Salt Dependence of DNA Binding Activity of Human Transcription Factor Dlx3.

Distal-less 3 (Dlx3) is a homeobox-containing transcription factor and plays a crucial role in the development and differentiation process. Human Dlx3 consists of two transactivation domains and a homeobox domain (HD) that selectively binds to the consensus site (5'-TAATT-3') of the DNA duplex. Here, we performed chemical shift perturbation experiments on Dlx3-HD in a complex with a 10-base-paired (10-bp) DNA duplex under various salt conditions. We also acquired the imino proton spectra of the 10-bp DNA to monitor the changes in base-pair stabilities during titration with Dlx3-HD. Our study demonstrates that Dlx3-HD selectively recognizes its consensus DNA sequences through the α3 helix and L1 loop regions with a unique dynamic feature. The dynamic properties of the binding of Dlx3-HD to its consensus DNA sequence can be modulated by varying the salt concentrations. Our study suggested that this unique structural and dynamic feature of Dlx3-HD plays an important role in target DNA recognition, which might be associated with tricho-dento-osseous syndrome.

A Green Chemical Approach for Iodination of Pyrimidine Derivatives by Mechanical Grinding under Solvent-Free Conditions.

The iodination of pyrimidines is usually carried out by using toxic reagents under acidic conditions, such as with sulfuric acid and nitric acid. To avoid toxic reagents, we developed a simple and eco-friendly approach for the iodination of pyrimidine derivatives under solvent-free conditions using solid iodine and AgNO3 as an electrophilic iodinating reagent. The advantages of this method are the relatively short reaction time (20-30 min), simple set-up procedure, high yields (70-98%), and environmentally friendly reaction conditions. Our novel approach for the iodination of pyrimidines, as well as a variety of their derivatives, will contribute to the development of nucleobase-related drug candidates.

Non-Canonical Helical Structure of Nucleic Acids Containing Base-Modified Nucleotides.

Chemically modified nucleobases are thought to be important for therapeutic purposes as well as diagnosing genetic diseases and have been widely involved in research fields such as molecular biology and biochemical studies. Many artificially modified nucleobases, such as methyl, halogen, and aryl modifications of purines at the C8 position and pyrimidines at the C5 position, are widely studied for their biological functions. DNA containing these modified nucleobases can form non-canonical helical structures such as Z-DNA, G-quadruplex, i-motif, and triplex. This review summarizes the synthesis of chemically modified nucleotides: (i) methylation, bromination, and arylation of purine at the C8 position and (ii) methylation, bromination, and arylation of pyrimidine at the C5 position. Additionally, we introduce the non-canonical structures of nucleic acids containing these modifications.

Protein-induced B-Z transition of DNA duplex containing a 2'-OMe guanosine.

Structural transformation of the canonical right-handed helix, B-DNA, to the non-canonical left-handed helix, Z-DNA, can be induced by the Zα domain of the human RNA editing enzyme ADAR1 (hZαADAR1). To characterize the site-specific preferences of binding and structural changes in DNA containing the 2'-O-methyl guanosine derivative (mG), titration of the imino proton spectra and chemical shift perturbations were performed on hZαADAR1 upon binding to Z-DNA. The structural transition between B-Z conformation as the changing ratio between DNA and protein showed a binding affinity of the modified DNA onto the Z-DNA binding protein similar to wild-type DNA or RNA. The chemical shift perturbation results showed that the overall structure and environment of the modified DNA revealed DNA-like properties rather than RNA-like characteristics. Moreover, we found evidence for two distinct regimes, "Z-DNA Sensing" and "Modification Sensing", based on the site-specific chemical shift perturbation between the DNA (or RNA) binding complex and the modified DNA-hZαADAR1 complex. Thus, we propose that modification of the sugar backbone of DNA with 2'-O-methyl guanosine promotes the changes in the surrounding α3 helical structural segment as well as the non-perturbed feature of the ß-hairpin region.

Depression and Its Severity Are Strongly Associated with Both Storage and Voiding Lower Urinary Tract Symptoms Independently of Prostate Volume.

Depression is related to various functional medical conditions. Its association with lower urinary tract symptoms (LUTS) is also expected. We evaluated whether depression and its severity are associated with LUTS when LUTS risk factors including prostate volume (PV) are taken into account in a large population of Korean men. Study subjects included 10,275 men who underwent routine health check-ups at the Healthcare System Gangnam Center of Seoul National University Hospital. Depression was assessed using Beck Depression Inventory-II and LUTS using international prostate symptom score. PV was measured using transrectal ultrasonography by a radiologist. Effect sizes of depression severity on total, storage, and voiding symptoms were assessed. In multivariate logistic regression analysis, mild, moderate and severe depression were associated with total (adjusted odds ratio: aOR = 2.99, 3.86 and 8.99; all P < 0.001), voiding (aOR = 3.04, 3.28 and 5.58; all P < 0.001) and storage symptoms (aOR = 2.43, 3.43 and 2.89; all P < 0.05) showing dose response relationships (all P trend < 0.001). In a subgroup analysis for participants with PV data (n = 1,925), mild and moderate-severe depression were also associated with LUTS (aOR = 3.29, 2.84; P < 0.001 and 0.018, respectively). In conclusion, depression and its severity are strongly associated with total, voiding, and storage symptoms independently of PV state.

Molecular basis of facilitated target search and sequence discrimination of TALE homeodomain transcription factor Meis1.

