression of PAXIP1-AS2 led each to a decrease in the amount of the RAD18 protein, but the effect on PCNA ubiquitination was variable. Still, TLS was reduced under these conditions, likely due a to a parallel decrease in DNA polymerase η. Bioinformatics analysis revealed that TLS error-prone DNA polymerase genes and their TENT4A-related regulators are frequently mutated in endometrial cancer genomes, suggesting that TLS is dysregulated in endometrial cancer.

2021-06-29 | GSE141870 | GEO

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