Cytosine modifications
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5-Hydroxymethylcytosine (5-hmC) was recently identified as a relatively frequent base in eukaryotic genomes. Its physiological function is still unclear, but it is supposed to serve as an intermediate in DNA de novo demethylation. Using X-ray diffraction, we solved five structures of four variants of the d(CGCGAATTCGCG) dodecamer, containing either 5-hmC or 5-methylcytosine (5-mC) at position 3 or at position 9. The observed resolutions were between 1.42 and 1.99 Å. Cytosine modification in all cases influences neither the whole B-DNA double helix structure nor the modified base pair geometry. The additional hydroxyl group of 5-hmC with rotational freedom along the C5-C5A bond is preferentially oriented in the 3' direction. A comparison of thermodynamic properties of the dodecamers shows no effect of 5-mC modification and a sequence-dependent only slight destabilizing effect of 5-hmC modification. Also taking into account the results of a previous functional study [Münzel et al. (2011) (Improved synthesis and mutagenicity of oligonucleotides containing 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxylcytosine. Chem. Eur. J., 17, 13782-13788)], we conclude that the 5 position of cytosine is an ideal place to encode epigenetic information. Like this, neither the helical structure nor the thermodynamics are changed, and polymerases cannot distinguish 5-hmC and 5-mC from unmodified cytosine, all these effects are making the former ones non-mutagenic.
Účel přehledu: Chronická obstrukční plicní nemoc (CHOPN) a karcinom plic představují celosvětově hlavní příčinu morbidity a mortality. Současný výzkum se zaměřuje na rozpoznání společných a odlišných pochodů zasahujících do epigenetických modifikací, které se současně odehrávají v patogenezi CHOPN i karcinomu plic. Cílem tohoto přehledového článku je informovat o současných znalostech ohledně epigenetických modifikací v patogenezi CHOPN a karcinomu plic. Nové poznatky: Tento přehledový článek poskytuje aktuální informace o pokroku ve zkoumání souvislostí epigenetických modifikací CHOPN a karcinomu plic, jejich společných rysů a rozdílů. Popisujeme zde klíčové enzymy epigenetických modifikací (např. DNA metyltransferázy – CpG metylace, histon-acetylázy/deacetylázy a histon-metyltransferázy/demetylázy), u kterých bylo zjištěno, že hrají důležitou úlohu ve vzniku a progresi jak CHOPN, tak plicních nádorů. Souhrn: Odlišné DNA-metyltransferázy a enzymy modifikující histony jsou do patogeneze CHOPN a karcinomu plic rozdílně zapojeny, i když některé tyto modifikace jsou společné pro obě chorobné jednotky. Pochopení epigenetických modifikací zapojených do patogeneze karcinomu plic či CHOPN z hlediska společných a odlišných mechanismů působení povede k zacílení postupů epigenetické léčby těchto onemocnění.
Chronic obstructive pulmonary disease (COPD) and lung cancer are the leading causes of morbidity and mortality worldwide. The current research is focused on identifying the common and disparate events involved in epigenetic modifications that concurrently occur during the pathogenesis of COPD and lung cancer. The purpose of this review is to describe the current knowledge and understanding of epigenetic modifications in pathogenesis of COPD and lung cancer. RECENT FINDINGS: This review provides an update on advances of how epigenetic modifications are linked to COPD and lung cancer, and their commonalities and disparities. The key epigenetic modification enzymes (e.g. DNA methyltransferases -- CpG methylation, histone acetylases/deacetylases and histone methyltransferases/demethylases) that are identified to play an important role in COPD and lung tumorigenesis and progression are described in this review. SUMMARY: Distinct DNA methyltransferases and histone modification enzymes are differentially involved in pathogenesis of lung cancer and COPD, although some of the modifications are common. Understanding the epigenetic modifications involved in pathogenesis of lung cancer or COPD with respect to common and disparate mechanisms will lead to targeting of epigenetic therapies against these disorders.
