DNA-PKcs inhibitor KU-57788 synergizes with ferroptosis in anaplastic thyroid cancer cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE319513 | GEO | 2026/06/24
REPOSITORIES: GEO
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Project description:DNA-PKcs inhibitor KU-57788 synergizes with ferroptosis in anaplastic thyroid cancer cells
| PRJNA1423652 | ENA
Project description:The DNA-dependent protein kinase (DNA-PK), composed of the KU heterodimer and the catalytic subunit (DNA-PKcs), is a classical non-homologous end-joining (cNHEJ) factor1. KU binds to DNA ends, initiates cNHEJ, and recruits and activates DNA-PKcs. Beyond DNA, KU also binds to RNA, with unknown significance in mammals. Using mouse models, we uncovered an unexpected role for DNA-PK in ribosomal RNA (rRNA) biogenesis and hematopoiesis. Expression of kinase-dead (KD) DNA-PKcs (DNA-PKcsKD/KD) abroagates cNHEJ2. But DNA-PKcsKD/KDTp53-/- mice develop myeloid disease rather than pro-B cell lymphoma, like other cNHEJ/Tp53-deficient mice3. DNA-PKcs is its own the best substrate. Blocking DNA-PKcs phosphorylation at the T2609, but not the S2056 cluster leads to KU-dependent 18S rRNA processing defects, compromises global protein synthesis in hematopoietic cells and causes bone marrow failure in mice. KU drives assembly of DNA-PKcs on a broad array of cellular RNAs, including the U3 small nucleolar RNA (snoRNA), which is essential for 18S rRNA processing4. U3 activates purified DNA-PK and triggers T2609 phosphorylation. DNA-PK, but not other cNHEJ factors, resides in nucleoli in an rRNA-dependent manner and is co-purified with the small subunit (SSU) processome. Together our data show that DNA-PK has RNA-dependent, but cNHEJ-independent, functions during ribosome biogenesis that require DNA-PKcs’ kinase activity and T2609 cluster’s phosphorylation.
2020-01-05 | GSE109026 | GEO
Project description:The non-homologous end-joining (NHEJ) pathway is critical for DNA double-strand break repair and is essential for lymphocyte development and maturation. The Ku70/Ku80 heterodimer (KU) binds to DNA ends, initiating NHEJ and recruiting additional factors, including DNA-dependent protein kinase catalytic subunit (DNA-PKcs) that caps the ends and pushes KU inward. The C-terminus of Ku70 in higher eukaryotes includes a flexible linker and a SAP domain, whose physiological role remains poorly understood. To investigate this, we generated a mouse model with knock-in deletion of the SAP domain (Ku70DSAP/DSAP). Ku70DSAP supports KU stability and its recruitment to DNA damage sites in vivo. In contrast to the growth retardation and immunodeficiency seen in Ku70-/- mice, Ku70DSAP/DSAP mice show no defects in lymphocyte development and maturation. Structural modeling of KU on long dsDNA, but not dsRNA suggests that the SAP domain can bind to an adjacent major groove, where it can limit KU’s rotation and lateral movement along the dsDNA. Consistent with this model, in the absence of DNA-PKcs that caps the ends, Ku70DSAP fails to support stable DNA damage-induced KU foci. In DNA-PKcs-/- mice, Ku70DSAP abrogates the leaky T cell development and reduces both the qualitative and quantitative aspects of residual V(D)J recombination. Moreover, purified Ku70DSAP also has reduced affinity for DNA ends and dissociates more readily. These findings revealed a physiological role of the SAP domain in NHEJ by restricting KU rotation and lateral movement on DNA that is largely masked by DNA-PKcs.
2024-12-31 | GSE276069 | GEO
Project description: Not available
| S-EPMC12395522 | biostudies-literature
Project description:Identification of OVOL2-related transcriptional program in anaplastic thyroid carcinoma-derived cell line, 8505c. Doxycycline-inducible system was obtained by infecting 8505c cells with lentiviral vector containing OVOL2 coding sequence fused with HA tag. Control cells were infected with empty vector (EV). Cells were collected 24 hours upon doxycycline treatment.
2023-10-05 | E-MTAB-11055 | biostudies-arrayexpress
Project description:Gene expression comparison between anaplastic thyroid carcinoma cells (CAL62 and 8505c) transfected with si-RNA against E2F7 or scramble oligos, with the intent of defining the gene expression program under the control of this transcription factor in this tumor subtype.
