Search

To date, the radiation-adaptive response has been reported as a low-dose-related phenomenon and has been associated with radiation hormesis. Well-known cancers are caused by non-radiation active reactants, in addition to radiation. A model of suppression for radiation-specific cancers was previously reported, but the model did not target radiation-nonspecific cancers. In this paper, we describe kinetic models of radiation-induced suppressors for general radiation non-specific cancers, estimating the dose M that induces the maximum hormesis effect while satisfying the condition that the risk is approximately proportional to a dose above NOAEL (No Observed Adverse Effect Level). The radiation hormesis effect is maximal when the rate constant for generation of a risk-reducing factor is the same as the rate constant for its decomposition. When the two rate constants are different, the dose M at which the radiation hormesis effect is maximized depends on both rate constants, but the dose M increases as the two rate constants approach each other, reaching a maximum dose. The theory proposed in this paper can only explain existing experiments with extremely short error bar lengths. This theory may lead to the discovery of unknown risk-reducing factor at low doses and the development of risk-reducing methods in the future.

Among the bases of DNA, guanine is the most easily oxidized. Imidazolone (Iz) is a guanine oxidative damage, and we sought to generate Iz-containing oligomers. In this paper, we describe the methods and conditions to increase the yield of Iz by employing photooxidation reactions using light-emitting diodes (LEDs) with emission wavelengths of 365 nm and 450 nm. For photooxidation performed with the 450 nm LED source at light intensities of 2.75–275 mW/cm2, peak yields of Iz were 35% at light intensities of 27.5 and 68.8 mW/cm2. For reactions performed with the 365 nm LED source at light intensities of 5.12–512 mW/cm2, the peak yield of Iz was 34% at a light intensity of 51.2 mW/cm2. By varying the irradiation time, the maximum yield of Iz (34–35%) was obtained with irradiation times of 5–20 min using the 450 nm LED source at an intensity of 13.8 mW/cm2. Using the 365 nm LED source at an intensity of 25.6 mW/cm2, the maximum Iz yield obtained was 31% at irradiation times of 2–5 min. Thus, we obtained conditions that can provide an Iz yield of up to 35%.

Abstract Urea (Ua) is produced in DNA as the result of oxidative damage to thymine and guanine. It was previously reported that Klenow fragment (Kf) exo− incorporated dATP opposite Ua, and that DNA polymerase β was blocked by Ua. We report here the following nucleotide incorporations opposite Ua by various DNA polymerases: DNA polymerase α, dATP and dGTP (dATP > dGTP); DNA polymerase δ, dATP; DNA polymerase ζ, dATP; Kf exo−, dATP; Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4), dGTP and dATP (dGTP > dATP); and DNA polymerase η, dCTP, dGTP, dATP, and dTTP (dCTP > dGTP > dATP > dTTP). DNA polymerases β and ε were blocked by Ua. Elongation by DNA polymerases δ and ζ stopped after inserting dATP opposite Ua. Importantly, the elongation efficiency to full-length beyond Ua using DNA polymerase η and Dpo4 were almost the same as that of natural DNA. Graphical abstract

The title compound, N′1,N′4-bis(2-(7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo[g]pteridin-10(2H)-yl)ethylidene)succinohydrazide (1), was obtained by the reaction of formylmethylflavin and succinic acid dihydrazide. The product 1 was characterized by 1H-NMR, 13C-NMR, HRMS and UV.

A mathematical model for radiation hormesis below 100 mSv has previously been reported, but the origins of the formula used in the previous report were not provided. In the present paper, we first considered a sequential reaction model with identical rate constants. We showed that the function of components produced in the second step of this model agreed well with the previously reported function. Furthermore, in a general sequential reaction model with different rate constants, it was mathematically proved that the function representing the component produced in the second step is always mountain-shaped: the graph has a peak with one inflection point on either side, and such a component may induce radiation hormesis.

Abstract It has yet to be determined whether or not the probability of developing cancer due to radiation exposure levels of low doses is proportional to the dose. Herein, for radiation hormesis occurring at low doses, mathematical models using functions that take a mountain-like shape having two inflection points are considered. The following perspectives were obtained: (i) When the probability of developing cancer decreases at radiation levels above the natural background dose, the radiation hormesis effect occurs up to ~ 12.4 mSv. (ii) When there is a proportional relationship at ≥750 mSv, the radiation hormesis effect occurs up to ~ 225 mSv. Thus, by performing studies at the molecular and cellular levels for radiation doses at ≤16.8 or 307 mSv, it is possible to investigate carcinogenesis resulting from low radiation doses.

