G-quadruplex located in the 5'UTR of the BAG-1 mRNA affects both its cap-dependent and cap-independent translation through global secondary structure maintenance.

Abstract

The anti-apoptotic BAG-1 protein isoforms are known to be overexpressed in colorectal tumors and are considered to be potential therapeutic targets. The isoforms are derived from alternative translation initiations occuring at four in-frame start codons of a single mRNA transcript. Its 5'UTR also contains an internal ribosome entry site (IRES) regulating the cap-independent translation of the transcript. An RNA G-quadruplex (rG4) is located at the 5'end of the BAG-1 5'UTR, upstream of the known cis-regulatory elements. Herein, we observed that the expression of BAG-1 isoforms is post-transcriptionally regulated in colorectal cancer cells and tumors, and that stabilisation of the rG4 by small molecules ligands reduces the expression of endogenous BAG-1 isoforms. We demonstrated a critical role for the rG4 in the control of both cap-dependent and independent translation of the BAG-1 mRNA in colorectal cancer cells. Additionally, we found an upstream ORF that also represses BAG-1 mRNA translation. The structural probing of the complete 5'UTR showed that the rG4 acts as a steric block which controls the initiation of translation at each start codon of the transcript and also maintains the global 5'UTR secondary structure required for IRES-dependent translation.

• Authors: Rachel Jodoin, Julie C Carrier, Nathalie Rivard, Martin Bisaillon, Jean-Pierre Perreault
• Journal: Nucleic acids research (Nucleic Acids Res) Vol. 47 Issue 19 Pg. 10247-10266 (11 04 2019) ISSN: 1362-4962 [Electronic] England
• PMID: 31504805 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.

Chemical References

• 5' Untranslated Regions
• BCL2-associated athanogene 1 protein
• Codon, Initiator
• DNA-Binding Proteins
• Internal Ribosome Entry Sites
• Ligands
• Protein Isoforms
• RNA Cap-Binding Proteins
• RNA, Messenger
• Transcription Factors

Topics

• 5' Untranslated Regions (genetics)
• Apoptosis (genetics)
• Codon, Initiator (genetics)
• DNA-Binding Proteins (chemistry, genetics)
• G-Quadruplexes
• Gene Expression Regulation (genetics)
• Humans
• Internal Ribosome Entry Sites (genetics)
• Ligands
• Peptide Chain Initiation, Translational (genetics)
• Protein Biosynthesis
• Protein Isoforms (chemistry, genetics)
• Protein Structure, Secondary
• RNA Cap-Binding Proteins (genetics)
• RNA, Messenger (genetics)
• Regulatory Sequences, Nucleic Acid
• Transcription Factors (chemistry, genetics)