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RNA structural analysis of the MYC mRNA reveals conserved motifs that affect gene expression
Collin A O'Leary1, Ryan J Andrews1, Van S Tompkins1
1Roy J. Carver Department of Biophysics, Biochemistry and Molecular Biology, Iowa State University, Ames, IA, United States of America.
Abstract:
The MYC gene encodes a human transcription factor and proto-oncogene that is dysregulated in over half of all known cancers. To better understand potential post-transcriptional regulatory features affecting MYC expression, we analyzed secondary structures in the MYC mRNA using a program that is optimized for finding small locally-folded motifs with a high propensity for function. This was accomplished by calculating folding metrics across the MYC sequence using a sliding analysis window and generating unique consensus base pairing models weighted by their lower-than-random predicted folding energy. A series of 30 motifs were identified, primarily in the 5' and 3' untranslated regions, which show evidence of structural conservation and compensating mutations across vertebrate MYC homologs. This analysis was able to recapitulate known elements found within an internal ribosomal entry site, as well as discover a novel element in the 3' UTR that is unusually stable and conserved. This novel motif was shown to affect MYC expression, potentially via the modulation of miRNA target accessibility or other trans-regulatory factors. In addition to providing basic insights into mechanisms that regulate MYC expression, this study provides numerous, potentially druggable RNA targets for the MYC gene, which is considered "undruggable" at the protein level.
Insights
Researchers identified functional RNA structures in the MYC mRNA, revealing novel regulatory mechanisms and potential therapeutic targets. These findings offer new avenues for targeting the MYC gene, a key player in numerous cancers.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- The MYC gene is a proto-oncogene frequently dysregulated in over 50% of human cancers.
- Understanding post-transcriptional regulation of MYC is crucial for developing novel cancer therapies.
- MYC's protein product is considered "undruggable," necessitating alternative therapeutic strategies.
Purpose of the Study:
- To investigate secondary RNA structures in MYC mRNA for potential regulatory functions.
- To identify novel RNA motifs that influence MYC gene expression.
- To explore druggable RNA targets within the MYC gene.
Main Methods:
- Utilized a computational program optimized for identifying functional, locally-folded RNA motifs in mRNA sequences.
- Performed sliding window analysis to calculate folding metrics and generate consensus base pairing models.
- Assessed structural conservation and compensating mutations across vertebrate MYC homologs.
Main Results:
- Identified 30 functional RNA motifs, predominantly in the 5' and 3' untranslated regions (UTRs) of MYC mRNA.
- Confirmed known elements within an internal ribosomal entry site (IRES).
- Discovered a novel, highly stable, and conserved motif in the 3' UTR that impacts MYC expression, potentially by modulating miRNA accessibility.
Conclusions:
- MYC mRNA possesses conserved secondary structures that play a role in its post-transcriptional regulation.
- A novel 3' UTR motif represents a significant finding with implications for MYC expression control.
- This study identifies potential RNA-based therapeutic targets for MYC-driven cancers, offering a new strategy against a previously undruggable target.
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