The linear no-threshold (LNT) theory describes the linear relationship between a radiation dose and its effects. However, whether the linear relationship is maintained at low radiation doses has yet to be determined. Many previous studies support the radiation hormesis theory, which states that radiation has beneficial effects on health. In this viewpoint, we propose a mathematical function fitted to a model consistent with both the LNT at ≥100 mSv and radiation hormesis theories at

Abstract Guanine is the most readily oxidized of the four DNA bases, and guanine oxidation products cause G:C-T:A and G:C-C:G transversions through DNA replication. 8-Oxo-7,8-dihydroguanine (8-oxoG) causes G:C-T:A transversions but not G:C-C:G transversions, and is more readily oxidized than guanine. This review covers four major findings. (i) 2,2,4-Triamino-5(2H)-oxazolone (Oz) is produced from guanine and 8-oxoG under various oxidative conditions. Guanine is incorporated opposite Oz by DNA polymerases, except REV1. (ii) Several enzymes exhibit incision activity towards Oz. (iii) Since the redox potential of GG is lower than that of G, contiguous GG sequences are more readily oxidized by a one-electron oxidant than a single guanine, and OzOz is produced from GG in double-stranded DNA. Unlike most DNA polymerases, DNA polymerase ζ efficiently extends the primer up to full-length across OzOz. (iv) In quadruplex DNA, 3′-guanine is mainly damaged by one-electron oxidation in quadruplex DNA, and this damage depends on the highest occupied molecular orbital (HOMO). The oxidation products in quadruplex DNA are different from those in single-stranded or double-stranded DNA.

Among the natural bases, guanine is the most oxidizable base. The damage caused by oxidation of guanine, commonly referred to as oxidative guanine damage, results in the formation of several products, including 2,5-diamino-4H-imidazol-4-one (Iz), 2,2,4-triamino-5(2H)-oxazolone (Oz), guanidinoformimine (Gf), guanidinohydantoin/iminoallantoin (Gh/Ia), spiroiminodihydantoin (Sp), 5-carboxamido-5-formamido-2-iminohydantoin (2Ih), urea (Ua), 5-guanidino-4-nitroimidazole (NI), spirodi(iminohydantoin) (5-Si and 8-Si), triazine, the M+7 product, other products by peroxynitrite, alkylated guanines, and 8,5′-cyclo-2′-deoxyguanosine (cG). Herein, we summarize the present knowledge about base pairs containing the products of oxidative guanine damage and guanine. Of these products, Iz is involved in G-C transversions. Oz, Gh/Ia, and Sp form preferably Oz:G, Gh/Ia:G, and Sp:G base pairs in some cases. An involvement of Gf, 2Ih, Ua, 5-Si, 8-Si, triazine, the M+7 product, and 4-hydroxy-2,5-dioxo-imidazolidine-4-carboxylic acid (HICA) in G-C transversions requires further experiments. In addition, we describe base pairs that target the RNA-dependent RNA polymerase (RdRp) of RNA viruses and describe implications for the 2019 novel coronavirus (SARS-CoV-2): When products of oxidative guanine damage are adapted for the ribonucleoside analogs, mimics of oxidative guanine damages, which can form base pairs, may become antiviral agents for SARS-CoV-2.

DNA is constantly being oxidized, and oxidized DNA is prone to mutation; moreover, guanine is highly sensitive to several oxidative stressors. Several oxidatively damaged forms of guanine—including 2,2,4-triamino-5(2H)-oxazolone (Oz), iminoallantoin (Ia), and spiroiminodihydantoin (Sp)—can be paired with guanine, and cause G:C-C:G transversions. Previous findings indicate that guanine is incorporated more efficiently opposite Oz than opposite Ia or Sp, and that these differences in efficiency cannot be explained by differences in the stabilities of G:Oz, G:Ia, and G:Sp base pairs calculated ab initio. Here, to explain previous experimental result, we used a 3-base-pair model DNA duplex to calculate the difference in the stability and the distortion of DNA containing a G:Oz, G:Ia, or G:Sp base pair. We found that the stability of the structure containing 5ꞌ and 3ꞌ base pairs adjacent to G:Oz was more stable than that containing the respective base pairs adjacent to G:Ia or G:Sp. Moreover, the distortion of the structure in the DNA model duplex that contained a G:Oz was smaller than that containing a G:Ia or G:Sp. Therefore, our discussion can explain the previous results involving translesion synthesis past an oxidatively damaged guanine.

