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Pleiotropic impact of DNA-PK in cancer and implications to therapeutic strategies

ABSTRACT: DNA-dependent protein kinase catalitic subunit (DNA-PK) is associated with aggressive disease. DNA-PK plays a role in transcriptional regulation of cancer-relevent pathways but it is not well understood. This study uses transcriptomic analyses to understand the transcriptional role of DNA-PK in castration resistent prostate cancer (CRPC) upon DNA-PK inhibition

ORGANISM(S): Homo sapiens

PROVIDER: GSE116765 | GEO | 2019/08/11

REPOSITORIES: GEO

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Pleiotropic impact of DNA-PK in cancer and implications to therapeutic strategies

Project description:Pleiotropic impact of DNA-PK in cancer and implications to therapeutic strategies

| PRJNA480169 | ENA

Pleiotropic Impact of DNA-PK in Cancer and Implications for Therapeutic Strategies.

Project description: Not available

| S-EPMC6744985 | biostudies-literature

Macrococcus sp. PK strain:PK

Project description:Macrococcus sp. PK strain:PK Genome sequencing and assembly

| PRJNA690223 | ENA

Construction of IRX4-inducible system in pancreatic cancer cell lines, PK-1 and PK-9

Project description:Epigenetic gene silencing by aberrant DNA methylation is one of the important mechanisms leading to the loss of key cellular pathways in tumorigenesis. We have previously reported that IRX4 (Iroquois homeobox 4) was highly downregulated by promoter hypermethylation in pancreatic cancer cell lines as well as in resected primary pancreatic cancers. Based on these data, we have constructed a tetracycline-inducible IRX4 expressing system using pancreatic cancer cell lines PK-1 and PK-9. IRX4 induction significantly suppressed cell growth and caused apoptosis in both PK-1 and PK-9. Because IRX4 is a sequence-specific transcription factor, we tried to analyze IRX4 downstream events by performing microarray analyses using IRX4 inducible PK-1 cells with or without tetracycline. We found that IRX4 induction upregulated several genes that had tumor suppressive functions such as PRDM1, CRYAB, and IL32, and downregulated several genes that had oncogenic functions such as PTCH1, CD36, TFAP2C, and MUC4. These results suggest that DNA methylation-mediated silencing of IRX4 may contribute to pancreatic tumorigenesis through aberrant transcriptional regulation of cancer-related genes.

2020-10-11 | GSE141246 | GEO

Selective DNA-PK inhibition enhances chemotherapy and ionizing radiation activity in soft-tissue sarcomas

Project description:Purpose: Patients with advanced soft-tissue sarcomas (STSs) exhibit a poor prognosis and have few therapeutic options. DNA-dependent protein kinase catalytic subunit (DNA-PK) is a multifunctional serine—threonine protein kinase that plays a crucial role in DNA double-strand damage repair via nonhomologous end joining (NHEJ). Experimental design: To investigate the therapeutic potential of DNA-PK targeting in STS, we first evaluated the prognostic value of DNA-PK expression in two large cohorts of patients with STS. We then used the potent and selective DNA-PK inhibitor AZD7648 compound to investigate the antitumor effect of the pharmacological inhibition of DNA-PK in vitro via MTT, apoptosis, cell cycle, and proliferation assays. In vivo studies were performed with patient-derived xenograft models to evaluate the effects of AZD7648 in combination with chemotherapy or ionizing radiation on tumor growth. The mechanisms of sensitivity and resistance to DNA-PK inhibition were investigated by using a genome-wide CRISPR-Cas9 positive screen. Results: DNA-PK overexpression is significantly associated with poor prognosis in patients with sarcomas. Selective pharmacological inhibition of DNA-PK strongly synergizes with radiation- and doxorubicin-based regimen in sarcoma models. By using a genome-wide CRISPR-Cas9 positive screen, we identified genes involved in sensitivity to DNA-PK inhibition. Conclusion: DNA-PK inhibition deserves clinical investigation to improve response to current therapies in patients with sarcoma

