Cytoprotective Activity of Polyamines Is Associated with the Alternative Splicing of <i>RAD51A</i> Pre-mRNA in Normal Human CD4<sup>+</sup> T Lymphocytes
Physiological polyamines are ubiquitous polycations with pleiotropic biochemical activities, including regulation of gene expression and cell proliferation as well as modulation of cell signaling. They can also decrease DNA damage and promote cell survival. In the present study, we demonstrated that...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-02-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/3/1863 |
| _version_ | 1797487130511933440 |
|---|---|
| author | Yulia A. Gladilina Lylia Bey Abdullah Hilal Ekaterina V. Neborak Varvara G. Blinova Dmitry D. Zhdanov |
| author_facet | Yulia A. Gladilina Lylia Bey Abdullah Hilal Ekaterina V. Neborak Varvara G. Blinova Dmitry D. Zhdanov |
| author_sort | Yulia A. Gladilina |
| collection | DOAJ |
| description | Physiological polyamines are ubiquitous polycations with pleiotropic biochemical activities, including regulation of gene expression and cell proliferation as well as modulation of cell signaling. They can also decrease DNA damage and promote cell survival. In the present study, we demonstrated that polyamines have cytoprotective effects on normal human CD4<sup>+</sup> T lymphocytes but not on cancer Jurkat or K562 cells. Pretreatment of lymphocytes with polyamines resulted in a significant reduction in cells with DNA damage induced by doxorubicin, cisplatin, or irinotecan, leading to an increase in cell survival and viability. The induction of <i>RAD51A</i> expression was in response to DNA damage in both cancer and normal cells. However, in normal cells, putrescin pretreatment resulted in alternative splicing of <i>RAD51A</i> and the switch of the predominant expression from the splice variant with the deletion of exon 4 to the full-length variant. Induction of <i>RAD51A</i> alternative splicing by splice-switching oligonucleotides resulted in a decrease in DNA damage and cell protection against cisplatin-induced apoptosis. The results of this study suggest that the cytoprotective activity of polyamines is associated with the alternative splicing of <i>RAD51A</i> pre-mRNA in normal human CD4<sup>+</sup> T lymphocytes. The difference in the sensitivity of normal and cancer cells to polyamines may become the basis for the use of these compounds to protect normal lymphocytes during lymphoblastic chemotherapy. |
| first_indexed | 2024-03-09T23:44:07Z |
| format | Article |
| id | doaj.art-b915e6fdc02947d0a716a3db3ae32048 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T23:44:07Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-b915e6fdc02947d0a716a3db3ae320482023-11-23T16:47:52ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-02-01233186310.3390/ijms23031863Cytoprotective Activity of Polyamines Is Associated with the Alternative Splicing of <i>RAD51A</i> Pre-mRNA in Normal Human CD4<sup>+</sup> T LymphocytesYulia A. Gladilina0Lylia Bey1Abdullah Hilal2Ekaterina V. Neborak3Varvara G. Blinova4Dmitry D. Zhdanov5Institute of Biomedical Chemistry, Pogodinskaya St. 10/8, 119121 Moscow, RussiaDepartment of Biochemistry, Peoples’ Friendship University of Russia (RUDN University), Miklukho—Maklaya St. 6, 117198 Moscow, RussiaInstitute of Biomedical Chemistry, Pogodinskaya St. 10/8, 119121 Moscow, RussiaDepartment of Biochemistry, Peoples’ Friendship University of Russia (RUDN University), Miklukho—Maklaya St. 6, 117198 Moscow, RussiaInstitute of Biomedical Chemistry, Pogodinskaya St. 10/8, 119121 Moscow, RussiaInstitute of Biomedical Chemistry, Pogodinskaya St. 10/8, 119121 Moscow, RussiaPhysiological polyamines are ubiquitous polycations with pleiotropic biochemical activities, including regulation of gene expression and cell proliferation as well as modulation of cell signaling. They