In a previous study, we showed that formylmethylflavin (FMF) can bind to cysteine. In this study, FMF was reacted with native peptides (CG and CKLVFF) containing an N-terminal cysteine. The formation of flavin-CG and flavin-CKLVFF was confirmed using HPLC and ESI-MS. Storage of flavin-CKLVFF in DMSO at −30 °C for 7 days resulted in no detectable deposition. In contrast, flavin-CKLVFF formed deposits when stored in water at −30 °C for 1 day, but no deposit was observed in the aqueous solution of flavin-CKLVFF after 7 days storage in the presence of 0.1% Triton X-100.

DNA is constantly exposed to endogenous and exogenous oxidative stresses. Damaged DNA can cause mutations, which may increase the risk of developing cancer and other diseases. G:C-C:G transversions are caused by various oxidative stresses. 2,2,4-Triamino-5(2H)-oxazolone (Oz), guanidinohydantoin (Gh)/iminoallantoin (Ia) and spiro-imino-dihydantoin (Sp) are known products of oxidative guanine damage. These damaged bases can base pair with guanine and cause G:C-C:G transversions. In this study, the stabilization energies of these bases paired with guanine were calculated in vacuo and in water. The calculated stabilization energies of the Ia:G base pairs were similar to that of the native C:G base pair, and both bases pairs have three hydrogen bonds. By contrast, the calculated stabilization energies of Gh:G, which form two hydrogen bonds, were lower than the Ia:G base pairs, suggesting that the stabilization energy depends on the number of hydrogen bonds. In addition, the Sp:G base pairs were less stable than the Ia:G base pairs. Furthermore, calculations showed that the Oz:G base pairs were less stable than the Ia:G, Gh:G and Sp:G base pairs, even though experimental results showed that incorporation of guanine opposite Oz is more efficient than that opposite Gh/Ia and Sp.

The title compound, N'-[2-(7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo[g]pteridin- 10(2H)-yl)ethylidene]-4-nitrobenzohydrazide (1), was obtained by the reaction of formylmethylflavin and p-nitrobenzohydrazide. The product 1 inhibited the DNA binding of nuclear factor-κB, and was characterized by 1H-NMR, 13C-NMR, electrospray ionization mass spectrometry, elemental analysis, IR and UV.

κ-Casein (CSN3) is known to play an essential role in controlling the stability of the milk micelles. We found that the expression of Csn3 was induced by all-trans retinoic acid (ATRA) during neural differentiation in P19 embryonal carcinoma cells from our study using DNA microarray. In this paper, we describe the detailed time course of Csn3 expression and the induction mechanism of Csn3 transcription activation in this process. The Csn3 expression was induced rapidly and transiently within 24 h of ATRA treatment. Retinoic acid receptor (RAR)-specific agonists were used in expression analysis to identify the RAR subtype involved upregulation of Csn3; a RARα-specific agonist mimicked the effects of ATRA on induction of Csn3 expression. Therefore, RARα may be the RAR subtype mediating the effects of ATRA on the induction of Csn3 gene transcription in this differentiation-promoting process of P19 cells. We found that the promoter region of Csn3 contained a typical consensus retinoic acid response element (RARE), and this RARE was necessary for ATRA-dependent transcriptional regulation. We confirmed that RARα bound to this RARE sequence in P19 cells. These findings indicated that the Csn3 expression is upregulated via ATRA-bound RARα and binding of this receptor to the RARE in the Csn3 promoter region. This will certainly serve as a first step forward unraveling the mysteries of induction of Csn3 in the process of neural differentiation.

