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CHD1 loss sensitizes prostate cancer to DNA damaging therapy by promoting error-prone double-strand break repair

ABSTRACT: CHD1 loss sensitizes prostate cancer to DNA damaging therapy by promoting error-prone double-strand break repair

OTHER RELATED OMICS DATASETS IN: GSE84610

PROVIDER: PRJNA330629 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR3932430_1.fastq.gz	Fastqsanger.gz
	SRR3932430_2.fastq.gz	Fastqsanger.gz
	SRR3932440_1.fastq.gz	Fastqsanger.gz
	SRR3932440_2.fastq.gz	Fastqsanger.gz
	SRR3932450_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

CHD1 loss sensitizes prostate cancer to DNA damaging therapy by promoting error-prone double-strand break repair

Project description:BACKGROUND: Deletion of the chromatin remodeler CHD1 is a common genomic alteration found in human prostate cancers (PCas). CHD1 loss represents a distinct PCa subtype characterized by SPOP mutation and higher genomic instability [1-3]. However, the role of CHD1 in PCa development in vivo and its clinical utility remain unclear. DESIGN: To study the role of CHD1 in PCa development and its loss in clinical management, we generated a genetically engineered mouse model with prostate-specific deletion of murine Chd1 as well as isogenic CHD1 WT and homozygous deleted human benign and PCa lines. We also developed patient-derived organoid cultures and screened patients with metastatic PCa for CHD1 loss. RESULTS: We demonstrate that CHD1 loss sensitizes cells to DNA damage and causes a synthetic lethal response to DNA damaging therapy in vivo, ex vivo and in a patient with metastatic PCa. Mechanistically, CHD1 loss leads to decreased error-free homologous recombination (HR) repair, which is compensated by increased error-prone non-homologous end joining (NHEJ) repair for DNA double-strand break (DSB) repair. CONCLUSIONS: Our study provides the first in vivo and in patient evidence supporting the role of CHD1 in DSB repair and in response to DNA damaging therapy. We uncover mechanistic insights that CHD1 modulates the choice between HR and NHEJ and suggest that CHD1 loss may contribute to genomic instability seen in this subset of PCa patients.

2017-07-26 | GSE84610 | GEO

CHD1 loss sensitizes prostate cancer to DNA damaging therapy by promoting error-prone double-strand break repair.

Project description:BackgroundDeletion of the chromatin remodeler chromodomain helicase DNA-binding protein 1 (CHD1) is a common genomic alteration found in human prostate cancers (PCas). CHD1 loss represents a distinct PCa subtype characterized by SPOP mutation and higher genomic instability. However, the role of CHD1 in PCa development in vivo and its clinical utility remain unclear.Patients and methodsTo study the role of CHD1 in PCa development and its loss in clinical management, we generated a genetically engineered mouse model with prostate-specific deletion of murine Chd1 as well as isogenic CHD1 wild-type and homozygous deleted human benign and PCa lines. We also developed patient-derived organoid cultures and screened patients with metastatic PCa for CHD1 loss.ResultsWe demonstrate that CHD1 loss sensitizes cells to DNA damage and causes a synthetic lethal response to DNA damaging therapy in vitro, in vivo, ex vivo, in patient-derived organoid cultures and in a patient with metastatic PCa. Mechanistically, CHD1 regulates 53BP1 stability and CHD1 loss leads to decreased error-free homologous recombination (HR) repair, which is compensated by increased error-prone non-homologous end joining (NHEJ) repair for DNA double-strand break (DSB) repair.ConclusionsOur study provides the first in vivo and in patient evidence supporting the role of CHD1 in DSB repair and in response to DNA damaging therapy. We uncover mechanistic insights that CHD1 modulates the choice between HR and NHEJ DSB repair and suggest that CHD1 loss may contribute to the genomic instability seen in this subset of PCas.

| S-EPMC5834074 | biostudies-literature

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

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

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

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

Chd1 regulates repair of promoter-proximal DNA breaks to sustain hypertranscription in embryonic stem cells

Project description:Stem and progenitor cells undergo a global elevation of nascent transcription, or hypertranscription, during key developmental transitions involving rapid cell proliferation. The chromatin remodeler Chd1 binds to RNA Pol I and II genes and is required for hypertranscription in embryonic stem (ES) cells in vitro and the early post-implantation epiblast in vivo. Biochemically, Chd1 has been shown to facilitate transcription at least in part by removing nucleosomal barriers to elongation, but its mechanism of action in stem cells remains poorly understood. Here we report a novel role for Chd1 in the repair of promoter-proximal endogenous double-stranded DNA breaks (DSBs) in ES cells. An unbiased proteomics approach revealed that Chd1 interacts with several DNA repair factors including ATM, Parp1, Kap1 and Topoisomerase 2. We show that wild-type ES cells display high levels of phosphorylated H2AX and Kap1 at chromatin, notably at rDNA in the nucleolus, in a Chd1-dependent manner. Loss of Chd1 leads to an extensive accumulation of DSBs at Chd1 target Pol II genes and rDNA. Genes prone to DNA breaks in Chd1-null ES cells tend to be longer genes with GC-rich promoters, a more labile nucleosomal structure and roles in chromatin organization, transcription and signaling. These results reveal a vulnerability of hypertranscribing stem cells to endogenous DNA breaks, with important implications for developmental and cancer biology.

2021-06-14 | PXD024604 | Pride

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

Histone exchange in wildtype, isw1, chd1, isw1 chd1 and ioc4 yeast strains

Project description:Histone exchange in wildtype, isw1, chd1, isw1 chd1 and ioc4 yeast strains.

2012-07-25 | GSE32043 | GEO

Microarray of CHD1 Knockdown in PC3 cells and CHD1 knockout in LNCaP cells

Project description:We used microarrays to study the global gene expression and identified differentially expressed genes in CHD1 knockdown PC-3 cells and CHD1 KO LNCaP cells, aiming to identify genes and pathways that are regulated by CHD1

2017-02-10 | GSE84970 | GEO

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