Daphnane diterpenoids for cancer therapy by suppressing ATR-mediated DNA damage response pathway
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PROVIDER: PRJNA1289710 | ENA |
REPOSITORIES: ENA
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Project description:In this study, 26 structurally diverse daphnane diterpenoids (1-26) including six undescribed ones (1-6) were isolated from the whole plants of Daphne odora. Compounds 1 and 2 were the most active with IC50 values of 3.57 ± 0.32 and 4.35 ± 0.14 μM, respectively. Mechanistic study indicated that 1 and 2 could significantly induce cell cycle arrest at the G2/M phase and cause cell apoptosis. Further examination by transcriptome sequencing analysis revealed that 1 and 2 significantly suppressed ATR-mediated DNA damage response and cell cycle checkpoint.
2025-07-15 | GSE302236 | GEO
Project description:Mitochondria are the central metabolic hub of the cell and their function is vital for cellular activities. Mitochondrial autophagy, or mitophagy, is a quality control mechanism to surveille the fitness and functionality of mitochondria and is therefore essential for life. Both mitochondrial dysfunction and malfunctional DNA damage response (DDR) are a major etiology for tissue impairment and aging. ATR has been shown mainly as a nuclear factor to conduct DNA damage response under DNA replication stress. Paradoxically, the human Seckel syndrome caused by ATR mutations is characterized by premature aging and neuropathies, suggesting a role of ATR in non-replicating tissues. Here we report a previously unknown yet direct role of ATR at mitochondria. We find that HSP90 chaperones ATR and PINK1 to mitochondria, where ATR interacts with and thereby stabilizes PINK1 docking at the mitochondrial translocase TOM/TIM complex as well as with the electron transport chain (ETC). ATR mutant cells are refractory to mitophagy initiation, which can be reverted by an ectopic expression of full length, but not ATR-interaction mutant, PINK1. ATR deletion alters mitochondrial dynamics and OXPHOS functions producing aberrantly high reactive oxygen species (ROS) that attack cytosolic macromolecules prior to damaging nuclear DNA. Intriguingly, pharmacological intervention of mitochondrial metabolism to prevent ROS overproduction can mute ATR-mediated nuclear DDR. This study demonstrates that ATR is an integrated component of the mitochondrial membrane to ensure mitochondrial fitness as a primary physiological function, which, together with its essential DDR function, safeguards the cell fate under physiological and genotoxic conditions.
2025-02-26 | GSE244464 | GEO
Project description:High-risk human papillomaviruses (HPVs) constitutively activate the ataxia telangiectasia and Rad3-related (ATR) DNA damage response pathway for their replication. Although ATR has many reported functions, knowledge of how it regulates viral replication is limited. Most studies regarding ATR function focus on its roles in cell survival and initiation of DNA damage response. In this study, we examined whether the transcriptional regulatory properties directed by ATR are critical for HPV pathogenesis, and if so which downstream targets are important. Using RNA-seq approaches, we observed that ATR knockdown increases expression of many inflammatory genes. This mechanism is dependent on the p62/GATA4 signaling pathway.
2020-07-27 | GSE142482 | GEO
Project description:Maintaining genome integrity presents a particular challenge for plants due to their sedentary lifestyle, which disables direct avoidance of unfavorable external conditions. Additionally, plants’ metabolic processes generate reactive molecules as by-products of e.g. photosynthesis, creating internal DNA-damaging conditions. Due to this, plants have developed a unique and strictly regulated web of DNA damage responses (DDR). We initiated analysis of the DDR system in cultivated barley (Hordeum vulgare), a temperate cereal model with a large and repeat rich genome. A series of DNA damaging assays was established to describe barley plants’ phenotypic response to chemically induced DNA double-strand breaks. The efficacy of assays as a tool to be used for assessing potential new DDR barley mutants was demonstrated. DNA damage response network activation in barley was assessed by transcriptome analysis using RNA sequencing for wild type and mutant in the DDR signaling kinase ATAXIA TELANGIECTASIA MUTATED AND RAD3-RELATED (ATR). Considering the barley genome had only recently been sequenced, and it lacks the in-depth gene analysis, a list of potential DNA damage response genes in barley was compiled based on their homology with Arabidopsis genes. The comparison of transcripts in wild-type plants and atr mutants following genotoxic stress
2023-10-19 | GSE235051 | GEO
Project description:Microcephaly and medulloblastoma result from mutations that compromise genomic stability. We report that Atr, which is mutated in the microcephalic disorder Seckel syndrome, is required to maintain chromosomal integrity during postnatal cerebellar neurogenesis. Atr deletion in cerebellar granule neuron progenitors (CGNPs) induced proliferation-associated DNA damage, p53 activation, apoptosis, and cerebellar hypoplasia. Co-deletions of either Bax and Bak or p53 prevented apoptosis in Atr-deleted CGNPs, but failed to fully rescue cerebellar growth. Atr-deficient CGNPs showed impaired cell cycle checkpoint function and continued to proliferate, accumulating chromosomal abnormalities. RNA-Seq demonstrated that the transcriptional response to Atr-deficient proliferation was p53-driven. Acute Atr inhibition in vivo by nanoparticle-formulated VE-822 reproduced the disruptions seen with Atr deletion. Our data show that p53-driven apoptosis and senescence, and non-apoptotic cell death redundantly limit growth in Atr-deficient progenitors. These overlapping mechanisms that suppress growth in Atr-disrupted CGNPs may be exploited for treatment of CGNP-derived medulloblastoma using Atr inhibition.
