Histones are positively charged proteins found in the chromatin of eukaryotic cells. They regulate gene expression and are required for the organization and packaging of DNA within the nucleus. Histones are extremely conserved, allowing for transcription, replication, and repair. This review delves into their complex structure and function in DNA assembly, their role in nucleosome assembly, and the higher-order chromatin structures they generate. We look at the five different types of histone proteins: H1, H2A, H2B, H3, H4, and their variations. These histones bind with DNA to produce nucleosomes, the basic units of chromatin that are essential for compacting DNA and controlling its accessibility. Their dynamic control of chromatin accessibility has important implications for genomic stability and cellular activities. We elucidate regulatory mechanisms in both normal and pathological situations by investigating their structural features, diverse interaction mechanisms, and chromatin impact. In addition, we discuss the functions of histone post-translational modifications (PTMs) and their significance in various disorders. These alterations, which include methylation, acetylation, phosphorylation, and ubiquitination, are crucial in regulating histone function and chromatin dynamics. We specifically describe and explore the role of changed histones in the evolution of cancer, neurological disorders, sepsis, autoimmune illnesses, and inflammatory conditions. This comprehensive review emphasizes histone's critical role in genomic integrity and their potential as therapeutic targets in various diseases.
- Klíčová slova
- Chromatin, Disease, Gene expression, Genomic stability, Histones, Nucleosomes, Post-translational modifications (PTMs),
- MeSH
- chromatin metabolismus genetika MeSH
- DNA * genetika metabolismus chemie MeSH
- histony * metabolismus genetika chemie MeSH
- lidé MeSH
- nádory * metabolismus genetika patologie MeSH
- nukleozomy metabolismus genetika MeSH
- posttranslační úpravy proteinů MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- chromatin MeSH
- DNA * MeSH
- histony * MeSH
- nukleozomy MeSH
Benzo[c]phenanthridine alkaloids are known for their stabilizing effects on non-canonical DNA structures, particularly G-quadruplexes (G4s). In this study, the interaction of fagaronine, a rare benzo[c]phenanthridine alkaloid, with several DNA structures (including B-DNA, parallel, antiparallel and hybrid G4s) is studied using molecular fluorescence and circular dichroism (CD) spectroscopy. It has been found that fagaronine significantly enhances the stability of all tested G4 conformations. Furthermore, a study by NMR spectroscopy provided valuable information on the mechanism of interaction of the ligand with the parallel G4 structure adopted by Pu22T14T23, a sequence mutated with respect to that found within the promoter region of the c-myc gene. Remarkably, when compared with data reported in the literature, fagaronine appears to exhibit one of the strongest G4 thermal stabilization effects ever recorded for a small ligand.
- Klíčová slova
- Circular dichroism spectroscopy, Docking simulation, Fagaronine, Fluorescence spectroscopy, G-quadruplex, NMR spectroscopy,
- MeSH
- alkaloidy * chemie MeSH
- cirkulární dichroismus MeSH
- DNA * chemie MeSH
- fenantridiny * chemie MeSH
- G-kvadruplexy * účinky léků MeSH
- magnetická rezonanční spektroskopie MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- alkaloidy * MeSH
- DNA * MeSH
- fenantridiny * MeSH
Boron doped diamond electrodes brought a new potential in bioanalytical chemistry including studies of structure and interactions of nucleic acids. Herein, deposition conditionswere optimized to produce a set of polycrystalline BDD electrodes with comparable boron concentration in solid phase of (1.8 - 2.1) · 1021 cm-3 akin to metallic-type conductivity but with increasing sp2carbon content. Increase of[CH4]/[H2]from 0.25 % to 2.0 % during deposition led to an obvious decrease in grain size from ca.300 nm (BDD0.25) to < 100 nm (BDD2.0). Adsorption of oligodeoxynucleotides and their structural changes in the presence of K+ and Li+ ions were evaluated through enzyme-linked DNA hybridization assay in which oxidizable 1-naphthol was released from its phosphoesterbystreptavidin-alkaline phosphatase conjugate upon successful hybridization of the target oligodeoxynucleotide with a biotinylated complementary probe. With increasing sp2carbon content, the hybridization assay showed improved discrimination between a target forming guanine quadruplex (stabilized by K+ ions), yielding by 40 % - 60 % lower hybridization signal with the complementary probe, compared to the same but unstructured target oligodeoxynucleotide in the presence of Li+ions that don't stabilize the quadruplex structure. Such behaviour was observed also for commercial BDD electrode with surface roughness < 10 nm.
