Human DNA primase/polymerase PrimPol synthesizes DNA primers de novo after replication fork stalling at damaged DNA sites, contributing to DNA damage tolerance. The contribution of PrimPol in response to the various types of DNA damage is not fully understood. We obtained the lung carcinoma cells A549 with PRIMPOL knockout and characterized its response to DNA damage caused by hydrogen peroxide, methylmethanesulfonate (MMS), cisplatin, bleomycin and ionizing radiation. Knockout of PRIMPOL reduced the number of proliferating cells and cells in G2 phase after treatment with MMS, caused a more pronounced delay of cisplatin-treated cells in S phase. A significant increase in the proportion of apoptotic cells was noted in PRIMPOL-/- cells in response to ionizing radiation at a dose of 10 Gy, while the proportion of cells prone to necroptosis increased significantly in both parental and knockout cells at any radiation dose. Under conditions of oxidative stress stimulated by hydrogen peroxide, PRIMPOL knockout increased cell viability, measured by the MTT method. The data obtained indicate the involvement of PRIMPOL in modulating stress-adaptive responses to various types of genotoxic stress.

Natural allylpolyalkoxybenzenes were used to synthesize polyalkoxychalcones featuring various conformations, including β-methyl-substituted S - trans -conformers and tetralone derivatives with restricted S - cis conformation. Antiproliferative antitubulin activity and cyto-toxicity of these compounds were studied using a sea urchin embryo model and human cancer cell lines. S - trans -Restricted chalcone 3y was found to exhibit high activity in the inhibition of cancer cell growth by microtubule destabilization with IC 50 = 0.02–0.04 µmol L −1 .

Many chemotherapy drugs block tumor cell division by damaging DNA. DNA polymerases eta (Pol η), iota (Pol ι), kappa (Pol κ), REV1 of the Y-family and zeta (Pol ζ) of the B-family efficiently incorporate nucleotides opposite a number of DNA lesions during translesion DNA synthesis. Primase-polymerase PrimPol and the Pol α-primase complex reinitiate DNA synthesis downstream of the damaged sites using their DNA primase activity. These enzymes can decrease the efficacy of chemotherapy drugs, contribute to the survival of tumor cells and to the progression of malignant diseases. DNA polymerases are promising targets for increasing the effectiveness of chemotherapy, and mutations and polymorphisms in some DNA polymerases can serve as additional prognostic markers in a number of oncological disorders.

Tens of thousands of DNA lesions are formed in mammalian cells each day. DNA translesion synthesis is the main mechanism of cell defense against unrepaired DNA lesions. DNA polymerases iota (Pol ι), eta (Pol η), kappa (Pol κ), and zeta (Pol ζ) have active sites that are less stringent toward the DNA template structure and efficiently incorporate nucleotides opposite DNA lesions. However, these polymerases display low accuracy of DNA synthesis and can introduce mutations in genomic DNA. Impaired functioning of these enzymes can lead to an increased risk of cancer.

This article was the first attempt to analyze the biological activity of ursodeoxycholic acid in the context of the in silico prediction of changes in activity of genes. Prediction of the dynamics of changes in gene activity was carried out using the DIGEP-Pred algorithm. The obtained gene arrays were analyzed using the GeneMANIA application. Gene annotation was obtained from The Human Protein Atlas. The results showed that the initial sample of genes is distributed according to the localization of expression into several groups: testes, cerebral cortex, placenta, and parathyroid glands. Groups of genes differed among themselves both in the number of members and in the number of relationships between them. The largest group included 25 genes. The activity of the genes of this group was localized to the testes. According to the prediction, all members of this group will be repressed after exposure to ursodeoxycholic acid. The next group consisted of 14 genes located in the cerebral cortex. Within this group, both an increase and a decrease in the activity of genes when exposed to ursodeoxycholic acid are predicted. Groups of the placenta and parathyroid glands contained relatively few genes (nine genes each) and were characterized by a low number of relationships between members. An analysis of the specialized literature revealed the effects of taking ursodeoxycholic acid, which may be associated with the changes in gene activity, which were predicted in silico. There was no unambiguous relationship between the groups of identified in silico genes and the effects described in the literature. It was revealed that 45 genes of the entire array of genes (81 genes) are prognostic markers of oncological processes.

Разработана клеточная модель для изучения фундаментальных механизмов патогенеза болезни Альцгеймера (БА). Модель представляет собой клеточную линию 3Т3-4R-Tay, клон 47, созданную на основе родительской линии клеток NIH-3T3 (фибробласты мыши), постоянно экспрессирующую белок тау человека (формы 4R). Стабильная экспрессия белка тау подтверждена с помощью иммунофлуоресцентного анализа с использованием моноклональных антител. Проведена сравнительная оценка цитотоксичности различных форм белка тау в условиях совместного культивирования клеток 3Т3-4R-Tay с первичными нейронами гиппокампа головного мозга мыши. Экспрессия фибриллярных форм белка тау (ФФТ) показана методом вестерн-блотинга. Данные о токсическом действии человеческого белка тау, экспрессируемого клетками 3Т3, на первичные нейроны мыши могут служить косвенным подтверждением сходного сценария развития патологического процесса в мозге человека. Клеточная линия 3Т3-4R-Tay позволяет моделировать условия, возникающие в головном мозге человека при БА и других нейродегенеративных заболеваниях более точно, чем другие клеточные модели, и может использоваться для направленного поиска лекарственных препаратов, тормозящих процессы нейродегенерации.

A cell model has been developed to study the fundamental mechanisms of pathogenesis of Alzheimer’s disease (AD). The model is based on the 3T3-4R-tau cell line, clone 47, derived from the parental cell line NIH-3T3 (mouse fibroblasts) permanently expressing the human tau (4R) protein. Stable expression of the tau protein was confirmed by immunofluorescence assay (IFA) and characterized by Western blotting with monoclonal antibodies. Cytotoxicity of different forms of tau protein was estimated in the Transwell two-chamber coculture system involving 3T3-4R-tau cells and primary mouse hippocampal neurons. The data on the toxic effect of human tau protein expressed by 3T3 cells on the primary mouse neurons may be an indirect evidence of a similar scenario of pathological process development in human brain. The 3T3-4R-tau cell line makes it possible to simulate the conditions in human brain during AD and other neurodegenerative diseases more exactly than other cell models and can be used for the directed search of drugs inhibiting neurodegenerative processes.