KMT Set7/9 affects genotoxic stress response via the Mdm2 axis.

Genotoxic stress inflicted by anti-cancer drugs causes DNA breaks and genome instability. DNA double strand breaks induced by irradiation or pharmacological inhibition of Topoisomerase II activate ATM (ataxia-telangiectasia-mutated) kinase signalling pathway that in turn triggers cell cycle arrest and DNA repair. ATM-dependent gamma-phosphorylation of histone H2Ax and other histone modifications, including ubiquitnylation, promote exchange of histones and recruitment of DNA damage response (DDR) and repair proteins.

Current genome editing tools in gene therapy: new approaches to treat cancer.

Gene therapy suggests a promising approach to treat genetic diseases by applying genes as pharmaceuticals. Cancer is a complex disease, which strongly depends on a particular genetic make-up and hence can be treated with gene therapy. From about 2,000 clinical trials carried out so far, more than 60% were cancer targeted.

Elevated Plasma Marinobufagenin, An Endogenous Cardiotonic Steroid, Is Associated With Right Ventricular Dysfunction and Nitrative Stress in Heart Failure.

Background: Plasma levels of cardiotonic steroids are elevated in volume-expanded states, such as chronic kidney disease, but the role of these natriuretic hormones in subjects with heart failure (HF) is unclear. We sought to determine the prognostic role of the cardiotonic steroids marinobufagenin (MBG) in HF, particularly in relation to long-term outcomes.

Methods And Results: We first measured plasma MBG levels and performed comprehensive clinical, laboratory, and echocardiographic assessment in 245 patients with HF.

FRET versus PET: ratiometric chemosensors assembled from naphthalimide dyes and crown ethers.

Novel bi-chromophoric naphthalimide derivatives containing benzo-15-crown-5 and N-phenyl-aza-15-crown-5 receptor moieties BNI2 and BNI3 were designed and prepared. Significant Förster resonance energy transfer (FRET) from donor (D) amido-naphthalimide to acceptor (A) amino-naphthalimide chromophores as well as photoinduced electron transfer (PET) between the N-aryl receptor and amido-naphthalimide fragment was revealed by the steady-state and time-resolved UV/Vis absorption and fluorescence spectroscopy. Upon the addition of alkaline-earth metal perchlorates to an acetonitrile solution of ligands, FRET mediated fluorescence enhancement was observed, which was a result of inhibition of the PET competitive deactivation pathway.

Marinobufagenin-induced vascular fibrosis is a likely target for mineralocorticoid antagonists.

Objective: Endogenous cardiotonic steroids, including marinobufagenin (MBG), stimulate vascular synthesis of collagen. Because mineralocorticoid antagonists competitively antagonize effect of cardiotonic steroids on the Na/K-ATPase, we hypothesized that spironolactone would reverse the profibrotic effects of MBG.

Methods: Experiment 1: Explants of thoracic aortae and aortic vascular smooth muscle cells from Wistar rats were cultured for 24 h in the presence of vehicle or MBG (100 nmol/l) with or without canrenone (10 μmol/l), an active metabolite of spironolactone.

Conformational Dynamics of DNA Repair by Escherichia coli Endonuclease III.

Escherichia coli endonuclease III (Endo III or Nth) is a DNA glycosylase with a broad substrate specificity for oxidized or reduced pyrimidine bases. Endo III possesses two types of activities: N-glycosylase (hydrolysis of the N-glycosidic bond) and AP lyase (elimination of the 3'-phosphate of the AP-site). We report a pre-steady-state kinetic analysis of structural rearrangements of the DNA substrates and uncleavable ligands during their interaction with Endo III.

The role of His-83 of yeast apurinic/apyrimidinic endonuclease Apn1 in catalytic incision of abasic sites in DNA.

Background: The apurinic/apyrimidinic (AP) endonuclease Apn1 from Saccharomyces cerevisiae is a key enzyme involved in the base excision repair (BER) at the cleavage stage of abasic sites (AP sites) in DNA. The crystal structure of Apn1 from S. cerevisiae is unresolved.

[Eye movement parameters in reading the sentences with syntactic ambiguity in Russian language].

We studied the eye movement parameters during reading of syntactically ambiguous sentences with feminine relative clause in Russian language. A priori difficulties of sentence structural analysis results in increase of time spent on reading as opposed to reading control sentences (unambiguous). Such a delay is caused by an increase of frequency of regressions (backward saccades) which are executed for rereading an ambiguous fragment ofsentence.