- Klíčová slova
- Boron doped diamond electrode, DNA hybridization, Enzyme-linked electrochemical assay, Guanine quadruplex, Linear scan voltammetry, Sp(2) carbon content,
- MeSH
- biosenzitivní techniky MeSH
- bor * chemie MeSH
- diamant * chemie MeSH
- DNA * chemie genetika MeSH
- elektrody MeSH
- G-kvadruplexy MeSH
- hybridizace nukleových kyselin * MeSH
- uhlík * chemie MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- bor * MeSH
- diamant * MeSH
- DNA * MeSH
- uhlík * MeSH
Previous research indicated that the cytotoxic activity of the antitumor platinum(II) complex [Pt(1S,2S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)]2+ (56MESS) was not primarily attributed to DNA binding, despite the complex being confirmed to localize also in the nucleus. In this study, we have demonstrated that the antiproliferative activity of 56MESS indeed involves DNA binding. Furthermore, in addition to binding duplex DNA, the complex also interacts with non-canonical secondary DNA structures, such as G-quadruplexes (G4s) and i-Motifs (iMs). This interaction leads to the suppression of G-regulated oncogene expression and disrupts key enzymatic processes associated with DNA, potentially contributing to DNA damage and the biological activity of 56MESS. These findings build upon previously published results, revealing that the anticancer activity of 56MESS is significantly more multifaceted than previously understood, involving multiple distinct mechanisms.
- Klíčová slova
- Antitumor platinum complex, DNA G-quadruplex, DNA i-Motif, c-MYC oncogene, k-RAS oncogene,
- MeSH
- DNA metabolismus chemie MeSH
- down regulace * účinky léků MeSH
- G-kvadruplexy * účinky léků MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- organoplatinové sloučeniny * farmakologie chemie MeSH
- poškození DNA * účinky léků MeSH
- proliferace buněk účinky léků MeSH
- protinádorové látky * farmakologie chemie MeSH
- protoonkogenní proteiny c-myc * genetika metabolismus MeSH
- protoonkogenní proteiny p21(ras) * genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- DNA MeSH
- organoplatinové sloučeniny * MeSH
- protinádorové látky * MeSH
- protoonkogenní proteiny c-myc * MeSH
- protoonkogenní proteiny p21(ras) * MeSH
This study provides a comprehensive investigation of the structural and vibrational properties of protonated cytosine monomers and dimers. Experimental IRPD spectroscopy, combined with theoretical calculations, revealed distinct behaviors for monomers and dimers. We find that protonated cytosine monomers predominantly adopt the enol form in the gas phase, with a contribution from the keto form between 25% and 33%. For dimers, our computations predict a keto-enol configuration to be more stable than the keto-keto form by 1.5 kcal mol-1. However, experimentally, the keto-keto form emerged as the dominant structure. The theoretically most stable keto-enol configuration undergoes a structural reorganization in MD simulations with explicit methanol, forming the dynamically unstable neutral-keto-protonated-keto complex. This reorganization highlights the role of environmental factors in modulating tautomer populations.
- MeSH
- cytosin * chemie MeSH
- dimerizace MeSH
- DNA * chemie MeSH
- simulace molekulární dynamiky MeSH
- spektrofotometrie infračervená MeSH
- teorie funkcionálu hustoty MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- cytosin * MeSH
- DNA * MeSH
Here we investigated cytotoxicity and DNA and protein binding of an iodido analog of picoplatin, the cis-ammine-diiodido(2-methylpyridine)platinum(II) complex (I-picoplatin). I-picoplatin (IC50 = 3.7-12.4 μM) outperforms picoplatin (IC50 = 11.8-22.6 μM) in the human cancer cell lines used and shows a greater ability to overcome the cisplatin resistance of A2780 ovarian cancer cells than does picoplatin. I-picoplatin also induces different cell cycle changes (reduced S-phase fraction and an increase in the G2/M phase arrest) in HeLa cervical carcinoma cells compared to both picoplatin and cisplatin. Binding of the metal compound to DNA model systems was investigated by ethidium bromide displacement assay and circular dichroism. Its reactivity with lysozyme (HEWL) and pancreatic RNase A was studied by X-ray diffraction and mass spectrometry experiments. I-picoplatin binds the DNA double helix and is able to retain the 2-methylpyridine ligand and at least one of the two iodido ligands when bound to the two proteins. Various Pt-containing moieties, including one based on the isomerized structure of I-picoplatin, coordinate the His and Met residues. A low-resolution structure of the I-picoplatin/human serum albumin (HSA) adduct has also been solved. The side chains of His146, Met289, and Met329 are the primary binding sites of the I-picoplatin moieties on HSA.
