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Eukaryotic mRNA translation is typically modulated by eukaryotic initiation factor 4E (eIF4E) binding to the 5'-m7G cap. However, under the hypoxic conditions within the cancer cell, eIF4E is segregated by 4E binding protein. Thus, cap-independent recruitment of the 40S ribosome to the 5' untranslated region (5' UTR) of the mRNA is required for tumorigenesis. Fibroblast growth factor 9 (FGF-9) is one such angiogenic growth factor upregulated in a cap-independent manner in breast and colorectal cancer cells. Previously, our lab has demonstrated that binding of death-associated factor 5 (DAP5), a eukaryotic initiation factor, to the FGF-9 5' UTR directly impacts cap-independent translational efficiency. However, the exact binding site of DAP5 within the 5' UTR is unknown. RNA secondary and tertiary structure within non-coding regions has been demonstrated to play a role in cap-independent translational efficiency; therefore, we hypothesized that specific structures act as eukaryotic initiation factor binding sites. Using SHAPE-sequencing data, we reveal that the 5' UTR of FGF-9 is highly structured and possesses a single-stranded region near the start codon. Through SHAPE footprinting and toeprinting experiments, we also demonstrate that DAP5 binds along a single face of the FGF-9 5' UTR and contacts the 3' single-stranded region. Our lab had previously reported that cap-independent translation of FGF-9 does not require a free 5' end, suggesting little to no ribosomal scanning for the start codon occurs. Our current data demonstrate that initiation factor binding is structurally-dependent and suggest that limited ribosomal scanning is due to DAP5-dependent restructuring of the 5' UTR to bring the start codon within striking distance of the 40S ribosome. We are currently examining whether cap-independent upregulation of other tumorigenic transcripts follows a similar pattern. © FASEB.


Amanda M Whittaker, Dixie J Goss. DAP5 Binding to the FGF-9 mRNA 5' UTR is Structurally-Dependent. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2022 May;36 Suppl 1

PMID: 35554027

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