Toxicity of Paederus species to eyes has scarcely been reported. This report presents a case of chemical blepharokeratoconjunctivitis with delayed re-epithelialization caused by Paederus fuscipes in a patient with dry eye after laser-assisted in situ keratomileusis (LASIK). A 47-year-old woman who had undergone LASIK for myopia 10 years prior experienced visual disturbance and pain in her left eye after being hit by a P. fuscipes insect in her eye 1 day prior to evaluation. At the initial presentation, dermatitis around the patient’s left eye, eyelid oedema, conjunctival chemosis, corneal epithelial defects, and a best corrected visual acuity (BCVA) of 20/200 were noted. No gram-positive/negative bacteria or indication of cellulitis/elevated inflammation was detected. Administration of topical steroids (betamethasone) and antibiotics (topical: cefmenoxime and levofloxacin; intravenous: ceftriaxone) improved the non-infectious chemical blepharokeratoconjunctivitis; however, the large corneal epithelial defect remained for 10 days. Switching from betamethasone to a preservative-free form facilitated re-epithelialization, and the patient’s BCVA improved to 20/16 after 2 months. Ophthalmologists should consider the toxicity of the Paederus species on the ocular surface and eyelid.

Abstract Background Companion diagnostic tests play a crucial role in guiding treatment decisions for patients with non‐small cell lung cancer (NSCLC). The Oncomine Dx Target Test (ODxTT) Multi‐CDx System has emerged as a prominent companion diagnostic method. However, its efficacy in detecting driver gene mutations, particularly rare mutations, warrants investigation. Aims This study aimed to assess the performance of the ODxTT in detecting driver gene mutations in NSCLC patients. Specifically, we aimed to evaluate its sensitivity in detecting epidermal growth factor receptor (EGFR) mutations, a key determinant of treatment selection in NSCLC. Materials and Methods We conducted a retrospective analysis of NSCLC patients who underwent testing with the ODxTT at Keio University Hospital between May 2020 and March 2022. Patient samples were subjected to both DNA and RNA tests. Driver gene mutation status was assessed, and instances of missed mutations were meticulously examined. Results Of the 90 patients, five had nucleic acid quality problems, while 85 underwent both DNA and RNA tests. Driver gene mutations were detected in 56/90 (62.2%) patients. Of the 34 patient specimens, driver mutations were not detected using the ODxTT; however, epidermal growth factor receptor (EGFR) mutations were detected using polymerase chain reaction‐based testing in two patients, and a KRAS mutation was detected by careful examination of the sequence data obtained using the ODxTT in one patient. For the above three cases, carefully examining the gene sequence information obtained using the ODxTT could identify driver mutations that were not mentioned in the returned test results. Additionally, we confirmed comparable instances of overlook results for EGFR mutations in the dataset from South Korea, implying that this type of oversight could occur in other countries using the ODxTT. EGFR mutation was missed in ODxTT in Japan (6.3%, 2/32), South Korea (2.0%, 1/49), and overall (3.7%, 3/81). Conclusion Even if sufficient tumor samples are obtained, rare EGFR mutations (which are excluded from the ODxTT's genetic mutation list) might not be detected using the current ODxTT system due to the program used for sequence analysis. However, such rare EGFR mutations can still be accurately detected on ODxTT's sequence data using next‐generation sequencing.

Plants of the Araceae family exude a sap containing calcium oxalate, a toxic substance that causes dermatitis. However, ocular injury due to exposure to Araceae sap has rarely been reported. Herein, we present a case of severe pseudomembranous conjunctivitis following exposure to Arisaema ringens, an Araceae species and popular houseplant in Japan. A 67-year-old man presented with pain in his right eye after exposure to the sap of A. ringens. At presentation, the best corrected visual acuity and intraocular pressure in the right eye were 20/800 and 15 mm Hg. Slit-lamp examination showed strong hyperemia, conjunctival chemosis, and corneal edema with many pseudomembranes, and fluorescein staining revealed corneal epithelial defects in the central area of the cornea. We washed the ocular surface with saline and initiated treatment with topical instillations of 1.5% levofloxacin and 0.1% betamethasone, combined with ofloxacin eye ointment. After repeatedly removing the pseudomembranes and increasing the frequency of the topical instillations, pseudomembranous conjunctivitis and corneal erosion gradually improved. One week following the injury, the corneal epithelial defects were no longer detectable, and the patient’s best corrected visual acuity recovered to 20/25. It is important for ophthalmologists and primary care physicians to be aware of the ocular toxicity of A. ringens and should counsel their patients accordingly. Moreover, preventative measures, such as the use of protective eyewear, should be taken when cutting this houseplant.

