Laboratory of Molecular Biology

The studies are conducted within the following RSW (research scientific work) topics:

I. Molecular mechanism of action of human cell-free DNA fragments on the functionality of different types of cells

The laboratory is currently engaged in studying the characteristics of cell-free DNA in health and various diseases (autoimmune, inflammatory, neurodegenerative, psychiatrical), critical states, stress, and pregnancy. It was shown that during pathology, such characteristics of cell-free DNA as blood plasma content, fragment sizes, fraction of GC-rich motifs, degree of oxidative modification of the bases substantially changes.

Biological activity of cell-free DNA is also explored. Simulating in vitro the processes, which occur after an exposure to cell-free DNA, makes it possible to study the changes of gene expression in pathology and to reveal cell signaling pathways invlolved in the pathogenesis. An exposure to cell-free DNA was shown to result in changes of the gene expression profile of signaling pathways, which control DNA repair, adaptive response, and antioxidant activity in the cell.

The laboratory team discovered a molecular mechanism, by dint of which the cell population (or the body) reacts to the oxidative stress. The main 'player' in the signaling cascade under study is oxidized and/or CpG-enriched cell-free DNA. Cell-free DNA have the property of penetrating the cell structures located close to the nuclear membrane, and inducing a sharp increase in the synthesis of reactive oxygen species (ROS) in mitochondria. The 'burst' of ROS synthesis close to the nucleus induces oxidation and break formation in nuclear DNA, as well as development of adaptive response in the cell population, which favors survival of cells, including cells with damaged DNA. This process can result in genome rearrangements and mutagenesis. The laboratory continues to study molecular mechanisms of the interaction between cell-free DNA and cells of differentn-types, and to search for receptors, through which cell-free DNA affects the cells.

II. Studying the effect of nanomaterials on the functional activity of human genome

The laboratory team performs studying the influence of novel water-soluble fullerene derivates [C60] and/or [C70] on the functional activity of human genome in cell cultures. A mechanism of antioxidant fullerene activity was for the first time described. It was shown, that fullerenes, which actively inhibit reactive oxygen species, nonetheless, induce oxidative stress in human cells. Fullerenes were demonstrated to be able to alter the lineage of human stem cells.

The following researches are currently conducted in Laboratory of Molecular Biology, supported with the following RFBR (Russian Foundation of Basic Research) grants:

1. "Cell-free DNA as a signaling molecule during an exposure to low doses of radiation. A study of the molecular mechanisms of action of low doses of radiation on human stem cells, – an adaptive response or nuclear DNA damage?" (16-04-01099)

The project is aimed to the examination of the molecular mechanisms of action of low doses of radiation on human stem cells. The project plans to justify a hypothesis of action of low doses of radiation though a extracellular mediator of the cell-to-cell signal transmission – fragments of GC-enriched oxidized cell-free DNA.

2. "A study of the role of cell-free DNA and disruptions of transcriptome of the signaling pathways in schizophrenia pathogenesis" (17-29-06017)

The project is aimed to the examination of the properties of cfDNA circulating in schizophrenia patients and to the clarification of the role of the circulating cell-free DNA in the alteration of the genome transcriptional activity profile in schizophrenia patients.

3. "Disruptions of transcriptome of signaling cascades in autism. A study of the role of cell-free DNA in autism pathogenesis" (17-04-01587)

The project is aimed to revealing cell signaling cascades involved in the development of autism. During implementation of the project, studying the role of cell-free DNA in the progression of autism and identifying potential target genes of the signaling pathways, which are engaged in the response of the autism patient's cell for oxidative stress the cfDNA fragments trigger, are planned.

4. "Examination of the role of mitochondria in the control of apoptosis process that results from an exposure to ionizing radiation in low and moderate doses" (18-34-00878)

The project is aimed to analysis of the role of mitochondria in the control of apoptosis process that results from an exposure to ionizing radiation in low and moderate doses and studying the molecular mechanisms that mediate the development of the adaptive response.

