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At least 19 recordsLinked to original sources
PubMed2026

Loss of BOK increases vulnerability of p53 deficient non-small cell lung cancer cells to ATR inhibition through its role in uridine metabolism.

BOK is a pro-apoptotic member of the BCL-2 family frequently repressed in cancer and with emerging roles beyond apoptosis. BOK interacts with and increases uridine monophosphate synthetase (UMPS) activity, thereby promoting uridine monophosphate (UMP) synthesis. We previously showed that BOK protein is downregulated in primary human lung cancer samples, correlating with poorer patient survival. Here, we demonstrate that BOK deficiency increases DNA damage, triggering p53 activation and cell cycle arrest in two independent non-small cell lung cancer (NSCLC) cell models that express either WT or defective p53. In a p53-deficient setting, BOK loss caused elevated baseline DNA damage rendering cells more dependent on alternative DNA repair pathways. We exploited this vulnerability by inhibiting the ATR-mediated DNA damage response pathway with the selective ATR inhibitor ceralasertib (AZD6738). ATR inhibition in BOK/p53 compound-deficient NSCLC cells exacerbated DNA damage and induced cell death, indicating a synthetic lethal interaction. The DNA damage in BOK-deficient cells was rescued by a cell permeable BOK-BH3-derived peptide, confirming the mechanistic link between BOK and UMPS. Taken together, our findings reveal a vulnerability in NSCLC, where combined loss of p53 and BOK sensitises cells to ATR inhibition. This synthetic interaction suggests that p53-deficient tumours with reduced BOK expression may be more reliant on ATR-mediated DNA repair, providing a mechanistic basis for their susceptibility to ATR inhibitors. Given the frequent inactivation of p53 in lung cancer, our study offers a rationale for clinical exploration of ATR inhibitors, in combination with standard chemotherapy, in the context of reduced BOK function. Future investigations into the broader role of BOK in genomic stability and nucleotide metabolism may uncover additional therapeutic strategies for cancers with repressed BOK.

Humans↗
PubMed2024

Disassembly of the TRIM56-ATR complex promotes cytoDNA/cGAS/STING axis-dependent intervertebral disc inflammatory degeneration.

As the leading cause of disability worldwide, low back pain (LBP) is recognized as a pivotal socioeconomic challenge to the aging population and is largely attributed to intervertebral disc degeneration (IVDD). Elastic nucleus pulposus (NP) tissue is essential for the maintenance of IVD structural and functional integrity. The accumulation of senescent NP cells with an inflammatory hypersecretory phenotype due to aging and other damaging factors is a distinctive hallmark of IVDD initiation and progression. In this study, we reveal a mechanism of IVDD progression in which aberrant genomic DNA damage promoted NP cell inflammatory senescence via activation of the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) axis but not of absent in melanoma 2 (AIM2) inflammasome assembly. Ataxia-telangiectasia-mutated and Rad3-related protein (ATR) deficiency destroyed genomic integrity and led to cytosolic mislocalization of genomic DNA, which acted as a powerful driver of cGAS/STING axis-dependent inflammatory phenotype acquisition during NP cell senescence. Mechanistically, disassembly of the ATR-tripartite motif-containing 56 (ATR-TRIM56) complex with the enzymatic liberation of ubiquitin-specific peptidase 5 (USP5) and TRIM25 drove changes in ATR ubiquitination, with ATR switching from K63- to K48-linked modification, c thereby promoting ubiquitin-proteasome-dependent dynamic instability of ATR protein during NP cell senescence progression. Importantly, an engineered extracellular vesicle-based strategy for delivering ATR-overexpressing plasmid cargo efficiently diminished DNA damage-associated NP cell senescence and substantially mitigated IVDD progression, indicating promising targets and effective approaches to ameliorate the chronic pain and disabling effects of IVDD.

Humans↗
PubMed2026

ATR-dependent phosphorylation of the histone acetyltransferase HBO1 suppresses chromatin binding and promotes replication stress responses.

