Thermodynamic and kinetic basis for recognition and repair of 8-oxoguanine in DNA by human 8-oxoguanine-DNA glycosylase

We have used a stepwise increase in ligand complexity approach to estimate the relative contributions of the nucleotide units of DNA containing 7,8-dihydro-8-oxoguanine (oxoG) to its total affinity for human 8-oxoguanine DNA glycosylase (OGG1) and construct thermodynamic models of the enzyme interaction with cognate and non-cognate DNA. Non-specific OGG1 interactions with 10–13 nt pairs within its DNA-binding cleft provides approximately 5 orders of magnitude of its affinity for DNA (ΔG° approximately −6.7 kcal/mol). The relative contribution of the oxoG unit of DNA (ΔG° approximately −3.3 kcal/mol) together with other specific interactions (ΔG° approximately −0.7 kcal/mol) provide approximately 3 orders of magnitude of the affinity. Formation of the Michaelis complex of OGG1 with the cognate DNA cannot account for the major part of the enzyme specificity, which lies in the kcat term instead; the rate increases by 6–7 orders of magnitude for cognate DNA as compared with non-cognate one. The kcat values for substrates of different sequences correlate with the DNA twist, while the KM values correlate with ΔG° of the DNA fragments surrounding the lesion (position from −6 to +6). The functions for predicting the KM and kcat values for different sequences containing oxoG were found

Abundances of microRNAs in human cells can be estimated as a function of the abundances of YRHB and RHHK tetranucleotides in these microRNAs as an ill-posed inverse problem solution

Mature microRNAs (miRNAs) are small endogenous non-coding RNAs 18-25 nt in length. They program the RNA Induced Silencing Complex (RISC) to make it inhibit either messenger RNAs or promoter DNAs. We have found that the mean abundance of miRNAs in Arabidopsis is correlated with the abundance of DRYD tetranucleotides near the 3’-end and the abundance of WRHB tetranucleotides in the center of the miRNA sequence. Based on this correlation, we have estimated miRNA abundances in seven organs of this plant, namely: inflorescences, stems, siliques, seedlings, roots, cauline, and rosette leaves. We have also found that the mean affinity of miRNAs for two proteins in the Argonaute family (Ago2 and Ago3) in man is correlated with the abundance of YRHB tetranucleotides near the 3’-end and that the preference of miRNAs for Ago2 is correlated with the abundance of RHHK tetranucleotides in the center of the miRNA sequence. This allowed us to obtain statistically significant estimates of miRNA abundances in human embryonic kidney cells, HEK293T. These findings in relation to two taxonomically distant entities (man and Arabidopsis) fit one another like pieces of a jigsaw puzzle, which allowed us to heuristically generalize them and state that the miRNA abundance in the human brain may be determined by the abundance of YRHB and RHHK tetranucleotides in these miRNAs

Candidate SNP markers of reproductive potential are predicted by a significant change in the affinity of TATA-binding protein for human gene promoters

Abstract Background The progress of medicine, science, technology, education, and culture improves, year by year, quality of life and life expectancy of the populace. The modern human has a chance to further improve the quality and duration of his/her life and the lives of his/her loved ones by bringing their lifestyle in line with their sequenced individual genomes. With this in mind, one of genome-based developments at the junction of personalized medicine and bioinformatics will be considered in this work, where we used two Web services: (i) SNP_TATA_Comparator to search for alleles with a single nucleotide polymorphism (SNP) that alters the affinity of TATA-binding protein (TBP) for the TATA boxes of human gene promoters and (ii) PubMed to look for retrospective clinical reviews on changes in physiological indicators of reproductive potential in carriers of these alleles. Results A total of 126 SNP markers of female reproductive potential, capable of altering the affinity of TBP for gene promoters, were found using the two above-mentioned Web services. For example, 10 candidate SNP markers of thrombosis (e.g., rs563763767) can cause overproduction of coagulation inducers. In pregnant women, Hughes syndrome provokes thrombosis with a fatal outcome although this syndrome can be diagnosed and eliminated even at the earliest stages of its development. Thus, in women carrying any of the above SNPs, preventive treatment of this syndrome before a planned pregnancy can reduce the risk of death. Similarly, seven SNP markers predicted here (e.g., rs774688955) can elevate the risk of myocardial infarction. In line with Bowles’ lifespan theory, women carrying any of these SNPs may modify their lifestyle to improve their longevity if they can take under advisement that risks of myocardial infarction increase with age of the mother, total number of pregnancies, in multiple pregnancies, pregnancies under the age of 20, hypertension, preeclampsia, menstrual cycle irregularity, and in women smokers. Conclusions According to Bowles’ lifespan theory—which links reproductive potential, quality of life, and life expectancy—the above information was compiled for those who would like to reduce risks of diseases corresponding to alleles in own sequenced genomes. Candidate SNP markers can focus the clinical analysis of unannotated SNPs, after which they may become useful for people who would like to bring their lifestyle in line with their sequenced individual genomes

Star-shaped D–π–A oligothiophenes with a tris(2-methoxyphenyl)amine core and alkyldicyanovinyl groups: synthesis and physical and photovoltaic properties

Synthesis of a series of star-shaped oligomers having a novel electron donating tris(2-methoxyphenyl)amine (m-TPA) core, which is linked through a bithiophene or terthiophene π-bridge with electron-deficient alkyldicyanovinyl (alkyl-DCV) groups, is described. A comprehensive study of the oligomers revealed significant dependence of their physical properties, including absorption, molecular frontier energy levels, crystal packing, and melting and glass transition temperatures, upon the chemical structure. A comparison of their photophysical properties to the nearest analog having the common dicyanovinyl (DCV) groups demonstrated a number of benefits to use alkyl-DCV units for the design of donor–acceptor small molecules: higher solubility, increased electrochemical stability, better photovoltaic performance, and possibility to control the relative physical and photovoltaic properties by a simple adjustment of alkyl and π-bridge lengths. Modification of the well-known triphenylamine (TPA) core in the star-shaped oligomers by methoxy groups increases not only solubility, but also crystallinity of the oligomers, whereas their photovoltaic performance stays on a similar level as their analogs with a TPA core. The study demonstrates that these design strategies represent interesting and simple tools for the effective modulation of properties of star-shaped molecules