In 2018, the Laboratory of Molecular Biology obtained the RSF (Russian Science Foundation) grant "The role of ribosomal genes in the etiology and nosogenesis of schizophrenia. Prognostic value of the characteristics of the patient's ribosomal gene complex in the response for schizophrenia therapy" (18-15-00437)

During implementation of the project, the structural-functional organization of ribosomal genes (rDNA) of schizophrenia patients will be explored and compared to ribosomal genes of mentally healthy controls with determining variability of the total number of rDNA copies per genome, methylation levels of different rDNA regions, rDNA damage degree, and rRNA gene expression (amount of rRNA). The characteristics of ribosomal gene complex will be put together with clinical forms of schizophrenia, and with the efficiency of the patient's response for treatment. In order to describe the common characteristics of schizophrenia genome, examination of variability of three repeats, – mitochondrial DNA (a marker of mitochondria abundance), telomere repeat (a marker of the oxidative stress degree and aging index) and satellite III(1q12) (evaluation of chromosomal instability) is planned. On primary cells and cell cultures derived from cases and controls, as well as rat brain neurons, the effect of a number of antipsychotics administered in domestic psychiatry upon the characteristics of the ribosomal gene complex and upon the variability of the other three above-mentioned genomic repeats will be studied. A possibility to reduce the transcriptional activity of ribosomal genes in the patient's cell using novel domestic compounds, which induce selective methylation of ribosomal DNA, will be studied.

The Laboratory of Molecular Biology conducts a research within the frameworks of Project supported by Research Program of the Presidium of RAS (Russian Academy of Sciences) "Fundamental Researches for Biomedical Technologies" for years 2018 – 2020: "A study of the role of GC-rich sequences of cell-free DNA in cell-to-cell interaction during the development of adaptive response in cancer cells; Designing medicinal agents that affect the cell-to-cell interaction during the therapy of oncological diseases."

The project has scheduled a study of possibility to reduce the tolerance of the malignant tumor cells to the applied therapy using genome editing and small interfering RNAs.

List of most topical published articles of the Laboratory of Molecular Biology for the recent five years:

