Analyses of human cancer driver genes uncovers evolutionarily conserved RNA structural elements involved in
Van S Tompkins1, Warren B Rouse1, Collin A O'Leary1
1Roy J. Carver Department of Biophysics, Biochemistry and Molecular Biology, Iowa State University, Ames, IA, United States of America.
Abstract:
Experimental breakthroughs have provided unprecedented insights into the genes involved in cancer. The identification of such cancer driver genes is a major step in gaining a fuller understanding of oncogenesis and provides novel lists of potential therapeutic targets. A key area that requires additional study is the posttranscriptional control mechanisms at work in cancer driver genes. This is important not only for basic insights into the biology of cancer, but also to advance new therapeutic modalities that target RNA-an emerging field with great promise toward the treatment of various cancers. In the current study we performed an in silico analysis on the transcripts associated with 800 cancer driver genes (10,390 unique transcripts) that identified 179,190 secondary structural motifs with evidence of evolutionarily ordered structures with unusual thermodynamic stability. Narrowing to one transcript per gene, 35,426 predicted structures were subjected to phylogenetic comparisons of sequence and structural conservation. This identified 7,001 RNA secondary structures embedded in transcripts with evidence of covariation between paired sites, supporting structure models and suggesting functional significance. A select set of seven structures were tested in vitro for their ability to regulate gene expression; all were found to have significant effects. These results indicate potentially widespread roles for RNA structure in posttranscriptional control of human cancer driver genes.
Insights
Researchers discovered that RNA secondary structures within cancer driver genes significantly impact gene expression. These stable, evolutionarily conserved RNA structures offer promising new therapeutic targets for cancer treatment.
Area of Science:
- Genomics
- Molecular Biology
- Bioinformatics
Background:
- Cancer driver genes are crucial for understanding oncogenesis and developing therapies.
- Posttranscriptional control mechanisms of cancer driver genes require further investigation.
- Targeting RNA represents a promising frontier in cancer therapeutics.
Purpose of the Study:
- To investigate the role of RNA secondary structures in the posttranscriptional control of human cancer driver genes.
- To identify evolutionarily conserved and functionally significant RNA structures within cancer-associated transcripts.
Main Methods:
- In silico analysis of transcripts from 800 cancer driver genes (10,390 unique transcripts).
- Identification and thermodynamic stability assessment of RNA secondary structural motifs.
- Phylogenetic comparison of sequence and structural conservation for predicted RNA structures.
- In vitro validation of selected RNA structures for gene expression regulation.
Main Results:
- Identified 179,190 secondary structural motifs with unusual thermodynamic stability.
- Discovered 7,001 RNA secondary structures showing evidence of covariation, suggesting functional roles.
- Seven selected RNA structures demonstrated significant gene expression regulatory effects in vitro.
Conclusions:
- RNA secondary structures play a potentially widespread role in the posttranscriptional regulation of human cancer driver genes.
- These findings highlight RNA structures as novel targets for cancer therapy.
- Further research into RNA structure-function relationships in cancer is warranted.
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