Transcription factors specifically bind to their consensus sequence motifs and regulate transcription efficiency. Transcription factors are also able to non-specifically contact the phosphate backbone of DNA through electrostatic interaction. The homeodomain of Meis1 TALE human transcription factor (Meis1-HD) recognizes its target DNA sequences via two DNA contact regions, the L1-α1 region and the α3 helix (specific binding mode). This study demonstrates that the non-specific binding mode of Meis1-HD is the energetically favored process during DNA binding, achieved by the interaction of the L1-α1 region with the phosphate backbone. An NMR dynamics study suggests that non-specific binding might set up an intermediate structure which can then rapidly and easily find the consensus region on a long section of genomic DNA in a facilitated binding process. Structural analysis using NMR and molecular dynamics shows that key structural distortions in the Meis1-HD-DNA complex are induced by various single nucleotide mutations in the consensus sequence, resulting in decreased DNA binding affinity. Collectively, our results elucidate the detailed molecular mechanism of how Meis1-HD recognizes single nucleotide mutations within its consensus sequence: (i) through the conformational features of the α3 helix; and (ii) by the dynamic features (rigid or flexible) of the L1 loop and the α3 helix. These findings enhance our understanding of how single nucleotide mutations in transcription factor consensus sequences lead to dysfunctional transcription and, ultimately, human disease.

Base-pair Opening Dynamics of Nucleic Acids in Relation to Their Biological Function.

Base-pair opening is a conformational transition that is required for proper biological function of nucleic acids. Hydrogen exchange, observed by NMR spectroscopic experiments, is a widely used method to study the thermodynamics and kinetics of base-pair opening in nucleic acids. The hydrogen exchange data of imino protons are analyzed based on a two-state (open/closed) model for the base-pair, where hydrogen exchange only occurs from the open state. In this review, we discuss examples of how hydrogen exchange data provide insight into several interesting biological processes involving functional interactions of nucleic acids: i) selective recognition of DNA by proteins; ii) regulation of RNA cleavage by site-specific mutations; iii) intermolecular interaction of proteins with their target DNA or RNA; iv) formation of PNA:DNA hybrid duplexes.

Relationship between Metabolic Syndrome and Rheumatoid Arthritis.

BACKGROUND: Rheumatoid arthritis (RA) and metabolic syndrome (Mets) are considered to be diseases with common traits that can increase the risk of cardiovascular disease incidence; studies in other countries examined the relationship between these diseases. However, existing studies did not show consistent results. In the present study, the relationship between RA and Mets in Koreans was examined using the data of the 4th and 5th Korea National Health and Nutrition Examination Survey (KNHANES). METHODS: The present study used the data of the 4th and 5th KNHANES, conducted between 2007 and 2012. Among 25,812 adults aged over 40, 19,893 were selected as study subjects, excluding 5,919 who did not have variable information needed for the analysis. T-test and chi-square test were used for the analysis of related variables. To determine the relationship between diagnostic status of RA and Mets, multivariate logistic regression analysis was performed by controlling confounding variables, which were selected through literature review and statistical analysis. RESULTS: Multivariate logistic regression analysis was conducted to examine the relationship between diagnostic status of RA and Mets. When age, education level, average monthly household income, smoking, alcohol consumption, and level of physical activity were adjusted, the prevalence of Mets was lower in RA patients (adjusted odds ratio [aOR], 0.79; 95% confidence interval [CI], 0.65 to 0.96). Multivariate logistic regression analysis was performed to examine the relationship between treatment status of RA and Mets. When age, education level, average monthly household income, smoking, alcohol consumption, and level of physical activity were adjusted, there was a significant negative correlation in women (aOR, 0.65; 95% CI, 0.44 to 0.96). CONCLUSION: The relationship between RA and Mets showed a significantly negative correlation in Korean women. The group that received RA treatment showed significantly lower prevalence of the Mets as compared to the untreated group in Korean RA women.

Physical Activity Level of Korean Adults with Chronic Diseases: The Korean National Health and Nutritional Examination Survey, 2010-2012.

BACKGROUND: Proper physical activities are known to be helpful in the prevention and management of chronic diseases. However, the physical activity level of patients with chronic diseases is low. Therefore, this study aimed to investigate the physical activity compliance of patients with hypertension, diabetes, and dyslipidemia in Korea. METHODS: This study analyzed the 2010-2012 Fifth Korean National Health and Nutrition Examination Survey data. We included 13,873 individuals in the analysis. The level of physical activity compliance was measured by performing multivariate logistic regression analyses. RESULTS: In the univariate analysis, the subjects with hypertension or diabetes tended to comply with the physical activity guidelines less faithfully than their healthy counterparts. The proportion of subjects with hypertension who were insufficiently physically active was 65.4% among the men and 75.8% among the women. For diabetes, the proportions were 66.7% and 76.8%, respectively. No significant difference was found between the subjects with dyslipidemia and their healthy counterparts. In the multivariate logistic regression analysis, no significant difference in physical activity compliance was observed between the subjects with hypertension, diabetes, or dyslipidemia and their healthy counterparts for both sexes. CONCLUSION: The patients with hypertension or diabetes tended to have lower physical activity prevlaence than their healthy counterparts. However, for dyslipidemia, no significant difference was found between the two groups. Given the significance of physical activities in the management of chronic diseases, the physical activities of these patients need to be improved.