Email this article 
Relationship between methylation of promoters of apoptosis genes in blood lymphocytes with the frequency of chromosomal aberrations and the dose of radiation
- Authors: Isubakova D.S.1, Tsymbal O.S.1, Litviakov N.V.1,2, Milto I.V.1,3, Takhauov R.M.1,3
-
Affiliations:
- Seversk Biophysical Research Center of the Federal Medical-Biological Agency
- Tomsk National Research Medical Center, Russian Academy of Science
- Siberian State Medical University
- Issue: Vol 20, No 4 (2022)
- Pages: 315-323
- Section: Genetic toxicology
- URL: https://journals.eco-vector.com/ecolgenet/article/view/109119
- DOI: https://doi.org/10.17816/ecogen109119
- ID: 109119
Cite item
Open Access
Access granted
Abstract
BACKGROUND: Impaired apoptosis can have serious consequences: the accumulation of mutant cells, the development of teratogenic effects and malignant neoplasms. In this regard, the study of the mechanisms of changes in the activity of apoptosis due to methylation under the influence of long-term irradiation is urgent.
AIM: The study of the degree of methylation of gene promoters involved in the induction of apoptosis in the personnel of the Siberian Chemical Plant, exposed to long-term technogenic irradiation of ionizing radiation in the course of their professional activities.
MATERIALS AND METHODS: The study was performed on peripheral blood samples of employees of the Siberian Chemical Plant, with a total dose of external exposure from 100 to 300 mSv. Chromosomal aberrations were detected by standard karyotyping of cultured blood lymphocytes. The degree of gene promoters methylation was determined using MethylScreen technology.
RESULTS: The degree of gene methylation BIRC2, CASP3, CASP9, CIDEB, CRADD, DAPK1, DFFA, FADD, GADD45A, LTBR, TNFRSF21, TNFRSF25 ranges from 0.31 to 41.75%. A strong negative correlation was found between the degree of methylation of GADD45A (r = –0.7364, р = 0.009) with an increased frequency of aberrant cells, moderate negative correlation GADD45A (r = –0.6347, р = 0.035) with an increased frequency of dicentric chromosomes, moderate negative correlation CASP9 (r = –0.6606, р = 0.026), and strong negative correlation CIDEB (r = –0.7982, р = 0.003) with an increased frequency of chromatid fragments. A moderate negative correlation of the methylation degree of CASP9 (r = –0.6636, р = 0.026), and CIDEB (r = –0.6636, р = 0.026) with the total dose of external exposure was shown.
CONCLUSIONS: The decrease in the level of apoptosis at doses of 100–300 mSv can be explained by the achievement of the demethylation threshold for the promoters of the proapoptotic genes GADD45A, CASP9, CIDEB. This once again testifies in favor of the threshold model of the dependence of the radiation effect on the radiation dose.
Full Text
About the authors
Daria S. Isubakova
Seversk Biophysical Research Center of the Federal Medical-Biological Agency
Author for correspondence.