2023-02-07 | E-MTAB-9788 | biostudies-arrayexpress
Project description:Ku70 and Ku80 form Ku , a ring-shaped protein that initiates the non-homologous end-joining (NHEJ) DNA repair pathway. Specifically, Ku binds to double-stranded DNA (dsDNA) ends and recruits other NHEJ factors (e.g., DNA-PKcs and LIG4). While Ku binds to double-stranded RNA (dsRNA) and traps mutated-DNA-PKcs on ribosomal RNA in vivo, the physiological significance of Ku-dsRNA interactions in otherwise wild-type cells remains elusive. Intriguingly, while dispensable for murine development, Ku is essential in human cells. Despite similar genome sizes, human cells express ~100-fold more Ku than mouse cells, implying functions beyond NHEJ, possibly through a dose-sensitive interaction with dsRNA, which is 10~100 times weaker than with dsDNA. While investigating the essentiality of Ku in human cells, we found that depletion of Ku - unlike LIG4 - induces profound interferon (IFN) and NF-kB signaling via dsRNA-sensor MDA5/RIG-I and adaptor MAVS. Prolonged Ku-degradation also activates other dsRNA-sensors, e.g. PKR that suppresses protein translation, and OAS/RNaseL that cleaves rRNAs and eventually induces growth arrest and cell death. MAVS, RIG-I, or MDA5 knockouts suppressed IFN signaling and, like PKR knockouts, all partially rescued Ku-depleted human cells. Ku-irCLIP analyses revealed that Ku binds to diverse dsRNA, predominantly stem-loops in primate-specific Alu elements at anti-sense orientation in introns and 3’-UTRs. Ku expression rose sharply in higher primates tightly correlating with Alu-expansion (r = 0.94/0.95). Together, our study identified a vital role of Ku in accommodating Alu-expansion in primates by mitigating a dsRNA-induced innate immune response, explaining the rise of Ku levels and its essentiality in human cells.
2025-04-16 | GSE294709 | GEO
Project description:RAD21 ChIA-PET in human KU-19-19 cells For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODE_Data_Use_Policy_for_External_Users_03-07-14.pdf
2019-03-03 | GSE127032 | GEO
Project description:We report the application of single-molecule-based sequencing technology for high-throughput profiling of RNAs in BRAFV600E+ thyroid cancer cell lines 8505C and WRO. We generated genome-wide transcriptome maps of 8505C and WRO cells after vemurafenib, BRAF inhibitor, treatment. In addition, we generated genome-wide transcriptome maps of clonally selected vemurafenib-resistant 8505C and WRO cells with or without vemurafenib treatment. Negative control treatment was 0.1% of dimethy solfoxide (DMSO), the diluent used to resuspend vemurafenib. The treatment regine of vemurafenib was 2 µM concentration for 24 hours. We find that both inducible response to BRAFi and acquired BRAFi resistance in thyroid cancer cells showed significant activation of the JAK/STAT pathway. Our study demonstrates that the JAK/STAT-signaling pathway is activated as thyroid cancer cells develop resistance to BRAFi and that this pathway is a potential target for anticancer activity and to overcome drug resistance that commonly develops to treatment with BRAFi in thyroid cancer and potentially in other malignancies.
2023-02-16 | GSE178267 | GEO
Project description:An ideal cancer gene therapy would selectively destroy the cancer cells without affecting much the healthy tissue. This would be possible if and only if the cancer and normal cells of the tumor are governed by distinct gene master regulators (GMRs). Logic dictates that, while being strongly protected by the homeostatic mechanisms, expression of a GMR governs the phenotype by modulating major functional pathways through controlling the expression of the involved genes. We determined the GMRs of the standard papillary (BCPAP) and anaplastic (8505C) thyroid cancer cell lines. The hierarchy of the known biomarkers was established based on their gene commanding height (GCH), an original measure combining the expression control and coordination with expression of other genes. We found that the sets of the GMRs are largely different in the two thyroid cancer cell lines, indicatibg that each type of thyroid cancer needs a different gene-targeting therapy. In this experiment, we determined the transcriptomic effects of the stable transfection of PANK2 gene In the papillary (BCPAP) and anaplastic (8505C) thyroid cancer cell lines. PANK2 was selected because it has significantly different GCHs in the two cell lines: 44.64 in BCPAP and 3.61 in 8505C. The significantly more up- and down-regulated genes in the transfected BCPAP than in the transfected 8505C cells compared to their untransfected counterparts validated the theory and indicated the usefulness of our personalized gene therapy approach.
2017-03-25 | GSE97030 | GEO