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[en] Highlights: • The rate of hydrolytic deamination of adenine is greatly affected by the absence of buffers. • Adenine deaminates significantly faster than cytosine in unbuffered nanopure water. • The deamination rate depends on the interaction sites between water and DNA base molecules. Adenine in unbuffered nanopure water at a concentration of 2 mM is completely deaminated (>99%) to hypoxanthine at room temperature in ca. 10 weeks, with an estimated half-life (t1/2) less than 10 days, about six orders of magnitude faster than previously reported. Cytosine is not deaminated under the same condition, even after 3 years. This is in contrast to previous observations that cytosine deaminates 20–40 times faster than adenine free base, in nucleoside, in nucleotide and in single-stranded DNA in buffered neutral aqueous solutions.
[en] This study was carried out to examine the effect of the DNA repair inhibitors, Cytosine Arabinoside(Ara C), 3-Aminobenzamide(3AB) and Hydroxyurea(HU) on the frequencies of radiation-induced MicroNuclei(MNi) and aneuploidy. Irradiated lymphocytes(1-3Gy) were treated with DNA repair inhibitors, Ara C, 3AB and HU for 3 hours and CBMN assay - FISH technique with DNA probe for chromosome 1 and 4 was performed. The frequencies of x-ray induced MNi and aneuploidy of chromosome 1 and 4 were increased in a dose-dependent manner. Ara C, 3AB and HU enhanced the frequencies of radiation-induced MNi and the frequencies of radiation-induced aneuploidy of chromosome 1 and 4 were enhanced by HU and Ara C while no effect was observed by 3AB. The frequency of radiation-induced aneuploidy of chromosome 1 was higher than that of chromosome 4. These results suggest that there are different mechanisms involved in the formation of MNi and aneuploidy by radiation
[en] The stereoselective synthesis 4',6'-dually branched carbocyclic nucleosides was accomplished in this study. The introduction of a methyl group in the 6'(α)-position was accomplished by Felkin-Anh controlled alkylation. The construction of the required 4'(α)-quaternary carbon was carried out using a [3,3]-sigmatropic rearrangement. Bis-vinyl 6 was successfully cyclized using a Grubbs' catalyst II. The natural bases (adenine, cytosine) were efficiently coupled using a Pd(0) catalyst. When the synthesized compounds were examined for their activity against several viruses such as the HIV-1, HSV-1, HSV-2 and HCMV, the cytosine analogue 13 exhibited good antiviral activity against the HCMV
[en] After gamma irradiation of cytosine in aerated aqueous solutions, two new radiolytic products were isolated and identified: N-formyl-biuret and carbamoyl-l-hydroxy-5-hydantoin. The position and importance of those products in the radiolytic degradation of cytosine were examined
[fr]Au cours de l'etude du rayonnement gamma sur la cytosine en solution aqueuse aeree, on a identifie deux nouveaux produits de radiolyse: le N-formyl-biuret et la carbamoyl-l-hydroxy-5-hydantoine. On a situe la place et l'importance de ces produits dans la degradation radiolytique de la cytosine
[en] The distance dependence of photoinduced electron transfer in deoxyribonucleic acid (DNA) duplex was investigated using the 'TAP cassette' systems of the general formula (AT)6A nXA9-n (X denote guanine (G) or cytosine (C)). The tetrakis-9-acridinyl peptide (TAP) binds tightly with (AT)6 duplex region showing strong fluorescence that was not quenched by the A nXA9-n single-stranded region. Quenching was observed after duplex formation with the complementary T9-nXT n strand (G-C pairing), showing clear dependence on the distance between the TAP and a guanine. An extremely low β value of 0.22 was obtained in our electron transfer (ET) system that suggests exceptional good mediation of ET process. Experiments with G-mismatches showed negligible quenching for systems with guanine separated by more than one AT base pair that indicated rather inefficient ET process for duplexes containing disrupted π-electronic system
[en] Cancer researchers have been looking for ways to harness the immune system and to reinstate immune surveillance, to kill cancer cells without collateral damage. Here we scan current approaches to targeting the immune system against cancer, and emphasize our own approach. We are using chemical vectors attached to a specific ligand, to introduce synthetic dsRNA, polyinosine/cytosine (polyIC), into tumors. The ligand binds to a receptor protein that is overexpressed on the surface of the tumor cells. Upon ligand binding, the receptor complex is internalized, introducing the polyIC into the cell. In this fashion a large amount of synthetic dsRNA can be internalized, leading to the activation of dsRNA-binding proteins, such as dsRNA dependent protein kinase (PKR), Toll-like receptor 3 (TLR3), retinoic acid-inducible gene I (RIG-1), and melanoma differentiation-associated gene 5 (MDA5). The simultaneous activation of these signaling proteins leads to the rapid demise of the targeted cell and to cytokine secretion. The cytokines lead to a strong bystander effect and to the recruitment of immune cells that converge upon the targeted cells. The bystander effects lead to the destruction of neighboring tumor cells not targeted themselves by the vector. Normal cells, being more robust than tumor cells, survive. This strategy has several advantages: (1) recruitment of the immune system is localized to the tumor. (2) The response is rapid, leading to fast tumor eradication. (3) The bystander effects lead to the eradication of tumor cells not harboring the target. (4) The multiplicity of pro-death signaling pathways elicited by PolyIC minimizes the likelihood of the emergence of resistance. In this chapter we focus on EGFR as the targeted receptor, which is overexpressed in many tumors. In principle, the strategy can be extended to other tumors that overexpress a protein that can be internalized by a ligand, which can be a small molecule, a single chain antibody, or an affibody.