2023-09-25 | GSE243758 | GEO

Integrative Structural Model of DNA-PK Synapsis

Project description:In non-homologous end joining repair of DNA double strand breaks, DNA dependent protein kinase catalytic subunit (DNA-PKcs) and Ku70/80 binds the free DNA ends forming the holoenzyme DNA-PK. DNA-PK synapses across the break to tether the broken ends in the initial long range synaptic complex. We generated an integrative structural model of DNA-PK synapsis at a precision of 13.5Å with crosslinking mass spectrometry (XL-MS) restraints. While our hydrogen deuterium exchange (HX) analysis revealed an allosteric axis in DNA-PK connecting DNA binding (including the plug domain) to the kinase domain. Our model presents a symmetrical synapsis primarily through head to head interactions and protection of the DNA by previously uncharacterized a plug domain. The offset of the DNA in our model allows access to downstream processing enzymes, while the combination of DNA binding and kinase loading creates a tensed state that could have roles in the re-arrangement/dissociation of DNA-PKcs as the repair process progresses.

2021-01-20 | PXD017931 | Pride

Genome-wide analysis of DNA-PK-bound MRN cleavage products supports a sequential model of DSB repair pathway choice

Project description:The Mre11-Rad50-Nbs1 (MRN) complex recognizes and processes DNA double-strand breaks for homologous recombination by performing short-range removal of 5ʹ strands. Endonucleolytic processing by MRN requires a stably bound protein at the break site—a role we postulate is played by DNA-dependent protein kinase (DNA-PK) in mammals. Here we interrogate the sites of MRN-dependent processing by isolating and sequencing DNA-PK-bound DNA fragments that are products of MRN cleavage. These intermediates are generated with highest efficiency when DNA-PK is catalytically blocked, yielding products within 200 bp of the break site, whereas DNA-PK products in the absence of kinase inhibition show much greater dispersal. Use of light-activated Cas9 to induce breaks facilitates temporal resolution of DNA-PK and Mre11 binding, showing that Mre11 and DNA-PK both bind to DNA ends before release of DNA-PK-bound products. These results support a sequential model of double-strand break repair involving collaborative interactions between homologous and non-homologous repair complexes.

2023-09-18 | GSE218590 | GEO

Transcriptome data for HEK293T cells depleted of one subunit of DNA-PK complex: Ku70, Ku80 or DNA-PKcs.

Project description:DNA-PK is a heterotrimeric complex that consists of Ku70 (XRCC6), Ku80 (XRCC5) and DNA-PKcs (PRKDC) subunits. DNA-PK complex is a major player in DNA double strand break (DSB) repair via non-homologous end joining pathway. This process requires all of DNA-PK subunits. Ku70/Ku80 heterodimers firstly bind to DNA-ends at DSB, that increase affinity of DNA-PKcs to DNA-ends. Recruitment of DNA-PKcs subunit to DSB leads to phosphorylation events near DSB, recruitment of another NHEJ-related genes that restore DNA integrity. However, today a lot of evidence demonstrate participation of DNA-PK components in other cellular process, e.g. cytosolic DNA sensing, apoptosis regulation, cellular movement and adhesion. It is important to note that not all subunits of DNA-PK complex are necessary for these process. This demonstrate the independent functions of DNA-PK subunits. Here we for the first time using NGS-sequencing analyzed the transcriptional changes in HEK293T cells under depletion of Ku70, Ku80 or DNA-PKcs to characterize the independent functions of each subunit.

2021-07-23 | GSE180581 | GEO

Thermococcus sp. PK strain:PK

Project description:Thermococcus sp. PK genome sequencing project

| PRJNA62219 | ENA

Gene expression profiling of the cell death induced by heat stress in DNA-PK-knockdown human cervical carcinoma HeLa cells

Project description:The objective of the present study is to investigate the role of DNA-PK inhibition in cell death induced by heat stress (44M-BM-0C, 60 min). Comparative gene expression analysis was performed with mock cells, negative control siRNA-treated cells and DNA-PK siRNA-treated cells. The expression of DNA-PK was confirmed by Western blotting. Gene expression was analyzed using GeneChip oligonucleotide microarrays and computational gene expression analysis tools. DNA-PK-knockdown human cervical carcinoma HeLa cells were treated with heat (44M-BM-0C, 60 min) and then were cultured at 37M-BM-0C for 6 h. Total RNA samples were prepared from the cells. Gene expression was analyzed by an Affymetrix GeneChipM-BM-. system with GeneChip Human Gene 1.0 ST arrays. Sample preparation for array hybridization was carried out as described in the manufacturer's instructions.

2012-07-12 | E-GEOD-39063 | biostudies-arrayexpress

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