Abstract Thoracoscopy under local anaesthesia is recommended for malignant tumours with negative pleural effusion cytology. Cryobiopsy from the visceral pleura by thoracoscopy under local anaesthesia can provide more diagnostic options for patients with thoracentesis‐negative malignant effusions. Here we present the first case in which this technique was used. The patient had a pleural metastasis that could not be diagnosed even with rapid cytology of the parietal pleura biopsy. Indications, technical pitfalls, and safety tips are discussed.

Abstract Background Entamoeba histolytica (E. histolytica) is rarely identified as a cause of amebic pericarditis. We report a case of amebic pericarditis complicated by cardiac tamponade, in which the diagnosis was missed initially and was made retrospectively by polymerase chain reaction (PCR) testing of a stored sample of pericardial fluid. Furthermore, we performed a systematic review of the literature on amebic pericarditis. Case presentation A 71-year-old Japanese man who had a history of sexual intercourse with several commercial sex workers 4 months previously, presented to our hospital with left chest pain and cough. He was admitted on suspicion of pericarditis. On hospital day 7, he developed cardiac tamponade requiring urgent pericardiocentesis. The patient’s symptoms temporarily improved, but 1 month later, he returned with fever and abdominal pain, and multiple liver lesions were found in the right lobe. Polymerase chain reaction of the aspiration fluid of the liver lesion and pericardial and pleural fluid stored from the previous hospitalization were all positive for E. histolytica. Together with the positive serum antibody for E. histolytica, a diagnosis of amebic pericarditis was made. Notably, the diagnosis was missed initially and was made retrospectively by performing PCR testing. The patient improved with metronidazole 750 mg thrice daily for 14 days, followed by paromomycin 500 mg thrice daily for 10 days. Conclusions This case suggests that, although only 122 cases of amebic pericarditis have been reported, clinicians should be aware of E. histolytica as a potential causative pathogen. The polymerase chain reaction method was used to detect E. histolytica in the pericardial effusion and was found to be useful for the diagnosis of amebic pericarditis in addition to the positive results for the serum antibody testing for E. histolytica. Because of the high mortality associated with delayed treatment, prompt diagnosis should be made.

Abstract We investigated the relation between corneal regular and irregular astigmatism in normal human eyes. In 951 eyes of 951 patients, corneal irregular astigmatism, such as asymmetry and higher-order irregularity components, was calculated using the Fourier harmonic analysis of corneal topography data within the central 3-mm zone of the anterior corneal surface. The eyes were classified by the type of corneal regular astigmatism into four groups; minimum (

Inverted takotsubo cardiomyopathy (ITC) is a rare disease that has a strong association with pheochromocytoma and intracranial hemorrhage. We describe the case of a patient who developed ITC after an extra dose, along with chronic exposure, of a weight management supplement containing caffeine and amphetamine-like stimulants, a combination that could potentially raise the local sympathetic tone of the myocardium. The patient was managed conservatively and recovered in 2 months. This report emphasizes the importance of the awareness of the potential association between ITC and the consumption of caffeine and amphetamine-like stimulants. Résumé: La cardiomyopathie de Takotsubo inversée (CTI) est une maladie rare fortement associée au phéochromocytome et à l’hémorragie intracrânienne. Nous décrivons le cas d’un patient ayant souffert d’une CTI après avoir pris une dose excédentaire, dans le contexte d’une exposition prolongée, d’un supplément de gestion du poids contenant de la caféine et des stimulants s’apparentant aux amphétamines, une combinaison susceptible d’accroître le tonus sympathique local du myocarde. Le patient a été pris en charge de manière conservatrice et s’est rétabli en l’espace de deux mois. Cet exposé fait ressortir l’importance de la sensibilisation à l’association possible entre la CTI et la consommation de caféine et de stimulants analogues des amphétamines.

