Inhibition of telomerase activity by splice-switching oligonucleotides targeting the mRNA of the telomerase catalytic subunit affects proliferation of human CD4+ T lymphocytes

• Published in: Biochemical and biophysical research communications Vol. 509; no. 3; pp. 790 - 796
• Main Authors: Zhdanov, Dmitry D., Plyasova, Anna A., Gladilina, Yulia A., Pokrovsky, Vadim S., Grishin, Dmitry V., Grachev, Vladimir A., Orlova, Valentina S., Pokrovskaya, Marina V., Alexandrova, Svetlana S., Lobaeva, Tatiana A., Sokolov, Nikolay N.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.02.2019
• Subjects: Alternative splicing; Lymphocytes; Proliferation; Splice-switching oligonucleotides; Telomerase; Alternative splicing; EGPO; CFSE; TRAP; Proliferation; SSO; MFI; AS; AU; Splice-switching oligonucleotides; Lymphocytes; PE; Telomerase
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2018.12.186

Telomerase activity is regulated at the mRNA level by alternative splicing (AS) of its catalytic subunit hTERT. The aim of this study was to define the ability of splice-switching oligonucleotides (SSOs) that pair with hTERT pre-mRNA to induce AS and inhibit telomerase activity in human CD4+ T lymphocytes. SSOs that blocked the binding of a single splicing regulatory protein, SRp20 or SRp40, to its site within intron 8 of hTERT pre-mRNA demonstrated rather moderate capacities to induce AS and inhibit telomerase. However, a SSO that blocked the interaction of both SRp20 and SRp40 proteins with pre-mRNA was the most active. Cultivation of lymphocytes with spliced hTERT and inhibited telomerase resulted in the reduction of proliferative activity without significant induction of cell death. These results should facilitate further investigation of telomerase activity regulation, and antitelomerase SSOs could become promising agents for antiproliferative cell therapy. •Splice-switching oligonucleotides inhibit telomerase activity.•Blocking of SRp20 and SRp40 proteins induces alternative splicing of hTERT.•Telomerase activity inhibition affects proliferation of human lymphocytes.