Mounting evidence has shown that histone acetyltransferase binding to ORC1 (HBO1) serves as an oncoprotein, warranting the use of the small molecule inhibitor WM-3835 for cancer therapy. However, HBO1 is ubiquitously expressed in both tumor and normal tissues, with potential to increase the risk of systemic toxicity. This unmet need highlights the importance of identifying suitable biomarkers to predict the sensitivity to HBO1 inhibitor. Here, we show that ATR, a key regulator of DNA replication stress, is a novel interacting partner of HBO1. In addition, we reveal a regulatory function of HBO1 in DNA replication stress responses, in an ATR-dependent manner. Mechanistically, ATR mediated HBO1 Ser50/53 phosphorylation interferes with the genomic binding of HBO1 and regulates gene expression. Notably, overexpression of HBO1 mutated at the ATR phosphorylation site (S50/53A) dampens the expression of DNA repair related genes and suppresses tumor colony formation, consistent with the observations of WM-3835 treatment. Inhibition of ATR significantly antagonized the sensitivity to WM-3835 treatment. Collectively, our findings uncovered a previously unidentified role of HBO1 in the regulation of replication stress and discovered ATR as a potential biomarker for WM-3835 treatment.

ATR↗
PubMed2026

Discovery of novel quinazoline-containing ATR inhibitor for treatment of acute myeloid leukemia.

ATR is a core kinase in the DNA damage response pathway, primarily sensing replication pressure and double strand breaks, initiating cell cycle arrest, DNA repair, and apoptosis programs, and maintaining genomic stability. In this work, we validated that intervention in ATR function might regulate the progression of AML through bioinformatics analysis. And a series of novel ATR inhibitors based on quinazoline moiety were obtained. The promising compound C7 achieved effective enzyme level and cellular level inhibitory activities, and exhibited acceptable liver S9 stability and oral bioavailability, with no high risk of drug-drug interactions. Research on the underlying mechanism indicated that compound C7 could inhibit the development of MOLM-13 through a dual mechanism of rapidly inducing cell apoptosis and exacerbating DNA damage levels. In brief, compound C7 might be a promising candidate or lead compound for the discovery of novel ATR inhibitors and the treatment of AML.

Quinazolines↗
PubMed1992

X-linked alpha-thalassemia/mental retardation (ATR-X) syndrome: localization to Xq12-q21.31 by X inactivation and linkage analysis.

We have examined seven pedigrees that include individuals with a recently described X-linked form of severe mental retardation associated with alpha-thalassemia (ATR-X syndrome). Using hematologic and molecular approaches, we have shown that intellectually normal female carriers of this syndrome may be identified by the presence of rare cells containing HbH inclusions in their peripheral blood and by an extremely skewed pattern of X inactivation seen in cells from a variety of tissues. Linkage analysis has localized the ATR-X locus to an interval of approximately 11 cM between the loci DXS106 and DXYS1X (Xq12-q21.31), with a peak LOD score of 5.4 (recombination fraction of 0) at DXS72. These findings provide the basis for genetic counseling, assessment of carrier risk, and prenatal diagnosis of the ATR-X syndrome. Furthermore, they represent an important step in developing strategies to understand how the mutant ATR-X allele causes mental handicap, dysmorphism, and down-regulation of the alpha-globin genes.

Dosage Compensation, Genetic↗
PubMedDate not supplied

FTIR-ATR spectra of protein A immobilized on to functionalized polypropylene membranes by gaseous plasma of oxygen and of anhydrous ammonia.

Polypropylene membranes were treated in a gaseous plasma of oxygen or anhydrous ammonia, in order to add hydroxyl groups (oxygen plasma) or amino groups (ammonia plasma) on their surfaces. The presence of these functional groups was detected by FTIR-ATR spectrometry. The FTIR-ATR spectrum of free Protein A was recorded and absorption bands for amide I and amide II at 1650 cm-1 and 1552 cm-1 were identified. The surfaces of immobilized Protein A on to hydroxylated polypropylene membranes and on to polypropylene membranes having amino groups, were characterized by FTIR-ATR spectrometry. The presence of amide I and amide II absorption bands confirmed the immobilization of Protein A on to functionalized polypropylene membranes by gaseous plasma modification.