DNA-ligand interactions gained and lost: light-induced ligand redistribution in a supramolecular cascade.

A supramolecular five-component cascade is presented that enables light-controlled transport of an in situ modified ligand between three host systems based on the different complexation preferences of cyclodextrin, cucurbituril, and double-stranded DNA. The results point out novel approaches for the control of drug-DNA interactions in DNA-targeting therapy.

[TUMOR SUPPRESSOR p63 REGULATES EXPRESSION OF UBIQUITIN LIGASE Pirh2].

Transcription factor p63 is a member of the p53 protein family. Due to the high degree of structural similarity p53, p63, and p73 are known to have overlapping functions relating to cell cycle regulation, apoptosis and tumor transformation. Furthermore, p63 plays crucial role in epidermal tissue development and differentiation.

[NEGATIVE REGULATORS OF TUMOR SUPPRESSOR P53 IN THE CONTEXT OF ANTICANCER THERAPY].

P53 protein is considered to be the major tumor suppressor in human cells. Cancer cells do not survive if the p53-mediated signaling pathways function properly. However, about half of all malignancies still express wild type p53.

Interaction of crown ether-annelated styryl dyes with double-stranded DNA.

DNA-binding properties of 15-crown-5-derived mono- and bis-styryl dyes were investigated in the presence of calf thymus DNA. To access the factors that influence the DNA association in the series of these ligands, the structure of the molecules was varied by either changing size of the heterocyclic moiety or altering the position of the styryl substituents. The major binding mode for the monostyryl dyes is intercalation.

Active destabilization of base pairs by a DNA glycosylase wedge initiates damage recognition.

Formamidopyrimidine-DNA glycosylase (Fpg) excises 8-oxoguanine (oxoG) from DNA but ignores normal guanine. We combined molecular dynamics simulation and stopped-flow kinetics with fluorescence detection to track the events in the recognition of oxoG by Fpg and its mutants with a key phenylalanine residue, which intercalates next to the damaged base, changed to either alanine (F110A) or fluorescent reporter tryptophan (F110W). Guanine was sampled by Fpg, as evident from the F110W stopped-flow traces, but less extensively than oxoG.

Photoinduced guest transformation promotes translocation of guest from hydroxypropyl-β-cyclodextrin to cucurbit[7]uril.

We report that three-component systems comprising styryl dyes (1 or 2) and two hosts (hydroxypropyl-β-cyclodextrin (HP-β-CD) and cucurbit[7]uril (CB[7])) undergo photoinduced transformation and translocation of the styryl guest from the cavity of HP-β-CD to CB[7]. We find that the protonation of guest trans-1 or the addition of Ba(2+) as competitor for CB[7] triggers dissociation of the container-guest complexes.

Plasma level of the endogenous sodium pump ligand marinobufagenin is related to the salt-sensitivity in men.

Objective: Salt-induced elevation of the endogenous digitalis like sodium pump ligand marinobufagenin (MBG) in the Dahl salt-sensitive rats resulted in elevated blood pressure (BP). Here, we tested, in humans, whether MBG levels are related to ambulatory 24-h BP (ABP), controlled long-term increase of salt-intake induces changes in MBG and any salt-induced change in MBG is related to salt sensitivity.

Methods: Thirty-nine healthy individuals (53 ± 11 years old; 20 men and 19 women) had a total daily NaCl intake of 50 mmol (low-salt) and 150 mmol (high-salt) for 4 weeks each, in a random order.

Pre-steady-state kinetic and structural analysis of interaction of methionine γ-lyase from Citrobacter freundii with inhibitors.

Methionine γ-lyase (MGL) catalyzes the γ-elimination of l-methionine and its derivatives as well as the β-elimination of l-cysteine and its analogs. These reactions yield α-keto acids and thiols. The mechanism of chemical conversion of amino acids includes numerous reaction intermediates.

[The morphofunctional prerequisites for the development of exudative otitis media in the children presenting with chronic adenoiditis].

