Journal
NUCLEIC ACIDS RESEARCH
Volume 50, Issue 17, Pages 9689-9704Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkac739
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Funding
- National Institutes of Health [R01 HL111527, R35 GM140844, F30 HL146174]
- ACS postdoctoral fellowship [y130845-RSG-17-114-01-RMC]
- K22 transition award [K22 CA262349]
- Alpha1 Foundation
- NIH
- Common Fund of the Office of the Director of the National Institutes of Health
- NCI
- NHGRI
- NHLBI
- NIDA
- NIMH
- NINDS
- MD-PhD training fellowship [F30 HL146174]
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SERPINA1 mRNAs encode the protease inhibitor alpha-1-antitrypsin and are regulated through post-transcriptional mechanisms. Alpha-1-antitrypsin deficiency is associated with COPD and liver cirrhosis, and specific variants in the 5'-UTR are linked to COPD. The structure of the NM_000295.4 5'-UTR plays a role in translation, with disruptions to specific helices affecting translation efficiency. This study shows that the complex folding of the NM_000295.4 5'-UTR promotes accessibility at the translation initiation site, rather than inhibiting translation as previously thought.
SERPINA1 mRNAs encode the protease inhibitor alpha-1-antitrypsin and are regulated through post-transcriptional mechanisms. alpha-1-antitrypsin deficiency leads to chronic obstructive pulmonary disease (COPD) and liver cirrhosis, and specific variants in the 5 '-untranslated region (5 '-UTR) are associated with COPD. The NM_000295.4 transcript is well expressed and translated in lung and blood and features an extended 5 '-UTR that does not contain a competing upstream open reading frame (uORF). We show that the 5 '-UTR of NM_000295.4 folds into a well-defined multi-helix structural domain. We systematically destabilized mRNA structure across the NM_000295.4 5 '-UTR, and measured changes in (SHAPE quantified) RNA structure and cap-dependent translation relative to a native-sequence reporter. Surprisingly, despite destabilizing local RNA structure, most mutations either had no effect on or decreased translation. Most structure-destabilizing mutations retained native, global 5 '-UTR structure. However, those mutations that disrupted the helix that anchors the 5 '-UTR domain yielded three groups of non-native structures. Two of these non-native structure groups refolded to create a stable helix near the translation initiation site that decreases translation. Thus, in contrast to the conventional model that RNA structure in 5 '-UTRs primarily inhibits translation, complex folding of the NM_000295.4 5 '-UTR creates a translation-optimized message by promoting accessibility at the translation initiation site.
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