Guanine is the most easily oxidized of the four DNA bases, and contiguous guanines (GG) in a sequence are more readily oxidized than a single guanine in a sequence. Continued oxidation of GGs results in a contiguous oxidized guanine lesion. Two contiguous 2,5-diamino-4H-imidazol-4-ones, an oxidized form of guanine that hydrolyses to 2,2,4-triamino-5(2H)-oxazolone (Oz), are detected following the oxidation of GG. In this study, we analysed translesion synthesis (TLS) across two contiguous Oz molecules (OzOz) using Klenow Fragment exo- (KF exo-) and DNA polymerases (Pols) α, β, ζ, η, ι,κ and REV1. We found that KF exo- and Pols α ,β, ι and REV1 inserted one nucleotide opposite the 3' Oz of OzOz and stalled at the subsequent extension, and that Pol κ incorporated no nucleotide. Pol η only inefficiently elongated the primer up to full-length across OzOz; the synthesis of most DNA strands stalled at the 3' or 5' Oz of OzOz. Surprisingly, however, Pol ζ effiiciently extended the primer up to full-length across OzOz, unlike the other DNA polymerases, but catalysed error-prone nucleotide incorporation. We therefore believe that Pol ζ is required for efficient TLS of OzOz. These results show that OzOz obstructs DNA synthesis by DNA polymerases except Pol ζ. [ABSTRACT FROM AUTHOR]

Objective: 2,2,4-Triamino-5(2H)-oxazolone (Oz) is a guanine lesion produced by reactive oxygen radicals and photosensitized oxidation. This nucleobase is a potentially mutagenic lesion, and is removed by several base excision repair enzymes. Our purpose is to analyze whether Oz is the substrate of nucleotide excision repair (NER). Materials and Methods: A lymphoblastoid cell line from the patient with xeroderma pigmentosum (XP) complementation group C (XP3BE) was used. Cell-free NER reactions with covalently closed circular DNAs containing the Oz lesion were performed using the XP3BE whole cell extracts with or without the XPC-RAD23B complex. In addition, DNA fragments (180 bp in length) containing the Oz lesion were used for binding reactions with the XPC-RAD23B complex. Results: We analyzed the cell-free NER activity on Oz and the binding affinity of XPC-RAD23B, which initiates NER. Human cell-free NER activity on Oz was detected, though the reactivity to Oz was lower than that on ultra violet (UV)-induced pyrimidine (6-4) pyrimidone photoproduct (6-4PP). Also, binding of XPC-RAD23B with Oz was lower than that with 6-4PP. Conclusion: Because of the low binding affinity of Oz for XPC-RAD23B, NER efficiency on Oz is very low. Therefore, general NER is not the appropriate repair system for Oz. [ABSTRACT FROM AUTHOR]

Introduction: 2,2,4-Triamino-5(2H)-oxazolone (Oz) in a DNA strand is an oxidation product of guanine and 8-oxo-7, 8-dihydroguanine, and such a lesion can cause G-to-C transversions. Previously, Fpg/Nei and Nth were shown to have incision activity on Oz. Findings: We investigated the activities of chlorella virus pyrimidine dimer glycosylase (cvPDG) and Escherichia coli endonucleases IV (Nfo) and V (Nfi) on Oz. Although the three enzymes have different repair mechanisms from Fpg/Nei and Nth, they still had incision activity on Oz. Conclusions: Given the incision activities of cvPDG, Nfo and Nfi on Oz in addition to Fpg/Nei and Nth, Oz is DNA damage that can be repaired by diverse enzymes. [ABSTRACT FROM AUTHOR]

Mutations induced by oxidative DNAdamage can cause diseases suchas cancer. In particular, G:C–T:A and G:C–C:G transversionsare caused by oxidized guanine and have been observed in the p53and K-rasgenes. We focused on an oxidizedform of guanine, 2,2,4-triamino-5(2H)-oxazolone (Oz),as a cause of G:C–C:G transversions based on our earlier elucidationthat DNA polymerases (Pols) α, β, γ, ε, η,I, and IV incorporate dGTP opposite Oz. The nucleotide insertion andextension of Pols δ, ζ, ι, κ, and REV1, belongingto the B- and Y-families of DNA polymerases, were analyzed for thefirst time. Pol δ incorporated dGTP, in common with other replicativeDNA polymerases. Pol ζ incorporated dGTP and dATP, and the efficiencyof elongation up to full-length beyond Oz was almost the same as thatbeyond G. Although nucleotide incorporation by Pols ι or κwas also error-prone, they did not extend the primer. On the otherhand, the polymerase REV1 predominantly incorporated dCTP oppositeOz more efficiently than opposite 8-oxo-7,8-dihydroguanine, guanidinohydantoin,or tetrahydrofuran. Here, we demonstrate that Pol ζ can efficientlyreplicate DNA containing Oz and that REV1 can prevent G:C–C:Gtransversions caused by Oz. [ABSTRACT FROM AUTHOR]

