Segmented poly(A) tails significantly reduce recombination of plasmid DNA without affecting mRNA translation efficiency or half-life
Open accessAbstract
Extensive research in the past decade has brought mRNA closer to the clinical realization of its therapeutic potential. One common structural feature for all cellular messenger RNAs is a poly(A) tail, which can either be brought in cotranscriptionally via the DNA template (plasmid- or PCR-based) or added to the mRNA in a post-transcriptional enzymatic process. Plasmids containing poly(A) regions recombine in E. coli, resulting in extensive shortening of the poly(A) tail. Using a segmented poly(A) approach, we could significantly reduce recombination of plasmids in E. coli without any negative effect on mRNA half-life and protein expression. This effect was independent of the coding sequence. A segmented poly(A) tail is characterized in that it consists of at least two A-containing elements, each defined as a nucleotide sequence consisting of 40–60 adenosines, separated by a spacer element of different length. Furthermore, reducing the spacer length between the poly(A) segments resulted in higher translation efficiencies compared to homogeneous poly(A) tail and reduced recombination (depending upon the choice of spacer nucleotide). Our results demonstrate the superior potential of segmented poly(A) tails compared to the conventionally used homogeneous poly(A) tails with respect to recombination of the plasmids and the resulting mRNA performance (half-life and translational efficiency).
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An alternative strategy to avoid poly(A) instability consists of including an internal 10-nucleotide linker into the poly(A) stretch.
“An alternative strategy has been developed to avoid this instability, consisting of including an internal 10-nucleotide linker into the poly(A) stretch.25,26”
From Combining an optimized mRNA template with a double purification process allows strong expression of in vitro transcribed mRNA (2021) · cites this paper as [26]
The Results and Discussion section (“Design of modified/segmented poly(A) tails”; page unavailable) describes inserting internal spacers to reduce instability of plasmid-encoded poly(A) tails. It reports spacers of 1, 6, 12, and 24 nucleotides, but not the claimed 10-nucleotide linker. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe segmented poly(A) tail extends mRNA half-life and improves translation efficiency compared to the long-chain poly(A) tail.
“Current studies have shown that the segmented poly(A) tail extends mRNA half-life and improves translation efficiency compared to the long-chain poly(A) tail.154”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [154]
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- Authors
- Trepotec, Z., Geiger, J., Plank, C., Aneja, M. K., & Rudolph, C.
- Affiliations
- Ethris (Germany) (DE)
- TUM Klinikum (DE)
- Venue
- RNA
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2019-01-15
- Volume
- 25
- Issue
- 4
- Pages
- 507-518
- ISSN
- 1355-8382 (ISSN-L)
- 1469-9001
- PMC
- PMC6426288
- OpenAlex
- W2910680408
- Cited by
- 129
- References
- 44
- Citations by year
- 2026: 20 · 2025: 29 · 2024: 25 · 2023: 22 · 2022: 20 · 2021: 10 · 2020: 2 · 2019: 1
- FWCI
- 2.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- RNA (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion, other-oa)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Funders
- NIM Excellence Cluster
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- poly(A) tail, plasmid recombination, Escherichia coli, mRNA half-life, translation efficiency, spacer length, mRNA therapeutics, plasmid DNA
- MeSH terms
- A549 Cells, Animals, Base Sequence, Escherichia coli, Genetic Engineering, Half-Life, Humans, Plasmids, Poly A, Recombination, Genetic, RNA, Messenger, Transfection, Protein Biosynthesis, HEK293 Cells
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