Albeit most studies demonstrate the inhibitory role of G-quadruplex in the 5' Untranslated Region (5' UTR), our previous report depicted its completely contrasting activating role in the 5' UTR of transforming growth factor β2 (TGFβ2) mRNA. Therefore, we screened the 5' UTR of TGFβ2 manually and identified a second putative G-quadruplex sequence. Our in vitro experiments encompassing CD and UV spectroscopy confirmed the ability of this sequence to form a G-quadruplex and in cellulo studies further indicated its activating role in modulation of TGFβ2 gene expression. Our study suggests that these two 5' UTR G-quadruplexes most probably operate additively to substantially increase gene expression of TGFβ2. Neither of the two G-quadruplex alone is sufficient enough to drastically augment protein production. Both G-quadruplexes are essential for increasing protein output. To the best of our knowledge, our study is the first report showcasing the combinatorial role of two G-quadruplexes in the 5' UTR of an mRNA.
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