TAL2 is a member of the basic helix-loop-helix family and is essential for the normal development of the mouse brain. However, the function of TAL2 during brain development is unclear. P19 cells are pluripotent mouse embryonal carcinoma cells that adopt neural fates upon exposure to all- transretinoic acid (atRA) and culture in suspension. We found that the expression of Tal2gene was induced in P19 cells after addition of atRA in suspension culture. Tal2expression was detected within 3 h after the induction, and had nearly returned to basal levels by 24 h. When GFP-tagged TAL2 (GFP-TAL2) was expressed in P19 cells, we observed GFP-TAL2 in the nucleus. Moreover, we showed that atRA and retinoic acid receptor α regulated Tal2expression. These results demonstrate for the first time that atRA induces Tal2expression in P19 cells, and suggest that TAL2 commits to the acquisition of neural fate in brain development. [ABSTRACT FROM AUTHOR]

Guanine is the most easily oxidized among the four DNA bases, and some guanine-rich sequences can form quadruplex structures. In a previous study using 6-mer DNA d(TGGGGT), which is the shortest oligomer capable of forming quadruplex structures, we demonstrated that guanine oxidation products of quadruplex DNA differ from those of single-stranded DNA. Therefore, the hotooxidation products of double-stranded DNA (dsDNA) may also differ from that of quadruplex or single-stranded DNA, with the difference likely explaining the influence of DNA structures on guanine oxidation pathways. In this study, the guanine oxidation products of the dsDNA d(TGGGGT)/d(ACCCCA) were analyzed using HPLC and electrospray ionization-mass spectrometry (ESI-MS). As a result, the oxidation products in this dsDNA were identified as 2,5-diamino-4H-imidazol-4-one (Iz), 8-oxo-7,8-dihydroguanine (8oxoG), dehydroguanidinohydantoin (Ghox), and guanidinohydantoin (Gh). The major oxidation products in dsDNA were consistent with a combination of each major oxidation product observed in single-stranded and quadruplex DNA. We previously reported that the kinds of the oxidation products in single-stranded or quadruplex DNA depend on the ease of deprotonation of the guanine radical cation (G++) at the N1 proton. Similarly, this mechanism was also involved in dsDNA. Deprotonation in dsDNA is easier than in quadruplex DNA and more difficult in single-stranded DNA, which can explain the formation of the four oxidation products in dsDNA. [ABSTRACT FROM AUTHOR]

There is adequate evidence for the carcinogenicity of cadmium (Cd). However, a significant unaddressed question remains as to how this metal actually causes malignant transformation (tumor initiation). Since it has been shown that Cd only has the weak direct interaction potential with DNA, the metal is recognized as an indirect genotoxicant and mutagen. Currently, Cd-mediated "epigenetic" modifications, such as changes in DNA methylation resulting in alteration in target gene expression, coupled with cancer progression, are the focus of mechanistic research. We have reported that the apolipoprotein E (ApoE) gene, a suppressor of cell invasion, is an early Cd target, and is involved in the malignant transformation of TRL 1215 rodent liver cells. Cd exposure suppresses ApoE expression which can be re-activated with 5-aza-2'-deoxycytidine, a DNA demethylating agent. In the present study, we sought direct evidence of Cd-induced DNA hypermethylation of the ApoE promoter region by performing bisulfite sequencing and real-time quantitative methylation-specific PCR. Our data clearly suggest that Cd can down-regulate the expression of ApoE via introduction of excess DNA methylation in the promoter region of ApoE during malignant transformation of TRL 1215 cells. [ABSTRACT FROM AUTHOR]