- MeSH
- DNA * metabolismus chemie MeSH
- lidé MeSH
- lidský sérový albumin * metabolismus chemie MeSH
- molekulární struktura MeSH
- muramidasa * metabolismus chemie MeSH
- nádorové buněčné linie MeSH
- organoplatinové sloučeniny * chemie farmakologie chemická syntéza metabolismus MeSH
- pankreatická ribonukleasa * metabolismus chemie MeSH
- proliferace buněk účinky léků MeSH
- protinádorové látky * farmakologie chemie chemická syntéza metabolismus MeSH
- screeningové testy protinádorových léčiv MeSH
- vazba proteinů MeSH
- vazebná místa MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- DNA * MeSH
- lidský sérový albumin * MeSH
- muramidasa * MeSH
- organoplatinové sloučeniny * MeSH
- pankreatická ribonukleasa * MeSH
- protinádorové látky * MeSH
G-quadruplexes (G4s) are functional elements of the human genome, some of which inhibit DNA replication. We investigated replication of G4s within highly abundant microsatellite (GGGA, GGGT) and transposable element (L1 and SVA) sequences. We found that genome-wide, numerous motifs are located preferentially on the replication leading strand and the transcribed strand templates. We directly tested replicative polymerase ϵ and δ holoenzyme inhibition at these G4s, compared to low abundant motifs. For all G4s, DNA synthesis inhibition was higher on the G-rich than C-rich strand or control sequence. No single G4 was an absolute block for either holoenzyme; however, the inhibitory potential varied over an order of magnitude. Biophysical analyses showed the motifs form varying topologies, but replicative polymerase inhibition did not correlate with a specific G4 structure. Addition of the G4 stabilizer pyridostatin severely inhibited forward polymerase synthesis specifically on the G-rich strand, enhancing G/C strand asynchrony. Our results reveal that replicative polymerase inhibition at every G4 examined is distinct, causing complementary strand synthesis to become asynchronous, which could contribute to slowed fork elongation. Altogether, we provide critical information regarding how replicative eukaryotic holoenzymes navigate synthesis through G4s naturally occurring thousands of times in functional regions of the human genome.
- MeSH
- aminochinoliny MeSH
- DNA-polymerasa II * antagonisté a inhibitory metabolismus MeSH
- DNA-polymerasa III * antagonisté a inhibitory metabolismus MeSH
- DNA chemie MeSH
- G-kvadruplexy * MeSH
- genom lidský * MeSH
- holoenzymy metabolismus MeSH
- kyseliny pikolinové farmakologie MeSH
- lidé MeSH
- mikrosatelitní repetice MeSH
- proteiny vázající poly-ADP-ribosu MeSH
- replikace DNA * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- aminochinoliny MeSH
- DNA-polymerasa II * MeSH
- DNA-polymerasa III * MeSH
- DNA MeSH
- holoenzymy MeSH
- kyseliny pikolinové MeSH
- POLD3 protein, human MeSH Prohlížeč
- POLE protein, human MeSH Prohlížeč
- proteiny vázající poly-ADP-ribosu MeSH
- pyridostatin MeSH Prohlížeč
Non-canonical (non-B) DNA structures-e.g. bent DNA, hairpins, G-quadruplexes (G4s), Z-DNA, etc.-which form at certain sequence motifs (e.g. A-phased repeats, inverted repeats, etc.), have emerged as important regulators of cellular processes and drivers of genome evolution. Yet, they have been understudied due to their repetitive nature and potentially inaccurate sequences generated with short-read technologies. Here we comprehensively characterize such motifs in the long-read telomere-to-telomere (T2T) genomes of human, bonobo, chimpanzee, gorilla, Bornean orangutan, Sumatran orangutan, and siamang. Non-B DNA motifs are enriched at the genomic regions added to T2T assemblies and occupy 9%-15%, 9%-11%, and 12%-38% of autosomes and chromosomes X and Y, respectively. G4s and Z-DNA are enriched at promoters and enhancers, as well as at origins of replication. Repetitive sequences harbor more non-B DNA motifs than non-repetitive sequences, especially in the short arms of acrocentric chromosomes. Most centromeres and/or their flanking regions are enriched in at least one non-B DNA motif type, consistent with a potential role of non-B structures in determining centromeres. Our results highlight the uneven distribution of predicted non-B DNA structures across ape genomes and suggest their novel functions in previously inaccessible genomic regions.