Ammonia↗
PubMed1979

Structural investigation of biological material in aqueous environment by means of infrared-ATR spectroscopy.

Infrared attenuated total reflection (ATR) spectroscopy may be used to investigate biological material (e.g., membranes, proteins, erythrocytes etc.) under biological conditions provided that adhesion of the sample can be achieved in aqueous environment. Uncharged lipid multilayer model membranes can be attached by hydrophobic interaction when hydrophobic internal reflection plates (e.g., ZnSe, CdTe) are used. However, if an electric field is applied across the membrane, germanium reflection elements would be preferred because of their low electric resistance (approximately 50 omega cm). This material can also be used if cells or proteins are linked chemically to the ATR plate because of the hydrophilic surface which is similar to that of glass and, thus, enables chemical modification by silanization. It has turned out that good adhesion of uncharged and negatively charged model membranes to germanium plates is achieved when they are coated with a monomolecular layer of aminopropylsilane. There is some evidence that erythrocytes remain more stable when adsorbed to a polymerized aminosilane coating (organic silanization) rather than to the corresponding monolayer (aqueous silanization). Negatively charged germanium surfaces have been obtained by succinylation of the aminosilane coating. Furthermore it has been demonstrated that proteins can be bound to the aminosilane coating by means of carbodiimide. Immobilized acetylcholinesterase was still enzymatically active.

Acetylcholinesterase↗
PubMed1988

Characterization of Langmuir-Blodgett films of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine and 1-palmitoyl-2-[10-(pyren-1-yl)decanoyl]-sn-glycero-3-phosphat idylcholine by FTIR-ATR.

Monomolecular films of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) and 1-palmitoyl-2-[10-(pyren-1-yl)decanoyl]-sn-glycero-3-phosphatidylc holine (PPDPC) were transferred from an air/water interface onto a germanium attenuated total reflection crystal by the Langmuir-Blodgett (LB) technique. The assemblies were thereafter investigated by Fourier transform infrared-attenuated total reflection (FTIR-ATR) spectroscopy. To determine the molecular organization in the deposited layers we monitored the CH2 and C = O stretching and the CH2 bending regions of the infrared spectra of these lipids in detail. Using Fourier self-deconvolution technique, the carbonyl stretching mode was resolved into two models corresponding to the conformational differences in the ester linkages of the phospholipid sn-1 and sn-2 acyl chains. By varying the temperature of the subphase and using different surface pressures, we were able to transfer different conformational states of DPPC onto a germanium ATR crystal. Deposition of DPPC at 40 mN m-1 and at 15 degrees C or at 20 mN m-1 and at 35 degrees C results in LB-assemblies in ordered or disordered states, respectively, as judged by the IR spectra. These structures in LB films correspond to the state of DPPC in liposomes below and above the temperature of the order-disorder phase transition. Irrespective of the surface pressure and subphase temperature used during the deposition, an ordering process was found in DPPC films when the number of the transferred layers was increased from one to five. The pyrene-labelled phosphatidylcholine analogue, PPDPC, behaved differently from DPPC. In the case where one to three layers of PPDPC transferred at 35 mN m-1 and at 20 degrees C only conformational structures resembling those in fully hydrated liposomes above the main transition temperature were observed.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1992

Fluorescence, CD, attenuated total reflectance (ATR) FTIR, and 13C NMR characterization of the structure and dynamics of synthetic melittin and melittin analogues in lipid environments.

