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Antisense suppression of the nonsense mediated decay factor Upf3b as a potential treatment for diseases caused by nonsense mutations.

ABSTRACT: About 11% of all human genetic diseases are caused by nonsense mutations that generate premature translation termination codons (PTCs) in messenger RNAs (mRNA). PTCs not only lead to the production of truncated proteins, but also often result in decreased mRNA abundance due to nonsense-mediated mRNA decay (NMD). Although pharmacological inhibition of NMD could be an attractive therapeutic approach for the treatment of diseases caused by nonsense mutations, NMD also regulates the expression of 10-20% of the normal transcriptome.Here, we investigate whether NMD can be inhibited to stabilize mutant mRNAs, which may subsequently produce functional proteins, without having a major impact on the normal transcriptome. We develop antisense oligonucleotides (ASOs) to systematically deplete each component in the NMD pathway. We find that ASO-mediated depletion of each NMD factor elicits different magnitudes of NMD inhibition in vitro and are differentially tolerated in normal mice. Among all of the NMD factors, Upf3b depletion is well tolerated, consistent with previous reports that UPF3B is not essential for development and regulates only a subset of the endogenous NMD substrates. While minimally impacting the normal transcriptome, Upf3b-ASO treatment significantly stabilizes the PTC-containing dystrophin mRNA in mdx mice and coagulation factor IX mRNA in a hemophilia mouse model. Furthermore, when combined with reagents promoting translational read-through, Upf3b-ASO treatment leads to the production of functional factor IX protein in hemophilia mice.These data demonstrate that ASO-mediated reduction of the NMD factor Upf3b could be an effective and safe approach for the treatment of diseases caused by nonsense mutations.

SUBMITTER: Huang L

PROVIDER: S-EPMC5769327 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Antisense suppression of the nonsense mediated decay factor Upf3b as a potential treatment for diseases caused by nonsense mutations.

Huang Lulu L Low Audrey A Damle Sagar S SS Keenan Melissa M MM Kuntz Steven S Murray Susan F SF Monia Brett P BP Guo Shuling S

Genome biology 20180115 1

<h4>Background</h4>About 11% of all human genetic diseases are caused by nonsense mutations that generate premature translation termination codons (PTCs) in messenger RNAs (mRNA). PTCs not only lead to the production of truncated proteins, but also often result in decreased mRNA abundance due to nonsense-mediated mRNA decay (NMD). Although pharmacological inhibition of NMD could be an attractive therapeutic approach for the treatment of diseases caused by nonsense mutations, NMD also regulates ...[more]

PMID: 29334995

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Project description:Nonsense-mediated RNA decay (NMD) is a highly conserved and selective RNA turnover pathway that has been subject to intense scrutiny. NMD identifies and degrades subsets of normal RNAs, as well as abnormal mRNAs containing premature termination codons. A core factor in this pathway-UPF3B-is an adaptor protein that serves as an NMD amplifier and an NMD branch-specific factor. UPF3B is encoded by an X-linked gene that when mutated causes intellectual disability and is associated with neurodevelopmental disorders, including schizophrenia and autism. Neu-Yilik et al. now report a new function for UPF3B: it modulates translation termination. Using a fully reconstituted in vitro translation system, they find that UPF3B has two roles in translation termination. First, UPF3B delays translation termination under conditions that mimic premature translation termination. This could drive more efficient RNA decay by allowing more time for the formation of RNA decay-stimulating complexes. Second, UPF3B promotes the dissociation of post-termination ribosomal complexes that lack nascent peptide. This implies that UPF3B could promote ribosome recycling. Importantly, the authors found that UPF3B directly interacts with both RNA and the factors that recognize stop codons-eukaryotic release factors (eRFs)-suggesting that UPF3B serves as a direct regulator of translation termination. In contrast, a NMD factor previously thought to have a central regulatory role in translation termination-the RNA helicase UPF1-was found to indirectly interact with eRFs and appears to act exclusively in post-translation termination events, such as RNA decay, at least in vitro. The finding that an RNA decay-promoting factor, UFP3B, modulates translation termination has many implications. For example, the ability of UPF3B to influence the development and function of the central nervous system may be not only through its ability to degrade specific RNAs but also through its impact on translation termination and subsequent events, such as ribosome recycling.

Dataset Information

Antisense suppression of the nonsense mediated decay factor Upf3b as a potential treatment for diseases caused by nonsense mutations.

Publications

Antisense suppression of the nonsense mediated decay factor Upf3b as a potential treatment for diseases caused by nonsense mutations.

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