1. Kostyuk S.V., Tabakov V.J., Chestkov V.V., Konkova M.S., Glebova K.V., Baydakova G.V., Ershova E.S., Izhevskaya V.L., Baranova A., Veiko N.N. Oxidized DNA induces an adaptive response in human fibroblasts // Mutat Res. – 2013. – V.747-748. – P.6-18.
2. Kostyuk S.V., Konkova M.S., Ershova E.S., Alekseeva A.J., Smirnova T.D., Stukalov S.V., Kozhina E.A., Shilova N.V., Zolotukhina T.V., Markova Z.G., Izhevskaya V.L., Baranova A., Veiko N.N. An exposure to the oxidized DNA enhances both instability of genome and survival in cancer cells. // PLoS One. – 2013. – V.8. – №10. – P.e77469.
3. Ermakov A.V., Konkova M.S., Kostyuk S.V., Izevskaya V.L., Baranova A., Veiko N.N. Oxidized extracellular DNA as a stress signal in human cells. Oxid. Med. Cell Longev. – 2013. – V.2013. – P. 649747.
4. Kostyuk S., Smirnova T., Kameneva L., Porokhovnik L., Speranskij A., Ershova E., Stukalov S., Izevskaya V., Veiko N. GC-Rich Extracellular DNA Induces Oxidative Stress, Double-Strand DNA Breaks, and DNA Damage Response in Human Adipose-Derived Mesenchymal Stem Cells // Oxid Med Cell Longev. – 2015. – V.2015. – P.782123.
5. Korzeneva I.B., Kostuyk S.V., Ershova L.S., Osipov A.N., Zhuravleva V.F., Pankratova G.V., Porokhovnik L.N., Veiko N.N. Human circulating plasma DNA significantly decreases while lymphocyte DNA damage increases under chronic occupational exposure to low-dose gamma-neutron and tritium β-radiation // Mutat Res. – 2015. – V.779. – P.1-15.
6. Glebova K., Veiko N., Kostyuk S., Izhevskaya V., Baranova A. Oxidized extracellular DNA as a stress signal that may modify response to anticancer therapy. // Cancer Lett. – 2015. – V.356. – №1. – P.22-33.
7. Korzeneva I.B., Kostuyk S.V., Ershova E.S., Skorodumova E.N.; Zhuravleva V.V.; Pankratova G.V.; Volkova I.V.; Stepanova E.V.; Porokhovnik L.N.; Veiko N.N. Human circulating ribosomal DNA content significantly increases while circulating satellit III (1q12) content decreases under chronic occupational exposure to low-dose gamma-neutron and tritium βeta- radiation // Mutation Research – Fundamental and Molecular Mechanisms of Mutagenesis. – 2016. – V.791-792 – P.49-60.
8. Sergeeva V.A., Kostyuk S.V., Ershova E.S., Malinovskaya E.M., Smirnova T.D., Kameneva L.V., Veiko N.N. GC-rich DNA fragments and oxidized cell-free DNA have different effect on NF-kB and NRF2 signaling in MSC. // Adv Exp Med Biol. – 2016. – V.924. – P.109-112
9. Alekseeva A. Y., Kameneva L.V., Kostyuk S.V., Veiko N.N. Multiple ways of cfDNA reception and following ROS production in endothelial cells // Adv Exp Med Biol. – 2016. – V.924. – P.127-131.
10. Ershova E.S., Sergeeva V.A., Chausheva A.I., Zheglo D.G., Nikitina V.A., Smirnova T.D., Kameneva L.V., Porokhovnik L.N., Kutsev S.I., Troshin P.A., Voronov I.I., Khakina E.A., Veiko N.N., Kostyuk S.V.   Toxic and DNA damaging effects of a functionalized fullerene in human embryonic lung fibroblasts // Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis. – 2016. – V.805. – Р.46-57.
11. Ershova E.S., Sergeeva V.A., Tabakov V.J., Kameneva L.A., Porokhovnik L.N., Voronov I.I., Khakina E.A., Troshin P.A., Kutsev S.I., Veiko N.N., Kostyuk S.V. Functionalized fullerene increases NF-kB activity and blocks genotoxic effect of oxidative stress in serum-starving human embryo lung diploid fibroblasts // Oxidative Medicine and Cellular Longevity. – 2016. – V.2016. – P.9895245.
12. Sergeeva V.A., Ershova E.S., Veiko N.N., Malinovskaya E.M., Kalyanov A.A., Kameneva L.V., Stukalov S.V., Dolgikh O.A., Konkova M.S., Ermakov A.V., Veiko V.P., Izhevskaya V.L., Kutsev S.I., Kostyuk S.V. Low-dose ionizing radiation affects mesenchymal stem cells via extracellular oxidized cell-free DNA: a possible mediator of bystander effect and adaptive response // Oxidative Medicine and Cellular Longevity. – 2017. – V.2017. – P. 5585687.
13. Ershova E.S., Jestkova E.M., Chestkov I.V., Porokhovnik L.N., Izevskaya V.L., Kutsev S.I., Veiko N.N., Shmarina G., Dolgikh O., Kostyuk S.V. Quantification of cell-free DNA in blood plasma and DNA damage degree in lymphocytes to evaluate dysregulation of apoptosis in schizophrenia patients // Journal of Psychiatric Research – 2017. – V.87. – P.15-22
14. Leshanskaya L.I., Klimovich I.V., Dashitsyrenova D.D., Frolova L.A., Ershova E.S., Sergeeva V.A., Tabakov V.Yu., Kostyuk S.V., Lyssenko K.A., Troshin P.A. Dibenzoindigo: a nature-inspired biocompatible semiconductor material for sustainable organic electronics. Advanced Optical Materials. - 2017. – №.9. – P1601033-1601040.
15. Kostyuk S.V., Porokhovnik L.N., Ershova E.S., Malinovskaya E.M., Konkova M.S., Kameneva L.V., Dolgikh O.A., Veiko V.P., Pisarev V.M., Martynov A.V., Sergeeva V.A., Kaliyanov A.A., Filev A.D., Abramova M.S., Kutsev S.I., Izhevskaya V.L., Veiko N.N. Changes of KEAP1/NRF2 and IKB/NF-kB expression levels induced by cell-free DNA in different cell types // Oxidative Medicine and Cellular Longevity. – 2018. – V.2018. – P. 1052413.
16. Chestkov I.V., Jestkova E.M., Ershova E.S., Golimbet V.E., Lezheiko T.V., Kolesina N.Y., Porokhovnik L.N., Lyapunova N.A., Izhevskaya V.L., Kutsev S.I., Veiko N.N., Kostyuk S.V. Abundance of ribosomal RNA gene copies in the genomes of chizophrenia patients // Schizophrenia Research. – 2018. – №197. – P.305-314.
17. Chestkov I.V., Jestkova E.M., Ershova E.S., Golimbet V.G., Lezheiko T.V., Kolesina N.Yu., Dolgikh O.A., Izhevskaya V.L., Kostyuk G.P., Kutsev S.I., Veiko N.N., Kostyuk S.V. ROS-induced DNA damage associates with abundance of mitochondrial DNA in white blood cells of the untreated schizophrenic patients // Oxidative Medicine and Cellular Longevity. – 2018. – V.2018. – P. 1-7.
18. Kostyuk S.V., Kvasha M.A., Khrabrova D.A., Kirsanova O.V., Ershova E.S., Malinovskaya E.M., Veiko N.N., Ivanov A.A., Koval V.S., Zhuze A.L., Tashlitsky V.H., Umriukhin P.E., Kutsev S.I., Gromova E.S. Symmetric dimeric bisbenzimidazoles DBP(n) reduce methylation of RARB and PTEN while significantly increase methylation of rRNA genes in MCF-7 cancer cells // PLoS One. – 2018. – V.13. – №1. – P. e0189826.
19. Glebova K.V., Veiko N.N., Nikonov A.A., Porokhovnik L.N., Kostuyk S.V. Cell-free DNA as a biomarker in stroke: Current status, problems and perspectives // Crit Rev Clin Lab Sci. – 2018. – V.55. – №1. – P.55-70.
20. Chestkov I.V., Jestkova E.M., Ershova E.S., Golimbet V.G., Lezheiko T.V., Kolesina N.Y., Dolgikh O.A., Izhevskaya V.L., Kostyuk G.P., Kutsev S.I., Veiko N.N., Kostyuk S.V. ROS-induced DNA damage associates with abundance of mitochondrial DNA in white blood cells of the untreated schizophrenic patients // Oxidative Medicine and Cellular Longevity. – 2018. – V.2018. – P. e.8587475.
21. Malinovskaya E.M., Ershova E.S., Golimbet V.E., Porokhovnik L.N., Lyapunova N.A., Kutsev S.I., Veiko N.N., Kostyuk S.V. Copy number of human ribosomal genes with aging: unchanged mean, but narrowed range and decreased variance in elderly group // Frontiers in Genetics / Genetics of aging. – 2018. – V. 9. – № 306.