- MeSH
- chronická obstrukční plicní nemoc genetika MeSH
- cytosin-specifické DNA-methylasy genetika MeSH
- DNA-(cytosin-5-)methyltransferasa genetika MeSH
- epigenomika MeSH
- histonacetyltransferasy genetika MeSH
- histondeacetylasy genetika MeSH
- histondemethylasy genetika MeSH
- histonlysin-N-methyltransferasa genetika MeSH
- lidé MeSH
- nádory plic genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Nature clinical practice. Oncology, ISSN 1743-4254 vol. 2, suppl. 1, December 2005
44 s. : il., tab. ; 28 cm
- MeSH
- azacytidin analogy a deriváty terapeutické užití MeSH
- DNA-(cytosin-5-)methyltransferasa antagonisté a inhibitory chemie MeSH
- epigeneze genetická MeSH
- heterochromatin chemie MeSH
- histonový kód MeSH
- klinické zkoušky jako téma MeSH
- metylace DNA MeSH
- myelodysplastické syndromy farmakoterapie genetika MeSH
- Publikační typ
- sborníky MeSH
BACKGROUND: The i-motif is a tetrameric DNA structure based on the formation of hemiprotonated cytosine-cytosine (C+.C) base pairs. i-motifs are widely used in nanotechnology. In biological systems, i-motifs are involved in gene regulation and in control of genome integrity. In vivo, the i-motif forming sequences are subjects of epigenetic modifications, particularly 5-cytosine methylation. In plants, natively occurring methylation patterns lead to a complex network of C+.C, 5mC+.C and 5mC+.5mC base-pairs in the i-motif stem. The impact of complex methylation patterns (CMPs) on i-motif formation propensity is currently unknown. METHODS: We employed CD and UV-absorption spectroscopies, native PAGE, thermal denaturation and quantum-chemical calculations to analyse the effects of native, native-like, and non-native CMPs in the i-motif stem on the i-motif stability and pKa. RESULTS: CMPs have strong influence on i-motif stability and pKa and influence these parameters in sequence-specific manner. In contrast to a general belief, i) CMPs do not invariably stabilize the i-motif, and ii) when the CMPs do stabilize the i-motif, the extent of the stabilization depends (in a complex manner) on the number and pattern of symmetric 5mC+.5mC or asymmetric 5mC+.C base pairs in the i-motif stem. CONCLUSIONS: CMPs can be effectively used to fine-tune i-motif properties. Our data support the notion of epigenetic modifications as a plausible control mechanism of i-motif formation in vivo. GENERAL SIGNIFICANCE: Our results have implications in epigenetic regulation of telomeric DNA in plants and highlight the potential and limitations of engineered patterning of cytosine methylations on the i-motif scaffold in nanotechnological applications.
- MeSH
- cytosin metabolismus MeSH
- DNA rostlinná chemie genetika MeSH
- epigeneze genetická * MeSH
- metylace DNA * MeSH
- molekulární modely MeSH
- nanotechnologie * MeSH
- nukleotidové motivy genetika MeSH
- sekvence nukleotidů MeSH
- telomery genetika MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Hyperglycaemia-induced oxidative stress appears to be involved in the aetiology of diabetic retinopathy (DR), a major public health issue, via altering DNA methylation process. We investigated the effect of hyperglycaemia on retinal DNA methyltransferase (DNMT) expression in diabetic mice, using Gene Expression Omnibus datasets. We also evaluated the effect of curcumin both on high glucose-induced reactive oxygen species (ROS) production and altered DNMT functions, in a cellular model of DR. We observed that three months of hyperglycaemia, in insulin-deficient Ins2 Akita mice, decrease DNMT1 and DNMT3a expression levels. In retinal pigment epithelium (RPE) cells, we also demonstrated that high glucose-induced ROS production precedes upregulation of DNMT expression and activity, suggesting that changes in DNMT function could be mediated by oxidative stress via a potential dual effect. The early effect results in decreased DNMT activity, accompanied by the highest ROS production, while long-term oxidative stress increases DNMT activity and DNMT1 expression. Interestingly, treatment with 25 μM curcumin for 6 hours restores ROS production, as well as DNMT functions, altered by the exposure of RPE to acute and chronic high glucose concentration. Our study suggests that curcumin may represent an effective antioxidant compound against DR, via restoring oxidative stress and DNMT functions, though further studies are recommended.
