Post-transcriptional Mechanisms in Endocrine Regulation by K.M.J. Menon PhD & Aaron Goldstrohm PhD

Author:K.M.J. Menon, PhD & Aaron Goldstrohm, PhD
Language: eng
Format: epub
Publisher: Springer International Publishing, Cham

3.4.2 RNA G-Quadruplex Structure

G-quadruplexes are guanine-rich regions of the mRNA that can fold up to form secondary structures organized in stacks of planar layers of guanine tetrad (or quartet) units. It is emerging that these elements have regulatory functions in different steps of RNA metabolism, including mRNA translation (Millevoi et al. 2012). G-quadruplexes are found in coding and non-coding mRNA. The majority of those that are located in 5′UTRs play an inhibitory role in cap-dependent translation (for example in Zic-1, ESR1, NRAS or MT3-MMP mRNA), probably through the recruitment of stabilizing proteins to prevent ribosome scanning (Bugaut and Balasubramanian 2012).

VEGF -A mRNA contains a 17 nucleotide-long element within the IRES -A site (nucleotides 774-790) that can fold into a two-G-quartet quadruplex structure. It is thought that this is important for IRES-A function since IRES-A activity was blocked by mutations that disrupted the intramolecular G-quadruplex structure (Morris et al. 2010). This finding is quite surprising since most naturally-occurring G-quadruplexes with the ability to regulate translation are at least three-G-quartet quadruplex structures while artificially engineered two-G-quartet quadruplexes like that found in VEGF-A have shown only a moderate stability (Bugaut and Balasubramanian 2012). Thus, it is important to establish whether the VEGF-A G-quadruplex contributes to IRES-A activation under stress conditions such as hypoxia , endoplasmic reticulum stress or ischemia, since this is when the IRESs are active and required for the initiation of translation. If this structure affects IRES-A activation under these conditions then G-quadruplex formation will be confirmed as yet another mechanism of VEGF-A regulation.

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