can also decrease DNA damage and promote cell survival. In the present study, we demonstrated that polyamines have cytoprotective effects on normal human CD4<sup>+</sup> T lymphocytes but not on cancer Jurkat or K562 cells. Pretreatment of lymphocytes with polyamines resulted in a significant reduction in cells with DNA damage induced by doxorubicin, cisplatin, or irinotecan, leading to an increase in cell survival and viability. The induction of <i>RAD51A</i> expression was in response to DNA damage in both cancer and normal cells. However, in normal cells, putrescin pretreatment resulted in alternative splicing of <i>RAD51A</i> and the switch of the predominant expression from the splice variant with the deletion of exon 4 to the full-length variant. Induction of <i>RAD51A</i> alternative splicing by splice-switching oligonucleotides resulted in a decrease in DNA damage and cell protection against cisplatin-induced apoptosis. The results of this study suggest that the cytoprotective activity of polyamines is associated with the alternative splicing of <i>RAD51A</i> pre-mRNA in normal human CD4<sup>+</sup> T lymphocytes. The difference in the sensitivity of normal and cancer cells to polyamines may become the basis for the use of these compounds to protect normal lymphocytes during lymphoblastic chemotherapy.https://www.mdpi.com/1422-0067/23/3/1863polyaminesalternative splicingDNA damagecytoprotectionapoptosis |
| spellingShingle | Yulia A. Gladilina Lylia Bey Abdullah Hilal Ekaterina V. Neborak Varvara G. Blinova Dmitry D. Zhdanov Cytoprotective Activity of Polyamines Is Associated with the Alternative Splicing of <i>RAD51A</i> Pre-mRNA in Normal Human CD4<sup>+</sup> T Lymphocytes International Journal of Molecular Sciences polyamines alternative splicing DNA damage cytoprotection apoptosis |
| title | Cytoprotective Activity of Polyamines Is Associated with the Alternative Splicing of <i>RAD51A</i> Pre-mRNA in Normal Human CD4<sup>+</sup> T Lymphocytes |
| title_full | Cytoprotective Activity of Polyamines Is Associated with the Alternative Splicing of <i>RAD51A</i> Pre-mRNA in Normal Human CD4<sup>+</sup> T Lymphocytes |
| title_fullStr | Cytoprotective Activity of Polyamines Is Associated with the Alternative Splicing of <i>RAD51A</i> Pre-mRNA in Normal Human CD4<sup>+</sup> T Lymphocytes |
| title_full_unstemmed | Cytoprotective Activity of Polyamines Is Associated with the Alternative Splicing of <i>RAD51A</i> Pre-mRNA in Normal Human CD4<sup>+</sup> T Lymphocytes |
| title_short | Cytoprotective Activity of Polyamines Is Associated with the Alternative Splicing of <i>RAD51A</i> Pre-mRNA in Normal Human CD4<sup>+</sup> T Lymphocytes |
| title_sort | cytoprotective activity of polyamines is associated with the alternative splicing of i rad51a i pre mrna in normal human cd4 sup sup t lymphocytes |
| topic | polyamines alternative splicing DNA damage cytoprotection apoptosis |
| url | https://www.mdpi.com/1422-0067/23/3/1863 |
| work_keys_str_mv | AT yuliaagladilina cytoprotectiveactivityofpolyaminesisassociatedwiththealternativesplicingofirad51aipremrnainnormalhumancd4supsuptlymphocytes AT lyliabey cytoprotectiveactivityofpolyaminesisassociatedwiththealternativesplicingofirad51aipremrnainnormalhumancd4supsuptlymphocytes AT abdullahhilal cytoprotectiveactivityofpolyaminesisassociatedwiththealternativesplicingofirad51aipremrnainnormalhumancd4supsuptlymphocytes AT ekaterinavneborak cytoprotectiveactivityofpolyaminesisassociatedwiththealternativesplicingofirad51aipremrnainnormalhumancd4supsuptlymphocytes AT varvaragblinova cytoprotectiveactivityofpolyaminesisassociatedwiththealternativesplicingofirad51aipremrnainnormalhumancd4supsuptlymphocytes AT dmitrydzhdanov cytoprotectiveactivityofpolyaminesisassociatedwiththealternativesplicingofirad51aipremrnainnormalhumancd4supsuptlymphocytes |