- MeSH
- buněčné linie MeSH
- cytosin-specifické DNA-methylasy metabolismus MeSH
- diabetická retinopatie farmakoterapie metabolismus MeSH
- experimentální diabetes mellitus farmakoterapie metabolismus MeSH
- kurkumin farmakologie terapeutické užití MeSH
- lidé MeSH
- oxidační stres účinky léků MeSH
- reaktivní formy kyslíku metabolismus MeSH
- viabilita buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The autonomous transcription of integrated retroviruses strongly depends on genetic and epigenetic effects of the chromatin at the site of integration. These effects are mostly suppressive and proviral activity can be finally silenced by mechanisms, such as DNA methylation and histone modifications. To address the role of the integration site at the whole-genome-scale, we performed clonal analysis of provirus silencing with an avian leucosis/sarcoma virus-based reporter vector and correlated the transcriptional silencing with the epigenomic landscape of respective integrations. We demonstrate efficient provirus silencing in human HCT116 cell line, which is strongly but not absolutely dependent on the de novo DNA methyltransferase activity, particularly of Dnmt3b. Proviruses integrated close to the transcription start sites of active genes into the regions enriched in H3K4 trimethylation display long-term stability of expression and are resistant to the transcriptional silencing after over-expression of Dnmt3a or Dnmt3b. In contrast, proviruses in the intergenic regions tend to spontaneous transcriptional silencing even in Dnmt3a(-/-) Dnmt3b(-/-) cells. The silencing of proviruses within genes is accompanied with DNA methylation of long terminal repeats, whereas silencing in intergenic regions is DNA methylation-independent. These findings indicate that the epigenomic features of integration sites are crucial for their permissivity to the proviral expression.
- MeSH
- Alpharetrovirus genetika MeSH
- DNA-(cytosin-5-)methyltransferasa genetika metabolismus MeSH
- epigeneze genetická MeSH
- genetická transkripce MeSH
- integrace viru MeSH
- lidé MeSH
- metylace DNA MeSH
- nádorové buněčné linie MeSH
- proviry genetika MeSH
- umlčování genů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The formation of intercalated motifs (iMs) - secondary DNA structures based on hemiprotonated C.C+ pairs in suitable cytosine-rich DNA sequences, is reflected by typical changes in CD and UV absorption spectra. By means of spectroscopic methods, electrophoresis, chemical modifications and other procedures, we characterized iM formation and stability in sequences with different cytosine block lengths interrupted by various numbers and types of nucleotides. Particular attention was paid to the formation of iMs at pH conditions close to neutral. We identified the optimal conditions and minimal requirements for iM formation in DNA sequences, and addressed gaps and inaccurate data interpretations in existing studies to specify principles of iM formation and modes of their folding.
- MeSH
- cytosin chemie metabolismus MeSH
- DNA chemie metabolismus MeSH
- kinetika MeSH
- koncentrace vodíkových iontů MeSH
- konformace nukleové kyseliny * MeSH
- nukleotidové motivy * MeSH
- párování bází MeSH
- sekvence nukleotidů MeSH
- termodynamika MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- azacytidin analogy a deriváty farmakologie terapeutické užití MeSH
- DNA modifikační methylasy genetika metabolismus MeSH
- DNA-(cytosin-5)-methyltransferasa 1 antagonisté a inhibitory MeSH
- epigeneze genetická MeSH
- hematopoetické kmenové buňky MeSH
- lidé MeSH
- metylace DNA * genetika účinky léků MeSH
- mutace genetika MeSH
- myelodysplastické syndromy * farmakoterapie genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
RNA modifications have been known for many years, but their function has not been fully elucidated yet. For instance, the regulatory role of acetylation on N4-cytidine (ac4C) in RNA can be explored not only in terms of RNA stability and mRNA translation but also in DNA repair. Here, we observe a high level of ac4C RNA at DNA lesions in interphase cells and irradiated cells in telophase. Ac4C RNA appears in the damaged genome from 2 to 45 min after microirradiation. However, RNA cytidine acetyltransferase NAT10 did not accumulate to damaged sites, and NAT10 depletion did not affect the pronounced recruitment of ac4C RNA to DNA lesions. This process was not dependent on the G1, S, and G2 cell cycle phases. In addition, we observed that the PARP inhibitor, olaparib, prevents the recruitment of ac4C RNA to damaged chromatin. Our data imply that the acetylation of N4-cytidine, especially in small RNAs, has an important role in mediating DNA damage repair. Ac4C RNA likely causes de-condensation of chromatin in the vicinity of DNA lesions, making it accessible for other DNA repair factors involved in the DNA damage response. Alternatively, RNA modifications, including ac4C, could be direct markers of damaged RNAs.
- MeSH
- acetylace MeSH
- chromatin MeSH
- cytidin * genetika metabolismus MeSH
- PARP inhibitory MeSH
- RNA * metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
