Vol 50, No 6 (2016)

Nucleic acids are the targets for various endogenous and exogenous genotoxic agents, including reactive oxygen species. The appearance of a hydroxyl racial (^•OH), the most harmful molecule, next to an oligonucleotide can lead to two types of DNA damage: strand breaks or nucleobase modifications. Since clustered DNA damage is defined as the presence of two or more lesions in one helix turn, purine 5′,8-cyclo-2′-deoxynucleosides are recognized as tandem lesions: both sugar moieties and base have been modified within one nucleoside/nucleotide. The hydrogen abstraction from the C5′ group of nucleosides/nucleotides by ^•OH, with subsequent C8 C5′ cyclisation results in purine 5′,8-cyclonucleoside formation. Due to its unusual 3D structure and the fact that only one radical hit is needed for purine 5′,8-cyclonucleoside formation their influence on genome stability/integrity and DNA repair processes are subjects of medical interest. In the present work the influence of 5′,8-cyclo-2′-deoxyadenosine on DNA spatial geometry and DNA repair hinder in connection with human health, such as neurological disorders is discussed.

Changes of chromatin structure require participation of chromatin remodeling factors (CRFs), which are ATP-dependent multisubunit complexes that change the structure of the nucleosome without covalently modifying its components. CRFs act together with other protein factors to regulate the extent of chromatin condensation. Four CRF families are currently distinguished based on their structural and biochemical characteristics: SWI/SNF, ISWI, Mi-2/CHD, and SWR/INO80. X-ray diffraction analysis and electron microscopy are the main methods to obtain structural information about macromolecules. CRFs are difficult to obtain in crystal because of their large sizes and structural heterogeneity, and transmission electron microscopy (TEM) is mostly employed in their structural studies. The review considers all structures obtained for CRFs by TEM and discusses several models of CRF–nucleosome interactions.

The comparative full-genome sequencing of transcriptomes of the renal cortex and medulla from hypertensive ISIAH rats and normotensive WAG rats revealed the differential expression of genes in the locus of chromosome 11 associated to the traits of resting blood pressure and relative kidney weight. Six differentially expressed genes (Kcne1, Rcan1, Mx1, Mx2, Tmprss2, and RGD1559516) were identified in the renal cortex, and three genes (Rcan1, Mx2, and Tmprss2) were identified in the renal medulla. An analysis of the functions of these genes pointed at the Rcan1 gene as the most relevant candidate gene associated with both the traits of resting blood pressure and relative kidney weight in ISIAH rats. The elevation of the transcription levels of the Mx1 and Mx2 genes in hypertensive ISIAH rats may represent an adaptation that contributes to the alleviation of inflammatory processes in the kidneys.

Testicular cancer is the most common form of solid cancer in young men. Testicular cancer is represented by testicular germ cell tumors (TGCTs) derived from embryonic stem cells with different degrees of differentiation in about 95% of cases. The development of these tumors is related to the formation of a pool of male germ cells and gametogenesis. Clinical factors that are predisposed to the development of germ-cell tumors include cryptorchidism and testicular microlithiasis, as well as infertility associated with the gr/gr deletion within the AZFс locus. KITLG, SPRY4, and BAK1 genes affect the development of the testes and gametogenesis; mutations and polymorphisms of these genes lead to a significant increase in the risk of the TGCT development. To determine the relationship between gene polymorphisms and the development of TGCTs, we developed a system for detection and studied the allele and genotype frequencies of the KITLG (rs995030, rs1508595), SPRY4 (rs4624820, rs6897876), and BAK1 (rs210138) genes in fertile men, patients with TGCTs, and patients with infertility that have the AZFс deletion. A significant association of rs995030 of the KITLG gene with the development of TGCTs (p = 0.029 for the allele G, p = 0.0124 for the genotype GG) was revealed. Significant differences in the frequencies of the studied polymorphisms in patients with the AZFc deletion and the control group of fertile men were not found. We showed significant differences in the frequencies for the combination of all high-risk polymorphisms in the control group, patients with the AZFc deletion and patients with TGCTs (p (TGCTs-AZF-control) = 0.0207). A fivefold increase in the frequency of the combination of all genotypes in the TGCT group (p = 0.0116; OR = 5.25 [1.44‒19.15]) and 3.7-fold increase was identified in patients with the AZFc deletion (p = 0.045; OR = 3.69 [1.11‒12.29]) were revealed. The genotyping of patients with infertility caused by the AZFc deletion can be used to identify individuals with an increased risk of TGCTs.