[en] The first synthesis of novel 5',5'-difluoro-30-hydroxy apiose nucleoside cyclomonophosphonic acid analogs was performed as potent anti-retroviral agents. Phosphonation was performed by direct displacement of a triflate intermediate with diethyl(lithiodifluoromethyl) phosphonate to give the corresponding(α, α-difluoroalkyl) phosphonate. Condensation successfully proceeded from a glycosyl donor with persilylated bases to yield the nucleoside phosphonate analogs. Deprotection of diethyl phosphonates provided the target nucleoside cyclomonophosphonic acid analogs. The synthesized nucleoside analogs were subjected to anti-viral screening against the human immunodeficiency virus-1 (HIV-1). Cytosine analogs show significant anti-HIV activity.
[en] Abnormal DNA methylation at the C-5 position of cytosine (5mC) of CpG dinucleotides is a well-known epigenetic feature of cancer. Levels of E-cadherin, which is regularly expressed in epithelial tissues, are frequently reduced in epithelial tumors due to transcriptional repression, sometimes accompanied by hypermethylation of the promoter region. δEF1 family proteins (δEF1/ZEB1 and SIP1/ZEB2), key regulators of the epithelial-mesenchymal transition (EMT), suppress E-cadherin expression at the transcriptional level. We recently showed that levels of mRNAs encoding δEF1 proteins are regulated reciprocally with E-cadherin level in breast cancer cells. Here, we examined the mechanism underlying downregulation of E-cadherin expression in three basal-type breast cancer cells in which the E-cadherin promoter region is hypermethylated (Hs578T) or moderately methylated (BT549 and MDA-MB-231). Regardless of methylation status, treatment with 5-aza-2′-deoxycytidine (5-aza), which inhibits DNA methyltransferases, had no effect on E-cadherin expression. Knockdown of δEF1 and SIP1 resulted in recovery of E-cadherin expression in cells lacking hypermethylation, whereas combined treatment with 5-aza synergistically restored E-cadherin expression, especially when the E-cadherin promoter was hypermethylated. Moreover, δEF1 interacted with DNA methyltransferase 1 (DNMT1) through the Smad-binding domain. Sustained knockdown of δEF1 family proteins reduced the number of 5mC sites in the E-cadherin promoter region, suggesting that these proteins maintain 5mC through interaction with DNMT1 in breast cancer cells. Thus, δEF1 family proteins appear to repress expression of E-cadherin during cancer progression, both directly at the transcriptional level and indirectly at the epigenetic level
[en] The APOBEC3 DNA cytosine deaminase family comprises a fundamental arm of the innate immune response and is best known for retrovirus restriction. Several APOBEC3 enzymes restrict HIV-1 and related retroviruses by deaminating viral cDNA cytosines to uracils compromising viral genomes. Human APOBEC3B (A3B) shows strong virus restriction activities in a variety of experimental systems, and is subjected to tight post-translational regulation evidenced by cell-specific HIV-1 restriction activity and active nuclear import. Here we ask whether lysines and/or lysine post-translational modifications are required for these A3B activities. A lysine-free derivative of human A3B was constructed and shown to be indistinguishable from the wild-type enzyme in DNA cytosine deamination, HIV-1 restriction, and nuclear localization activities. However, lysine loss did render the protein resistant to degradation by SIV Vif. Taken together, we conclude that lysine side chains and modifications thereof are unlikely to be central to A3B function or regulation in human cells. - Highlights: • APOBEC3B is an antiviral DNA cytosine deaminase with nuclear localization. • Lysines are dispensable for DNA cytosine deaminase activity of APOBEC3B. • Lysines are dispensable for HIV restriction activity of APOBEC3B. • Lysines are dispensable for nuclear localization of APOBEC3B. • Lysines are required for SIV Vif-mediated degradation.