Email: isubakova.daria@yandex.ru
ORCID iD: 0000-0002-5032-9096
SPIN-code: 5196-7471
Research Associate, Department of Molecular and Cellular Radiobiology
Russian Federation, SeverskOlga S. Tsymbal
Seversk Biophysical Research Center of the Federal Medical-Biological Agency
Email: olga-tsymbal@mail.ru
ORCID iD: 0000-0002-2311-0451
SPIN-code: 6194-6434
Research Associate, Department of Molecular and Cellular Radiobiology
Russian Federation, SeverskNikolai V. Litviakov
Seversk Biophysical Research Center of the Federal Medical-Biological Agency; Tomsk National Research Medical Center, Russian Academy of Science
Email: nvlitv72@yandex.ru
ORCID iD: 0000-0002-0714-8927
SPIN-code: 2546-0181
Dr. Sci. (Biol.), Leading Research Associate, Department of Molecular and Cellular Radiobiology
Russian Federation, Seversk; TomskIvan V. Milto
Seversk Biophysical Research Center of the Federal Medical-Biological Agency; Siberian State Medical University
Email: milto_bio@mail.ru
ORCID iD: 0000-0002-9764-4392
SPIN-code: 4919-2033
Dr. Sci. (Biol.), Assistant Professor, Department Head, Department of Molecular and Cellular Radiobiology
Russian Federation, Seversk; TomskRavil M. Takhauov
Seversk Biophysical Research Center of the Federal Medical-Biological Agency; Siberian State Medical University
Email: niirm2007@yandex.ru
ORCID iD: 0000-0002-1994-957X
SPIN-code: 5254-2461
Dr. Sci. (Med.), Professor, Director
Russian Federation, Seversk; TomskReferences
- Goodhead DT. Initial events in the cellular effects of ionizing radiations: clustered damage in DNA. Int J Radiat Biol. 1994;65(1):7–17. doi: 10.1080/09553009414550021
- Pendina AA, Grinkevich VV, Kuznetsova TV, Baranov VS. DNA metylation as one of the main mechanisms of gene activity regulation. Ecological genetics. 2004;2(1):27–37. (In Russ.) doi: 10.17816/ecogen2127-37
- Kozlov VA. Methylation of cellular DNA and pathology of the organism. Medical Immunology (Russia). 2008;10(4–5):307–318. (In Russ.) doi: 10.15789/1563-0625-2008-4-5-307-318
- Kuz’mina NS, Myazin AE, Lapteva NSh, Rubanovich AV. Izuchenie aberrantnogo metilirovaniya v leikotsitakh krovi likvidatorov avarii na CHaEhS. Radiation biology. Radioecology. 2014;54(2):127–139. (In Russ.) doi: 10.7868/S0869803114020064
- Kuzmina NS, Lapteva NSh, Rusinova GG, et al. Dose dependence of hypermethylation of gene promoters in blood leukocytesin humans occupationally exposed to external γ-radiation. Radiation biology. Radioecology. 2018;58(6):581–588. (In Russ.) doi: 10.1134/S0869803118060073
- Kim J-G, Bae J-H, Kim J-A, et al. Combination effect of epigenetic regulation and ionizing radiation in colorectal cancer cells. PLoS One. 2014;9(8): e105405. doi: 10.1371/journal.pone.0105405
- Takhauov RM, Karpov AB, Zerenkov AG, et al. Mediko-dozimetricheskii registr personala Sibirskogo khimicheskogo kombinata — baza dlya otsenki ehffektov khronicheskogo oblucheniya. Radiation biology. Radioecology. 2015;55(5):467–473. (In Russ.) doi: 10.7868/S0869803115050124
- Erdtmann L, Franck N, Lerat H, et al. The hepatitis C virus NS2 protein is an inhibitor of CIDE-B-induced apoptosis. J Biol Chem. 2003;278(20):18256–18264. doi: 10.1074/jbc.M209732200
- Cai H, Yao W, Li L, et al. Cell-death-inducing DFFA-like effector B contributes to the assembly of hepatitis C virus (HCV) particles and interacts with HCV NS5A. Sci Rep. 2016;6:27778. doi: 10.1038/srep27778
- Yu M, Wang H, Zhao J, et al. Expression of CIDE proteins in clear cell renal cell carcinoma and their prognostic significance. Mol Cell Biochem. 2013;378(1):145–151. doi: 10.1007/s11010-013-1605-y