The objective of the present study was to elucidate the structural and functional mechanisms underlying disturbances of the protective nasolaryngeal barrier with special reference to the following histological and immunohistochemical characteristics of the pharyngeal tonsils (CD4, CD20, CD68, IgA, P53, BCL2, Ki67, TGF-beta) in the children aged 3-6 years and presenting with complicated (n=20) or uncomplicated (n=20) chronic adenoiditis (CA). It was shown that adenoids of the patients with complicated chronic adenoiditis less frequently exhibit markers of active inflammation, such as hyperemia, intraepithelial infiltration, and hemosiderophages. Also, they have the smaller mean area of lymphoid follicles and the number of functional intrafollicular macrophages suggesting impaired immunological reactivity.

Structural Features of the Interaction between Human 8-Oxoguanine DNA Glycosylase hOGG1 and DNA.

The purpose of the present review is to summarize the data related with the structural features of interaction between the human repair enzyme 8-oxoguanine DNA glycosylase (hOGG1) and DNA. The review covers the questions concerning the role of individual amino acids of hOGG1 in the specific recognition of the oxidized DNA bases, formation of the enzyme-substrate complex, and excision of the lesion bases from DNA. Attention is also focused upon conformational changes in the enzyme active site and disruption of enzyme activity as a result of amino acid mutations.

In vitro characterization of the splicing efficiency and fidelity of the RmInt1 group II intron as a means of controlling the dispersion of its host mobile element.

Group II introns are catalytic RNAs that are excised from their precursors in a protein-dependent manner in vivo. Certain group II introns can also react in a protein-independent manner under nonphysiological conditions in vitro. The efficiency and fidelity of the splicing reaction is crucial, to guarantee the correct formation and expression of the protein-coding mRNA.

Effect of Some Substituents Increasing the Solubility of Zn(II) and Al(III) Phthalocyanines on Their Photophysical Properties.

Water solubility of phthalocyanines (Pcs) usually increases by the introduction of charged or carboxy substituents in the peripheral positions of the macrocycle. As a result, such structural changes influence their photophysical and photochemical properties as photosensitizers. Phthalocyanines substituted with four or eight terminal carboxyl groups and having in some cases additional eight positive charges (water soluble phthalocyanines) were studied in order to evaluate the spectroscopic and photophysical effects of these side residues on the chromophore properties.

KMTase Set7/9 is a critical regulator of E2F1 activity upon genotoxic stress.

During the recent years lysine methyltransferase Set7/9 ((Su(var)-3-9, Enhancer-of-Zeste, Trithorax) domain containing protein 7/9) has emerged as an important regulator of different transcription factors. In this study, we report a novel function for Set7/9 as a critical co-activator of E2 promoter-binding factor 1 (E2F1)-dependent transcription in response to DNA damage. By means of various biochemical, cell biology, and bioinformatics approaches, we uncovered that cell-cycle progression through the G1/S checkpoint of tumour cells upon DNA damage is defined by the threshold of expression of both E2F1 and Set7/9.

Real-Time Interaction between TBP and the TATA Box of the Human Triosephosphate Isomerase Gene Promoter in the Norm and Pathology.

The TATA-binding protein (TBP) is a key part of the transcription complex of RNA polymerase II. Alone or as a part of the basal transcription factor TFIID, TBP binds the TATA box located in the core region of the TATA-containing promoters of class II genes. Previously, we studied the effects of single nucleotide polymorphisms (SNPs) on TBP/TATA-box interactions using gel retardation assay.

Pre-steady-state fluorescence analysis of damaged DNA transfer from human DNA glycosylases to AP endonuclease APE1.

Background: DNA glycosylases remove the modified, damaged or mismatched bases from the DNA by hydrolyzing the N-glycosidic bonds. Some enzymes can further catalyze the incision of a resulting abasic (apurinic/apyrimidinic, AP) site through β- or β,δ-elimination mechanisms. In most cases, the incision reaction of the AP-site is catalyzed by special enzymes called AP-endonucleases.

[The prevalence of food allergy to peanut and hazelnut in children in Tomsk Region].

Food allergy to peanuts and nuts is an actual problem of practical health care, associated with significant prevalence of this disease, severe clinical symptoms and difficulty of diet organization. Purpose of the study--to study the prevalence of food allergy to peanut and hazelnut in Russian children, the investigation of clinical characteristics of this disease, and the mechanisms of sensitization to allergen components. The cross-sectional study was performed in the framework of the EuroPrevall (No FP6-2006-TTC-TU-5 Proposal 045879).