RNA editing enzymes: structure, biological functions and applications

Zhang, Dejiu; Zhu, Lei; Gao, Yanyan; Wang, Yin; Li, Peifeng

doi:10.1186/s13578-024-01216-6

Cited by 7 publications

(2 citation statements)

References 183 publications

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“…While these results suggest that RNA editing affects splicing, in a therapeutic context, it remains to be investigated which ADAR isoform (cytoplasmic versus nuclear-localized) is recruited by exogenous PTC-targeting guide RNAs. This could be important when not delivering an exogenous ADAR, especially considering that the ADAR1 p150 isoform is mainly localized in the cytoplasm, while ADAR1 p110 is primarily found in the nucleus [ 101 ].…”

Section: Nonsense Suppression Strategiesmentioning

confidence: 99%

Therapeutic Nonsense Suppression Modalities: From Small Molecules to Nucleic Acid-Based Approaches

Morais,

Zhang,

2024

Biomedicines

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Nonsense mutations are genetic mutations that create premature termination codons (PTCs), leading to truncated, defective proteins in diseases such as cystic fibrosis, neurofibromatosis type 1, Dravet syndrome, Hurler syndrome, Beta thalassemia, inherited bone marrow failure syndromes, Duchenne muscular dystrophy, and even cancer. These mutations can also trigger a cellular surveillance mechanism known as nonsense-mediated mRNA decay (NMD) that degrades the PTC-containing mRNA. The activation of NMD can attenuate the consequences of truncated, defective, and potentially toxic proteins in the cell. Since approximately 20% of all single-point mutations are disease-causing nonsense mutations, it is not surprising that this field has received significant attention, resulting in a remarkable advancement in recent years. In fact, since our last review on this topic, new examples of nonsense suppression approaches have been reported, namely new ways of promoting the translational readthrough of PTCs or inhibiting the NMD pathway. With this review, we update the state-of-the-art technologies in nonsense suppression, focusing on novel modalities with therapeutic potential, such as small molecules (readthrough agents, NMD inhibitors, and molecular glue degraders); antisense oligonucleotides; tRNA suppressors; ADAR-mediated RNA editing; targeted pseudouridylation; and gene/base editing. While these various modalities have significantly advanced in their development stage since our last review, each has advantages (e.g., ease of delivery and specificity) and disadvantages (manufacturing complexity and off-target effect potential), which we discuss here.

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Section: Nonsense Suppression Strategiesmentioning

confidence: 99%

Therapeutic Nonsense Suppression Modalities: From Small Molecules to Nucleic Acid-Based Approaches

Morais,

Zhang,

2024

Biomedicines

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“…4−6 RNA modifications, recognized as critical post-transcriptional regulators of gene expression, include more than 170 chemically distinct modifications known collectively as the epitranscriptome. 7 One of the most prevalent RNA modifications, 5-methylcytosine (m5C), plays a crucial role in RNA transcription and translation. 8 The m5C alteration of RNA was first discovered in the 1970s, which occurred at position 5 of cytidine residues on RNA.…”

Section: ■ Introductionmentioning

confidence: 99%

HCV 5-Methylcytosine Enhances Viral RNA Replication through Interaction with m5C Reader YBX1

Li,

Xie,

Xie

et al. 2024

ACS Chem. Biol.

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Hepatitis C virus (HCV) is a positive-stranded RNA virus that mainly causes chronic hepatitis, cirrhosis and hepatocellular carcinoma. Recently we confirmed m5C modifications within NS5A gene of HCV RNA genome. However, the roles of the m5C modification and its interaction with host proteins in regulating HCV's life cycle, remain unexplored. Here, we demonstrate that HCV infection enhances the expression of the host m5C reader YBX1 through the transcription factor MAX. YBX1 acts as an m5C reader, recognizing the m5C-modified NS5A C7525 site in the HCV RNA genome and significantly enhancing HCV RNA stability. This m5Cmodification is also required for YBX1 colocalization with lipid droplets and HCV Core protein. Moreover, YBX1 facilitates HCV RNA replication, as well as viral assembly/budding. The tryptophan residue at position 65 (W65) of YBX1 is critical for these functions. Knockout of YBX1 or the application of YBX1 inhibitor SU056 suppresses HCV RNA replication and viral protein translation. To our knowledge, this is the first report demonstrating that the interaction between host m5C reader YBX1 and HCV RNA m5C methylation facilitates viral replication. Therefore, hepatic-YBX1 knockdown holds promise as a potential host-directed strategy for HCV therapy.

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A stochastic RNA editing process targets a limited number of sites in individualDrosophilaglutamatergic motoneurons

Crane,

Jetti,

Littleton

2024

Preprint

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RNA editing is a post-transcriptional source of protein diversity and occurs across the animal kingdom. Given the complete profile of mRNA targets and their editing rate in individual cells is unclear, we analyzed single cell RNA transcriptomes from Drosophila larval tonic and phasic glutamatergic motoneuron subtypes to determine the most highly edited targets and identify cell-type specific editing. From ~15,000 genes encoded in the genome, 316 high confidence A-to-I canonical RNA edit sites were identified, with 102 causing missense amino acid changes in proteins regulating membrane excitability, synaptic transmission, and cellular function. Some sites showed 100% editing in single neurons as observed with mRNAs encoding mammalian AMPA receptors. However, most sites were edited at lower levels and generated variable expression of edited and unedited mRNAs within individual neurons. Together, these data provide insights into how the RNA editing landscape alters protein function to modulate the properties of two well-characterized neuronal populations in Drosophila.

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RNA editing enzymes: structure, biological functions and applications

Cited by 7 publications

References 183 publications

Therapeutic Nonsense Suppression Modalities: From Small Molecules to Nucleic Acid-Based Approaches

Therapeutic Nonsense Suppression Modalities: From Small Molecules to Nucleic Acid-Based Approaches

HCV 5-Methylcytosine Enhances Viral RNA Replication through Interaction with m5C Reader YBX1

A stochastic RNA editing process targets a limited number of sites in individualDrosophilaglutamatergic motoneurons

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