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DNA topological regulation by topoisomerase IIβ-DNA-PK interaction is important for controlled hypoxia-inducible gene expression [RNA-Seq]

ABSTRACT: Hypoxic stress responses are crucial for cellular and organismal survival and provoke gene regulation in diverse biological pathways including cell cycle progression and energy metabolism. Here, we identified that topoisomerase IIβ (TOP2B) regulates DNA topology and transcription in hypoxiainducible genes (HIGs) in a DNA-PK-dependent manner. Cellular, mutational, and genomic analyses showed antagonistic relation between TOP2B and DNA-PK. TOP2B associates with HIGs and represses transcription by suppressing negative supercoiling formation under normoxic conditions.Under hypoxia, TOP2B is released, whereas DNA-PK and HIF1a are recruited to and activate HIGs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE285698 | GEO | 2025/01/26

REPOSITORIES: GEO

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DNA topological regulation by topoisomerase IIβ-DNA-PK interaction is important for controlled hypoxia-inducible gene expression [TMP-seq]

Project description:Hypoxic stress responses are crucial for cellular and organismal survival and provoke gene regulation in diverse biological pathways including cell cycle progression and energy metabolism. Here, we identified that topoisomerase IIβ (TOP2B) regulates DNA topology and transcription in hypoxiainducible genes (HIGs) in a DNA-PK-dependent manner. Cellular, mutational, and genomic analyses showed antagonistic relation between TOP2B and DNA-PK. TOP2B associates with HIGs and represses transcription by suppressing negative supercoiling formation under normoxic conditions.Under hypoxia, TOP2B is released, whereas DNA-PK and HIF1a are recruited to and activate HIGs.Intriguingly, DNA-PK is responsible for TOP2B to be repressive because DNA-PK knockout overturns both TOP2B activity and release and increases the expression of a number of HIGs. Mutational and genomic analyses confirmed that DNA-PK phosphorylates TOP2B at T1403 to stimulate TOP2B catalysis for DNA topological relaxation, which is important for controlled HIG transcription. Collectively, our findings suggest a novel role of TOP2B and DNA-PK-mediated TOP2B regulation as important transcriptional elements in HIG expression. We propose that TOP2B catalysis modulated by protein phosphorylation is coordinated with transcriptional activation and determines DNA topology to stimulate Pol II transcription in response to hypoxic stresses.

2025-01-26 | GSE285699 | GEO

DNA topological regulation by topoisomerase IIβ-DNA-PK interaction is important for controlled hypoxia-inducible gene expression [RNA-Seq]

Project description:DNA topological regulation by topoisomerase IIβ-DNA-PK interaction is important for controlled hypoxia-inducible gene expression [RNA-Seq]

| PRJNA1205669 | ENA

DNA topological regulation by topoisomerase IIβ-DNA-PK interaction is important for controlled hypoxia-inducible gene expression [TMP-seq]

Project description:DNA topological regulation by topoisomerase IIβ-DNA-PK interaction is important for controlled hypoxia-inducible gene expression [TMP-seq]

| PRJNA1205668 | ENA

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

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

Project description: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

2019-08-11 | GSE116765 | GEO

Haemming et al. A lncRNA integrates a DNA-PK-mediated DNA damage response and vascular senescence

Project description:Proteomic analysis on lncRNA associated proteins . Functional role of DNA-PK .

2019-10-04 | MSV000084424 | MassIVE

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

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

Ubiquitin ligase WWP2 targets RNA polymerase II in a DNA-PK-dependent transcription shutoff circuitry for DNA repair

Project description:DNA double-strand breaks (DSBs) at RNA polymerase II (RNAPII)-transcribed genes lead to inhibition of transcription. DNA protein kinase (DNA-PK) complex plays a pivotal role in transcription inhibition at DSBs by stimulating proteasome-dependent eviction of RNAPII at these lesions. How DNA-PK triggers RNAPII eviction to inhibit transcription at DSBs remained unclear. Here we show that the HECT E3 ubiquitin ligase WWP2 associates with components of the DNA-PK and RNAPII complexes and is recruited to DSBs at RNAPII-transcribed genes. In response to DSBs, WWP2 targets the RNAPII subunit RPB1 for K48-linked ubiquitylation, thereby driving DNA-PK- and proteasome-dependent eviction of RNAPII. The lack of WWP2 or expression of non-ubiquitylatable RPB1 abrogates the loading of Non-Homologous End-Joining (NHEJ) factors, including DNA-PK and XRCC4/DNA ligase IV, and impairs DSB repair. These findings suggest that WWP2 operates in a DNA-PK-dependent shut-off circuitry for RNAPII clearance that promotes DSB repair by protecting the NHEJ machinery from collision with the transcription machinery.

2019-03-29 | PXD012606 | Pride

DNA-PK Promotes DNA End Resection at DNA Double Strand Breaks in G0 cells [ChIP-Seq]

Project description:DNA double-strand break (DSB) repair by homologous recombination is confined to the S and G2 phases of the cell cycle partly due to 53BP1 antagonizing DNA end resection in G1 phase and non-cycling quiescent (G0) cells where DSBs must be repaired by non-homologous end joining (NHEJ). Unexpectedly, we uncovered extensive MRE11- and CtIP-dependent DNA end resection at DSBs in G0 mammalian cells. A whole genome CRISPR/Cas9 screen revealed the DNA-dependent kinase (DNA-PK) complex as a key factor in promoting DNA end resection in G0 cells. In agreement, depletion of FBXL12, which promotes ubiquitylation and removal of the KU70/KU80 subunits of DNA-PK from DSBs, promotes even more extensive resection in G0 cells. In contrast, a requirement for DNA-PK in promoting DNA end resection in cycling cells at the G1 or G2 phase cells was not observed. Our findings establish that DNA-PK uniquely promotes DNA end resection in G0, but not in G1 or G2 phase cells, and has important implications for DNA DSB repair in quiescent cells.

2022-05-16 | GSE186086 | GEO

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