- Fialkova V, Vidomanova E, Balharek T, et al. DNA methylation as mechanism of apoptotic resistance development in endometrial cancer patients. Gen Physiol Biophys. 2017;36(5):521–529. doi: 10.4149/gpb_2017032
- Shalini S, Dorstyn L, Dawar S, Kumar S. Old, new and emerging functions of caspases. Cell Death Differ. 2015;22:526–539. doi: 10.1038/cdd.2014.216
- Vasin MV, Ushakov IB. Potential ways of increase in bogy resistance to damaging actionof ionizing radiation with the aids of radiomitigators. Uspekhi sovremennoi biologii. 2019;139(3):235–253. (In Russ.) doi: 10.1134/S0042132419030098
- Zhang Y, Dimtchev A, Dritschilo A, Jung M. Ionizing Radiation-induced Apoptosis in Ataxia-Telangiectasia Fibroblasts: Roles of caspase-9 and cellular inhibitor of apoptosis protein-1. J Biol Chem. 2001;276(31):28842–28848. doi: 10.1074/jbc.M010525200
- Andollo N, Boyano MD, Andrade R, et al. Structural and functional preservation of specific sequences of DNA and mRNA in apoptotic bodies from ES cells. Apoptosis. 2005;10(2):417–428. doi: 10.1007/s10495-005-0815-5
- Tamura RE, de Vasconcellos JF, Sarkar D, et al. GADD45 proteins: central players in tumorigenesis. Curr Mol Med. 2012;12(5):634–651. doi: 10.2174/156652412800619978
- Liebermann DA, Tront JS, Sha X, et al. GADD45 stress sensors in malignancy and leukemia. Crit Rev Oncog. 2011;16(1–2):129–140. doi: 10.1615/critrevoncog.v16.i1-2.120
- Yang Z, Song L, Huang C. GADD45 proteins as critical signal transducers linking NF-kappaB to MAPK cascades. Cancer Drug Targets. 2009;9(8):915–30. doi: 10.2174/156800909790192383
- Liebermann DA, Hoffman B. GADD45 in the response of hematopoietic cells to genotoxic stress. Blood Cells Mol Dis. 2007;39(3): 329–335. doi: 10.1016/j.bcmd.2007.06.006
- Gupta M, Gupta SK, Hoffman B, Liebermann DA. GADD45a and GADD45b protect hematopoietic cells from UV-induced apoptosis via distinct signaling pathways, including p38 activation and JNK inhibition. J Biol Chem. 2006;281(26):17552–17558. doi: 10.1074/jbc.M600950200
- Gupta M, Gupta SK, Balliet AG, et al. Hematopoietic cells from GADD45a- and GADD45b-deficient mice are sensitized to genotoxic-stress-induced apoptosis. Oncogene. 2005;24(48):7170–7179. doi: 10.1038/sj.onc.1208847
- Barreto G, Schäfer A, Marhold J, et al. Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation. Nature. 2007;445:671–675. doi: 10.1038/nature05515
- Fornace AJ Jr, Alamo I Jr, Hollander MC. DNA damage-inducible transcripts in mammalian cells. PNAS. 1988;85(23):8800–8804. doi: 10.1073/pnas.85.23.8800
- Hollander MC, Alamo I, Jackman J, et al. Analysis of the mammalian gadd45 gene and its response to DNA damage. J Biol Chem. 1993;268(32):24385–24393. doi: 10.1016/S0021-9258(20)80537-7
- Shaposhnikov MV, Plyusnina EN, Plyusnin SN, et al. Analysis of gene expression patterns as a method for detecting low doses of ionizing radiation, formaldehyde and dioxins. Theoretical and Applied Ecology. 2013;(2):25–33. (In Russ.) doi: 10.25750/1995-4301-2013-2-025-033
- Goldberg Z, Schwietert CW, Lehner B, et al. Effects of low-dose ionizing radiation on gene expression in human skin biopsies. Int J Radiat Oncol Biol Phys. 2004;58(2):567–574. doi: 10.1016/j.ijrobp.2003.09.033
- Litvyakov NV, Takhauov RM, Ageeva AM, et al. Caspase-3 activity of blood lymphocytes in radiation exposed persons. Medical Radiology and Radiation Safety. 2009;54(6):41–48. (In Russ.)
Supplementary files
