When the ribosome encounters such a stop codon, translation typically ends. However, in some cases, a near-cognate tRNA is incorporated, enabling the addition of a short C-terminal extension. This phenomenon, known as stop codon readthrough (SCR), has been observed to serve important regulatory functions, particularly in certain viruses, as well as in Drosophila and mammals. Despite its significance, mRNA translation termination remains underexplored, and our current understanding of the underlying mechanisms is limited. Additionally, nonsense mutations occur in approximately 11% of patients with genetic diseases. Therefore, understanding the fundamental biology behind SCR, might uncover possible therapies for these patients.
Various factors, including cis-elements, trans-acting factors, and the cellular environment, can all influence readthrough, highlighting the complexity of this process. Consequently, elucidating the principles of programmed readthrough is critical for developing new therapeutic approaches for patients with nonsense mutations.
Previous work has shown that, in Drosophila melanogaster, the drifter (dfr) gene produces two distinct isoforms via SCR. Dfr gene has been shown to be important for development in Drosophila melanogaster. These isoforms differ by tissue type, indicating a developmental regulation of SCR. Specifically, our findings suggest that cis-elements, such as the leakage of the stop codon itself and RNA hairpin structures immediately downstream, are necessary for SCR. At the same time, trans-acting factors such as microRNAs also seem to play a significant role in the regulation of this process.
Therefore, my overall aim is to perform genome-wide screening to search for conservation candidates in Drosophila species of other genes with SCR that are regulated by the RNA hairpin and microRNA sites near the stop codon.
1. Which genes have conserved RNA hairpins at their 3’UTR near the stop codon?
2. Which genes have microRNA sites at their 3’UTR near the stop codon?
3. What common features can be found in these genes?