A New Chapter in Genetic Medicine: RNA Editing and its Role in Disease Pathogenesis

Gagnidze, Khatuna; Rayon-Estrada, Violeta; Harroch, Sheila; Bulloch, Karen; Papavasiliou, F. Nina

doi:10.1016/j.molmed.2018.01.002

Cited by 40 publications

(26 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…APOBEC deaminase activity is regulated by their subcellular distribution, their expression level, and in some cases, binding of a protein cofactor or nonsubstrate RNA. However, off-target mRNA and gene editing have been documented throughout the history of this field and have been implicated in numerous cancers (recently reviewed in 4 , 5 , 6 , 7 , 8 ). To understand the circumstances and mechanisms that determine APOBEC/AID editing site fidelity or off-target mutagenesis, this review will focus on the emerging understanding of the molecular and structural requirements of APOBEC interactions with both substrate and nonsubstrate nucleic acids .…”

Section: Apobec Interactions With Nucleic Acid Substrate Are Criticalmentioning

confidence: 99%

Modeling the Embrace of a Mutator: APOBEC Selection of Nucleic Acid Ligands

Salter

Smith

2018

Trends in Biochemical Sciences

View full text Add to dashboard Cite

The 11-member APOBEC (apolipoprotein B mRNA editing catalytic polypeptide-like) family of zinc-dependent cytidine deaminases bind to RNA and single-stranded DNA (ssDNA) and, in specific contexts, modify select (deoxy)cytidines to (deoxy)uridines. In this review, we describe advances made through high-resolution co-crystal structures of APOBECs bound to mono- or oligonucleotides that reveal potential substrate-specific binding sites at the active site and non-sequence-specific nucleic acid binding sites distal to the active site. We also discuss the effect of APOBEC oligomerization on functionality. Future structural studies will need to address how ssDNA binding away from the active site may enhance catalysis and the mechanism by which RNA binding may modulate catalytic activity on ssDNA.

show abstract

Section: Apobec Interactions With Nucleic Acid Substrate Are Criticalmentioning

confidence: 99%

Modeling the Embrace of a Mutator: APOBEC Selection of Nucleic Acid Ligands

Salter

Smith

2018

Trends in Biochemical Sciences

View full text Add to dashboard Cite

show abstract

“…Mammalian RNA editing encompasses a process in which select sequences within the original genomic template are enzymatically altered to produce a change in the corresponding RNA transcript (for review, see Gagnidze et al 2018). By far the most prevalent form of RNA editing is adenosine to inosine deamination (A-to-I), which is mediated by members of the family of adenosine deaminases acting on RNA (ADARs) (for review, see Nishikura 2010; Keegan et al 2017).…”

Section: Introductionmentioning

confidence: 99%

Apobec1 complementation factor (A1CF) and RBM47 interact in tissue-specific regulation of C to U RNA editing in mouse intestine and liver

Blanc

Xie

Kennedy

et al. 2018

RNA

View full text Add to dashboard Cite

Mammalian C to U RNA is mediated by APOBEC1, the catalytic deaminase, together with RNA binding cofactors (including A1CF and RBM47) whose relative physiological requirements are unresolved. Although A1CF complements APOBEC1 for in vitro RNA editing, A1cf -/mice exhibited no change in apolipoproteinB (apoB) RNA editing, while Rbm47 mutant mice exhibited impaired intestinal RNA editing of apoB as well as other targets. Here we examined the role of A1CF and RBM47 in adult mouse liver and intestine, following deletion of either one or both gene products and also following forced (liver or intestinal) transgenic A1CF expression. There were minimal changes in hepatic and intestinal apoB RNA editing in A1cf -/mice and no changes in either liver-or intestine-specific A1CF transgenic mice. Rbm47 liver-specific knockout (Rbm47 LKO ) mice demonstrated reduced editing in a subset (11 of 20) of RNA targets, including apoB. By contrast, apoB RNA editing was virtually eliminated (<6% activity) in intestine-specific (Rbm47 IKO ) mice with only five of 53 targets exhibiting C-to-U RNA editing. Double knockout of A1cf and Rbm47 in liver (AR LKO ) eliminated apoB RNA editing and reduced editing in the majority of other targets, with no changes following adenoviral APOBEC1 administration. Intestinal double knockout mice (AR IKO ) demonstrated further reduced editing (<10% activity) in four of five of the residual APOBEC1 targets identified in AR IKO mice. These data suggest that A1CF and RBM47 each function independently, yet interact in a tissue-specific manner, to regulate the activity and site selection of APOBEC1 dependent C-to-U RNA editing.

show abstract

“…At expressed loci, the difference between DNA-and RNAallele counts is driven by two major mechanisms -allele-preferential expression and RNA-editing. By using RNA-allele counts, ReQTLs are readily applicable to study both of the above mechanisms and to help elucidate their increasingly recognized role in diverse cellular processes (Imprialou et al, 2017;Casamassimi et al, 2017;Do et al, 2017;Eisenberg and Erez Y Levanon, 2018;Gagnidze et al, 2018;Moreno-Moral et al, 2017;Vandiedonck, 2018). Furthermore, compared to DNA-allele count, correlation of variant RNAallele frequency with gene expression holds several technical advantages.…”

Section: Discussionmentioning

confidence: 99%

ReQTL – an allele-level measure of variation-expression genomic relationships

Alomran

Słowiński

et al. 2018

Preprint

View full text Add to dashboard Cite

Motivation:By testing for association of DNA genotypes with gene expression levels, expression quantitative trait locus (eQTL) analyses have been instrumental in understanding how thousands of single nucleotide variants (SNVs) may affect gene expression. As compared to DNA genotypes, RNA genetic variation represents a phenotypic trait that reflects the actual allele content of the studied system. RNA genetic variation can be measured at expressed genome regions, and differs from the DNA genotype in sites subjected to regulatory forces. Therefore, assessment of correlation between RNA genetic variation and gene expression can reveal regulatory genomic relationships in addition to eQTLs. Results:We introduce ReQTL, an eQTL modification which substitutes the DNA allele count for the variant allele frequency (VAF) at expressed SNV loci in the transcriptome. We exemplify the method on sets of RNA-sequencing data from human tissues obtained though the Genotype-Tissue Expression Project (GTEx) and demonstrate that ReQTL analyses show consistently high performance and sufficient power to identify both previously known and novel molecular associations. The majority of the SNVs implicated in significant cis-ReQTLs identified by our analysis were previously reported as significant cis-eQTL loci. Notably, trans ReQTL loci in our data were substantially enriched in RNA-editing sites. In summary, ReQTL analyses are computationally feasible and do not require matched DNA data, hence they have a high potential to facilitate the discovery of novel molecular interactions through exploration of the increasingly accessible RNA-sequencing datasets.Availability and implementation: Sample scripts used in our ReQTL analyses are available with the Supplementary Material (ReQTL_sample_code).

show abstract

A New Chapter in Genetic Medicine: RNA Editing and its Role in Disease Pathogenesis

Cited by 40 publications

References 60 publications

Modeling the Embrace of a Mutator: APOBEC Selection of Nucleic Acid Ligands

Modeling the Embrace of a Mutator: APOBEC Selection of Nucleic Acid Ligands

Apobec1 complementation factor (A1CF) and RBM47 interact in tissue-specific regulation of C to U RNA editing in mouse intestine and liver

ReQTL – an allele-level measure of variation-expression genomic relationships

Contact Info

Product

Resources

About