Siberian Tatars form the largest Turkic-speaking ethnic group in Western Siberia. The group has a complex hierarchical system of ethnographically diverse populations. Five subethnic groups of Tobol–Irtysh Siberian Tatars (N = 388 samples) have been analyzed for 50 informative Y-chromosomal SNPs. The subethnic groups have been found to be extremely genetically diverse (F_ST = 21%), so the Siberian Tatars form one of the strongly differentiated ethnic gene pools in Siberia and Central Asia. Every method employed in our studies indicates that different subethnic groups formed in different ways. The gene pool of Isker–Tobol Tatars descended from the local Siberian indigenous population and an intense, albeit relatively recent gene influx from Northeastern Europe. The gene pool of Yalutorovsky Tatars is determined by the Western Asian genetic component. The subethnic group of Siberian Bukhar Tatars is the closest to the gene pool of the Western Caucasus population. Ishtyak–Tokuz Tatars have preserved the genetic legacy of Paleo-Siberians, which connects them with populations from Southern, Western, and Central Siberia. The gene pool of the most isolated Zabolotny (Yaskolbinsky) Tatars is closest to Ugric peoples of Western Siberia and Samoyeds of the Northern Urals. Only two out of five Siberian Tatar groups studied show partial genetic similarity to other populations calling themselves Tatars: Isker–Tobol Siberian Tatars are slightly similar to Kazan Tatars, and Yalutorovsky Siberian Tatars, to Crimean Tatars. The approach based on the full sequencing of the Y chromosome reveals only a weak (2%) Central Asian genetic trace in the Siberian Tatar gene pool, dated to 900 years ago. Hence, the Mongolian hypothesis of the origin of Siberian Tatars is not supported in genetic perspective.

The gene transcription of guanyl-specific ribonucleases (RNases), which provide available phosphate to cells of Bacillus, is controlled by the signal transduction system PhoP‒PhoR. However, the biosynthesis of B. circulans RNase does not depend on the signal-transduction regulatory proteins of Pho regulon. It has been found that raising the salt molar concentration in culture medium increases the level of extracellular guanyl-specific ribonuclease Bci synthesized by B. circulans. Sequences homologous to the binding sites of the regulatory protein DegU were found in RNase Bci promoter. The functioning of the DegS–DegU signal transduction system is stimulated by a high salt concentration. Using a strain of B. subtilis that is defective in the DegU regulatory protein, we have shown that the DegS–DegU system participates in the regulation of RNase Bci expression under salt stress.

B7-H4 plays an important role in tumor immune evasion. In previous studies we have found that B7-H4 can translocate to the nucleus, and the exposure to PI3K inhibitor Ly294002 affects B7-H4 subcellular distribution. In this study we report the role of PI3K/Akt pathway in the B7-H4 subcellular distribution and the effect of PI3K/Akt inhibitors on B7-H4-mediated immunoresistance. The involvement of PI3K/Akt pathway in B7-H4 subcellular distribution was evident in experiments with wortmannin, while MDM2 inhibitor nutlin-3 and the mTOR inhibitor rapamycin were used to dissect the signaling downstream of Akt. Wortmannin and rapamycin demonstrated similar effects on B7-H4 subcellular distribution. Exposure to any of these inhibitors decreased levels of membrane B7-H4 while at the same time inducing its nuclear accumulation, while exposure to nutlin-3 had no effect on B7-H4 subcellular distribution. In the T cell proliferation assay, both wortmannin and rapamycin effectively inhibited B7-H4 WT/293 cells-mediated T cell proliferation while exerting no effect on Mock/293 cells. PI3K/Akt/mTOR plays a role in B7-H4 subcellular distribution, while MDM2 does not take part in it. Moreover, we show that wortmannin and rapamycin inhibit B7-H4-mediated tumor immunoresistance through regulating B7-H4 subcellular distribution. Taken together, these results suggest that PI3K/Akt/mTOR inhibitors might be used for adjuvant therapy aimed at inhibition of immune evasion.

In warm-blooded vertebrates, the α- and β-globin genes are organized in domains of different types and are regulated in different fashion. In cold-blooded vertebrates and, in particular, the tropical fish Danio rerio, the α- and β-globin genes form two gene clusters. A major D. rerio globin gene cluster is in chromosome 3 and includes the α- and β-globin genes of embryonic-larval and adult types. The region upstream of the cluster contains c16orf35, harbors the main regulatory element (MRE) of the α-globin gene domain in warm-blooded vertebrates. In this study, transient transfection of erythroid cells with genetic constructs containing a reporter gene under the control of potential regulatory elements of the domain was performed to characterize the promoters of the embryonic-larval and adult α- and β-globin genes of the major cluster. Also, in the 5th intron of c16orf35 in Danio rerio was detected a functional analog of the warm-blooded vertebrate MRE. This enhancer stimulated activity of the promoters of both adult and embryonic-larval α- and β-globin genes.

The IL-6 family of cytokines includes a variety of proteins that function not only within the immune system, but also in other organs, tissues, and types of cells, including neurons. The common evolutionary origin of the IL-6 family proteins determines similar mechanisms of reception and intracellular signaling, although their primary structures are highly variable, as well as their biological functions. We have demonstrated that the members of the IL-6 family have high evolutionary plasticity. This manifests in a high degree of population polymorphism for IL-6 family genes, as well as varying degrees of evolutionary conservation among members of the family. The degree of evolutionary conservation of IL-6 family proteins does not correlate with the mechanisms of interaction between these cytokines and their receptors.

Zinc ions form complexes with β-amyloid peptides and play an important role in Alzheimer’s disease pathogenesis. It has been demonstrated by turbidimetry and correlation spectroscopy that synthetic peptide Aβ16 representing the metal-binding domain of β-amyloid is able to interact with nucleic acids, chondroitin polysulfate, and dextran sulfates in the presence of zinc ions. The amino acid D7H substitution enhanced the peptide binding to polyanions, whereas the H6R and H6A-H13A substitutions abolished this interaction. It is suggested that the metal-binding domain may serve as a zinc-dependent site of β-amyloid interaction with biological polyanions including DNA, RNA, and glycosaminoglycans.