The structure and dynamics of synthetic melittin (MLT) and MLT analogues bound to monomyristoylphosphatidylcholine micelles, dimyristoylphosphatidylcholine vesicles, and diacylphosphatidylcholine films have been investigated by fluorescence, CD, attenuated total reflectance (ATR) FTIR, and 13C NMR spectroscopy. All of these methods provide information about peptide secondary structure and/or about the environment of the single tryptophan side chain in these lipid environments. ATR-FTIR data provide additional information about the orientation of helical peptide segments with respect to the bilayer plane. Steady-state fluorescence anisotropy, fluorescence lifetime, and 13C NMR relaxation data are used in concert to provide quantitative information about the dynamics of a single 13C-labeled tryptophan side chain at position 19 in lipid-bound MLT, and at positions 17, 11, and 9, respectively, in lipid-bound MLT analogues. Peptide chain dynamics are probed by NMR relaxation studies of 13C alpha-labeled glycine incorporated into each of the MLT peptides at position 12. The cumulative structural and dynamic data are consistent with a model wherein the N-terminal alpha-helical segment of these peptides is oriented perpendicular to the bilayer plane. Correlation times for the lysolipid-peptide complexes provide evidence for binding of a single peptide monomer per micelle. A model for the membranolytic action of MLT and MLT-like peptides is proposed.

Circular Dichroism↗
PubMed2026

Anoxia tolerant DNA replication is supported by ATR kinase in the annual killifish Austrofundulus limnaeus.

Hypoxia and anoxia suppress cell proliferation due to an increase in replication stress and activation of DNA damage checkpoints. Embryos of the annual killifish Austrofundulus limnaeus tolerate prolonged anoxia, indicating improved genomic stability under oxygen starvation. We investigated the cell cycle regulation of the anoxia tolerant killifish embryonic cell line PSU-AL-WS40NE during anoxia. Live-cell imaging confirms continued proliferation of WS40NE cells for the first 24 h of anoxia with minimal cell death. Fluorescence imaging shows that cells accumulate in G1 after the first day in anoxia with a rapid entry into S phase upon reoxygenation. Pharmacological inhibition shows a reliance on ataxia telangiectasia and Rad3 related (ATR) signaling, suggesting that increased γH2AX levels are driven by replication stress instead of DNA damage. This conclusion is supported by a lack of induction of a G2 checkpoint, suggesting minimal DNA damage during anoxic exposure. Maintaining cellular proliferation during anoxia and accumulating cells in the G1 phase for extended anoxic exposure is likely one way that embryos of the killifish can survive prolonged anoxia, which provides insight into mechanisms that enable cells to proliferate under metabolic stress.

Animals↗
PubMed1986

Quantitative surface analysis of Cardiothane 51 by FT-IR-ATR spectroscopy.

Surface analysis has been carried out for Cardiothane 51 samples as commercially available balloon pumps and cast films prepared from the solution. Silicone contents on surfaces have been quantitatively determined by FT-IR-ATR spectroscopy coupled with a subtraction technique. The contents on the air-facing surface vary from 0.7 to 5.3% among six balloon pumps examined; three of them contain less silicone on the air-facing surface than on the substrate-facing surface, whereas just the opposite is true for one, and the other two have nearly and quite an equal content of it between the two surfaces. Silicone contents on surfaces of cast films vary also from a sample to another even when sample films were prepared from the same Cardiothane solution, indicating difficulty in quality control of Cardiothane surfaces. An appreciable fraction of silicone was found not to be covalently bonded to polyurethane in Cardiothane 51 for the cast film samples.

Biocompatible Materials↗
PubMed1986

FTIR-ATR studies of the effect of shear rate upon albumin adsorption onto polyurethaneurea.

The effect of wall shear rate upon albumin adsorption onto a polyurethaneurea, Biomer, was studied using FTIR-ATR spectroscopy. In these experiments, nondiffusion controlled adsorption was observed from 10 mg/ml solutions at known wall shear rates. Results show that increasing wall shear rate during adsorption does not significantly affect the adsorption kinetics, but does decrease the rate of protein desorption. These results suggest that albumin adsorbed at higher shear rates is more tightly bound to the surface. Comparison of the data to simple mathematical models suggests that more than one layer of protein adsorbs in 2 h.

Adsorption↗
PubMed1991

ATR-FTIR analysis of protein adsorption on polymeric surfaces.

ATR-FTIR spectroscopy was used to study the adsorption of bovine serum albumin on poly(vinyl chloride), poly(vinylidene fluoride), poly(methyl methacrylate), and poly(ethylene glycol)-grafted poly(methyl methacrylate) surfaces. The results were analyzed in terms of the amount of albumin adsorbed on the various polymeric surfaces when immersed in a 1 g/1 protein solution. Experimental results were compared with the Van Straaten and Peppas model (1990) and satisfactory agreement was obtained. It was confirmed that poly(ethylene glycol) surfaces exhibited the lowest albumin adsorption patterns.