1. Шубаева Наталья Олеговна - диссертация «Молекулярно-генетические характеристики рибосомных генов и процессы гибели клеток у больных ревматоидным артритом» (кандидат биологических наук, специальность 03.00.26 «Молекулярная генетика», 2004).
2. Костюк Светлана Викторовна - диссертация «Фрагменты рибосомных генов человека в составе внеклеточной ДНК: факторы стресс-сигнализации» (кандидат биологических наук, специальность 03.00.15 «Генетика», 2007).
3. Малиновская Елена Михайловна - диссертация «Изменения комплекса рибосомных генов человека в процессе естественного и репликативного старения» (кандидат биологических наук, специальность 03.00.15 «Генетика», 2008).
4. Конькова Марина Сергеевна - диссертация «Внеклеточная ДНК – фактор сигнализации при радиационном эффекте свидетеля» (кандидат биологических наук, специальность 03.02.07 «Генетика», 2011).
5. Алексеева Анна Юрьевна – диссертация «Влияние внеклеточной ДНК на функциональную активность клеток эндотелия»(кандидат биологических наук, специальность 03.02.07 «Генетика», 2013).
6. Костюк Светлана Викторовна - диссертация «Роль внеклеточной ДНК в функциональной активности генома человека» (доктор биологических наук, специальность 03.02.07 «Генетика», 2014).
7. Честков Илья Валерьевич - диссертация «Исследование вариабельности числа копий рРНК-кодирующих генов и митохондриальной ДНК в геноме пациентов с шизофренией», (кандидат биологических наук, специальность 03.02.07 «Генетика», 2018).
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10. Кальянов А.А.  - диссертация «Исследование молекулярного механизма действия малых доз радиации на функциональную активность генов стволовых клеток человека» (кандидат биологических наук, специальность 03.02.07 «Генетика», 2021).

1. Коммерсантъ наука. Сколько человеку нужно рибосом для долгой жизни. Костюк С.В.
2. «Дни без турникетов» в рамках фестиваля науки NAUKA 0+. Костюк С.В., Малиновская Е.М., Мартынов А.В., Кальянов А.А.
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4. Выявлены новые грани биологической активности неорганических энзимов. М.М.Созарукова, Е.В.Проскурнина, А.Л.Калинкин, В.К.Иванов.
5. Новые грани биологической активности неорганических энзимов. М.М.Созарукова, Е.В.Проскурнина, А.Л.Калинкин, В.К.Иванов.
6. У оксида церия обнаружили два новых типа ферментоподобной активности. М.М.Созарукова, Е.В.Проскурнина, А.Л.Калинкин, В.К.Иванов.