- MeSH
- DNA * chemie genetika MeSH
- G-kvadruplexy MeSH
- genom lidský MeSH
- genom * MeSH
- Hominidae * genetika MeSH
- lidé MeSH
- nukleotidové motivy MeSH
- Pan troglodytes genetika MeSH
- repetitivní sekvence nukleových kyselin MeSH
- telomery * genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- DNA * MeSH
Developing novel anticancer agents requires understanding their interactions with biological systems at both the cellular and molecular levels. Enantiomeric lactones have demonstrated notable cytotoxic activities against various cancer cell lines. Building on this foundation, we investigated enantiomeric piperonal-derived trans-β-aryl-δ-iodo-γ-lactones ((-)-(4S,5R,6S) and (+)-(4R,5S,6R)), focusing on their impact on cancer cells membrane (Jurkat and GL-1), model membranes, and biomacromolecules such as human serum albumin (HSA) and DNA. Also, the cytotoxicity toward red blood cells and the antitumor activity of the compounds were evaluated against a set of canine lymphoma and/or leukemia cell lines. Membrane interaction studies revealed that both enantiomers interact with the hydrophobic core of lipid bilayers, enhancing lipid acyl chain packing, with the (-)-(4S,5R,6S) isomer showing a stronger impact on membrane fluidity. Comprehensive spectroscopic and theoretical studies revealed distinct stereochemical differences in binding affinities to HSA, where the (-)-(4S,5R,6S) isomer showed higher binding affinity and significant hydrophobic interactions. Detailed biological studies demonstrated that both enantiomers exhibit antiproliferative and proapoptotic activities, with the (-)-(4S,5R,6S) enantiomer showing higher activity. This study underscores the biological activity and interactions of enantiomeric iodolactones derived from piperonal with biomacromolecules, providing comprehensive insights into their biophysical behavior and potential anticancer properties.
- Klíčová slova
- DNA, Enantiomeric iodolactones, HSA, Single-molecule fluorescence spectroscopy, cancer cell membrane,
- MeSH
- buněčná membrána * účinky léků metabolismus chemie MeSH
- DNA * metabolismus chemie MeSH
- hydrofobní a hydrofilní interakce MeSH
- Jurkat buňky MeSH
- laktony * chemie farmakologie MeSH
- lidé MeSH
- lidský sérový albumin chemie metabolismus MeSH
- lipidové dvojvrstvy chemie metabolismus MeSH
- nádorové buněčné linie MeSH
- protinádorové látky * farmakologie chemie MeSH
- psi MeSH
- stereoizomerie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- psi MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- DNA * MeSH
- laktony * MeSH
- lidský sérový albumin MeSH
- lipidové dvojvrstvy MeSH
- protinádorové látky * MeSH
The activity of the light-oxygen-voltage/helix-turn-helix (LOV-HTH) photoreceptor EL222 is regulated through protein-protein and protein-DNA interactions, both triggered by photo-excitation of its flavin mononucleotide (FMN) cofactor. To gain molecular-level insight into the photocycle of EL222, we applied complementary methods: macromolecular X-ray crystallography (MX), nuclear magnetic resonance (NMR) spectroscopy, optical spectroscopies (infrared and UV-visible), molecular dynamics/metadynamics (MD/metaD) simulations, and protein engineering using noncanonical amino acids. Kinetic experiments provided evidence for two distinct EL222 conformations (lit1 and lit2) that become sequentially populated under illumination. These two lit states were assigned to covalently bound N5 protonated, and noncovalently bound hydroquinone forms of FMN, respectively. Only subtle structural differences were observed between the monomeric forms of all three EL222 species (dark, lit1, and lit2). While the dark state is largely monomeric, both lit states undergo monomer-dimer exchange. Furthermore, molecular modeling revealed differential dynamics and interdomain separation times arising from the three FMN states (oxidized, adduct, and reduced). Unexpectedly, all three EL222 species can associate with DNA, but only upon blue-light irradiation, a high population of stable complexes is obtained. Overall, we propose a model of EL222 activation where photoinduced changes in the FMN moiety shift the population equilibrium toward an open conformation that favors self-association and DNA-binding.
- MeSH
- bakteriální proteiny * chemie metabolismus genetika MeSH
- DNA vazebné proteiny * chemie metabolismus MeSH
- DNA * metabolismus chemie MeSH
- flavinmononukleotid * chemie metabolismus MeSH
- flaviny * chemie metabolismus MeSH
- fotoreceptory mikroorganismů * chemie metabolismus MeSH
- kinetika MeSH
- konformace proteinů účinky záření MeSH
- krystalografie rentgenová MeSH
- molekulární modely MeSH
- oxidace-redukce MeSH
- simulace molekulární dynamiky MeSH
- světlo * MeSH
- transkripční faktory * chemie metabolismus MeSH
- vazba proteinů MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- bakteriální proteiny * MeSH
- DNA vazebné proteiny * MeSH
- DNA * MeSH
- flavinmononukleotid * MeSH
- flaviny * MeSH
- fotoreceptory mikroorganismů * MeSH
- transkripční faktory * MeSH