Adsorption↗
PubMedDate not supplied

The structure of lipids and proteins studied by attenuated total reflection (ATR) infrared spectroscopy. II. Oriented layers of a homologous series: phosphatidylethanolamine to phosphatidylcholine.

Polarized infrared ATR spectra of dry oriented multilayers of dipalmitoylphosphatidylethanolamine, sheep brain phosphatidylethanolamine, dipalmitoylphosphatidyl-N-methylethanolamine, dipalmitoylphosphatidyl-N-N-dimethylethanolamine, dipalmitoylphosphatidylcholine and egg phosphatidylcholine are reported. Structural features of hydrocarbon chains and polar headgroups are discussed. The average deviation fo hydrocarbon chains from the normal to the plane of the bilayer was found to be 20-30 degrees. However it was not possible to decide whether the chains are oriented parallel to each other. The fatty acid ester groups in beta- and gamma-position have different conformations. The phosphate group of dipalmitoylphosphatidylethanolamine exists probably in the protonated (formula: see text) and not in the ionized (greater than PO2-) state. However, the latter state is expected for all other phospholipids of this series. The deviation of the bisector of (formula: see text) of the greater than PO2- group from the normal to the bilayer is less than 45 degrees and the mean orientation of all polar head groups is rather parallel than perpendicular to the plane of the bilayer. The polar headgroup of phosphatidylcholine assumes at least two different conformations of the O-C-C-N moiety, i.e. gauche and trans. A variety of conformers has to be expected also for the polar head groups of most of the other phospholipids investigated in this work.

Animals↗
PubMed1979

Laser absorption spectroscopy with an ATR prism--noninvasive in vivo determination of glucose.

The use of lasers as light sources in IR spectroscopy allows an improvement in measuring sensitivity by a factor of about 100 as compared with the conventional technique. In addition, the monochromaticity of lasers appreciably improves the resolution. Combining lasers with an ATR plate acting as test prism gets rid of transmission cells without impairing the measuring sensitivity. It also considerably reduces the thermal load on the test sample; in vivo measurements on biological tissue can thus be made simply.

Blood Glucose↗
PubMed1990

Orientation studies of hydrated dipalmitoylphosphatidylcholine multibilayers by polarized FTIR-ATR spectroscopy.

Polarized Fourier-transform infrared-attenuated total reflection spectroscopy has been applied to explore the temperature-dependence of molecular orientations in multibilayers of 1,2-dipalmitoyl-sn-glycero-3- phosphocholine (DPPC) of various degrees of hydration. The order parameter of the hydrocarbon chain, evaluated from the dichroic ratios of the antisymmetric and symmetric CH2 stretching bands, was drastically decreased at the main (or gel to liquid-crystalline phase) transition temperature (Tm) irrespective of the water content, suggesting that the hydrocarbon chain is in a disordered state as a result of chain-melting associated with an increase in the number of the gauche conformers. On the other hand, the dichroic ratios of the polar bands of hydrated DPPC assignable to the symmetric PO2- stretching and asymmetric N+ (CH3)3 stretching modes were increased mainly at the pretransition temperature (Tp), except for less hydrated case. The dichroic ratios of both the OH stretching and OH2 bending bands of water showed the same temperature-dependence as those of the polar bands. These results indicate that the pretransition is ascribable mainly to the reorientation of the polar groups of the DPPC and bound water, while the main transition is due to the orientational disorder of the hydrocarbon chains. For less hydrated DPPC, the reorientation of the polar groups and water did not occur around Tp, but in the higher temperature region around Tm. This is in accord with the previously reported observation that the pretransition disappears for less hydrated DPPC. In this case, the polar groups and water may reorient following the reorientation of the hydrocarbon chains near Tm.

1,2-Dipalmitoylphosphatidylcholine↗