2016-09-01 | GSE85393 | GEO
Project description:Daphnane diterpenoids as potent and tolerable importin-b1 inhibitors to treat castration-resistant prostate cancer
| PRJNA743226 | ENA
Project description:Microcephaly and medulloblastoma result from mutations that compromise genomic stability. We report that Atr, which is mutated in the microcephalic disorder Seckel syndrome, is required to maintain chromosomal integrity during postnatal cerebellar neurogenesis. Atr deletion in cerebellar granule neuron progenitors (CGNPs) induced proliferation-associated DNA damage, p53 activation, apoptosis, and cerebellar hypoplasia. Co-deletions of either Bax and Bak or p53 prevented apoptosis in Atr-deleted CGNPs, but failed to fully rescue cerebellar growth. Atr-deficient CGNPs showed impaired cell cycle checkpoint function and continued to proliferate, accumulating chromosomal abnormalities. RNA-Seq demonstrated that the transcriptional response to Atr-deficient proliferation was p53-driven. Acute Atr inhibition in vivo by nanoparticle-formulated VE-822 reproduced the disruptions seen with Atr deletion. Our data show that p53-driven apoptosis and senescence, and non-apoptotic cell death redundantly limit growth in Atr-deficient progenitors. These overlapping mechanisms that suppress growth in Atr-disrupted CGNPs may be exploited for treatment of CGNP-derived medulloblastoma using Atr inhibition.
2016-09-01 | GSE83720 | GEO
Project description:UV irradiation causes significant changes in gene expression and induces DNA damage. DNA damage is detrimental to the cell and has to be repaired in a timely manner. DNA damage checkpoints regulate progression through the cell cycle when DNA damage is detected and give time for the cell to repair the damage efficiently. We have preliminary evidence suggesting that ATR, otherwise known for its role of DNA damage checkpoint in S phase and G2/M phase, might also be involved in a yet unheeded UV-induced G1 block. To investigate this, we performed mRNA sequencing, in the hope to unravel which genes/gene families are involved in this checkpoint in response to UV, how this changes in response to ATR inhibition, and the overall changes in gene expression.
2025-01-01 | GSE253798 | GEO
Project description:Next generation sequencing of neuroblastoma (NB) tumors have revealed frequent somatic and germline genetic alterations in genes encoding proteins involved in DNA damage response (DDR) pathways. Despite being well-studied in many adult cancers, roles for DDR disruption in pediatric solid tumors have not been fully elucidated. To address this, patient-relevant loss-of-function mutations in DDR pathway components including Brca2, Atm, and Palb2 were incorporated into an established zebrafish MYCN transgenic model (Tg(dbh:EGFP-MYCN)). These mutations were found to enhance NB formation and metastasis in vivo, and result in upregulation of proliferation, cell cycle checkpoint and DNA damage repair transcriptional signatures, revealing novel molecular vulnerabilities in DDR-deficient NB. Zebrafish DDR-deficient NB and human NB cells with DDR protein knock-down were sensitive to the poly(ADP-ribose)-polymerase (PARP) inhibitor olaparib, and this effect was further enhanced by inhibition of the ataxia telangiectasia and rad3 related (ATR) kinase. Altogether, our data supports a functional role for DDR-deficiency in NB in vivo and therapeutic potential for combination PARP + ATR inhibition in NB patients with alterations in DDR genes.
2025-02-10 | GSE283976 | GEO
Project description:ATR, a DNA damage kinase, modulates DNA replication timing in Leishmania major.
| PRJEB83661 | ENA