RNA Editing—Systemic Relevance and Clue to Disease Mechanisms?

Meier, Jochen C.; Kankowski, Svenja; Krestel, Heinz; Hetsch, Florian

doi:10.3389/fnmol.2016.00124

Cited by 24 publications

(30 citation statements)

References 105 publications

(128 reference statements)

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“…9B). Its noteworthy that, although direct evidence for the role of h ADAR1 in pseudoachondroplasia is not well-established, its hyper/altered editing in several neurodegenerative disorders has been well-documented (13,14,16). In line with this, the hypothesis presented here offers new insight into the role of non-genetic A-to-I mutation in pseudoachondroplasia.…”

Section: Model For Pathogenicity In D(gac) N Expansion Disorders Throsupporting

confidence: 67%

“…Yet another property that can support the formation of Z-DNA in the midst of B-DNA in the d(GAC) 6 ⅐d(GAC) 6 duplex is the angle formed by three adjacent phosphates. For the average structure calculated over the last 10 ns, the angles at the central phosphate in the following steps are below 110°, which further supports the formation of local Z-DNA (ϳ110°) (21): G 4 pA 5 (119°), C 6 pG 7 (96°), G 7 pA 8 (90°), C 9 pG 10 (81°), G 10 pA 11 (99°), C 12 pG 13 (92°), G 13 S2A).…”

Section: Starting Model With Anti Anti Glycosyl Conformationsupporting

confidence: 65%

“…ADAR family proteins mainly catalyze the adenosine-toinosine editing process in pre-mRNA substrates (12). In fact, the role of hyper/altered A-to-I editing mediated by ADAR in several neurological disorders is well-established (13)(14)(15)(16). The N terminus of ADAR1 contains a Z-DNA-binding winged helix-turn-helix domain.…”

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confidence: 99%

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A B–Z junction induced by an A … A mismatch in GAC repeats in the gene for cartilage oligomeric matrix protein promotes binding with the hZαADAR1 protein

Kolimi

Ajjugal

Rathinavelan

2017

Journal of Biological Chemistry

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GAC repeat expansion from five to seven in the exonic region of the gene for cartilage oligomeric matrix protein (COMP) leads to pseudoachondroplasia, a skeletal abnormality. However, the molecular mechanism by which GAC expansions in the gene lead to skeletal dysplasias is poorly understood. Here we used molecular dynamics simulations, which indicate that an A … A mismatch in a d(GAC)·d(GAC) duplex induces negative supercoiling, leading to a local B-to-Z DNA transition. This transition facilitates the binding of d(GAC)·d(GAC) with the Zα-binding domain of human adenosine deaminase acting on RNA 1 (ADAR1, hZα), as confirmed by CD, NMR, and microscale thermophoresis studies. The CD results indicated that hZα recognizes the zigzag backbone of d(GAC)·d(GAC) at the B-Z junction and subsequently converts it into Z-DNA via the so-called passive mechanism. Molecular dynamics simulations carried out for the modeled hZα-d(GAC)d(GAC) complex confirmed the retention of previously reported important interactions between the two molecules. These findings suggest that hZα binding with the GAC hairpin stem in can lead to a non-genetic, RNA editing-mediated substitution in COMP that may then play a crucial role in the development of pseudoachondroplasia.

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Section: Model For Pathogenicity In D(gac) N Expansion Disorders Throsupporting

confidence: 67%

Section: Starting Model With Anti Anti Glycosyl Conformationsupporting

confidence: 65%

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A B–Z junction induced by an A … A mismatch in GAC repeats in the gene for cartilage oligomeric matrix protein promotes binding with the hZαADAR1 protein

Kolimi

Ajjugal

Rathinavelan

2017

Journal of Biological Chemistry

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“…The complex interaction of a nuclear encoded gene family of RNA editing factors with the “simple” haploid genome can create functional alleles that differ from their haploid template. These interactions result in the population of different of alleles, which can vary across time and developmental phase ( Meier et al. 2016 ) from the unedited primary transcript to the fully edited functional form, ultimately presenting a complex assemblage of possible alleles.…”

Section: Resultsmentioning

confidence: 99%

PacBio-Based Mitochondrial Genome Assembly of Leucaena trichandra (Leguminosae) and an Intrageneric Assessment of Mitochondrial RNA Editing

Kovar

Nageswara-Rao

Ortega-Rodriguez

et al. 2018

Genome Biology and Evolution

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Reconstructions of vascular plant mitochondrial genomes (mt-genomes) are notoriously complicated by rampant recombination that has resulted in comparatively few plant mt-genomes being available. The dearth of plant mitochondrial resources has limited our understanding of mt-genome structural diversity, complex patterns of RNA editing, and the origins of novel mt-genome elements. Here, we use an efficient long read (PacBio) iterative assembly pipeline to generate mt-genome assemblies for Leucaena trichandra (Leguminosae: Caesalpinioideae: mimosoid clade), providing the first assessment of non-papilionoid legume mt-genome content and structure to date. The efficiency of the assembly approach facilitated the exploration of alternative structures that are common place among plant mitochondrial genomes. A compact version (729 kbp) of the recovered assemblies was used to investigate sources of mt-genome size variation among legumes and mt-genome sequence similarity to the legume associated root holoparasite Lophophytum. The genome and an associated suite of transcriptome data from select species of Leucaena permitted an in-depth exploration of RNA editing in a diverse clade of closely related species that includes hybrid lineages. RNA editing in the allotetraploid, Leucaena leucocephala, is consistent with co-option of nearly equal maternal and paternal C-to-U edit components, generating novel combinations of RNA edited sites. A preliminary investigation of L. leucocephala C-to-U edit frequencies identified the potential for a hybrid to generate unique pools of alleles from parental variation through edit frequencies shared with one parental lineage, those intermediate between parents, and transgressive patterns.

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“…The ADAR gene family catalyzes the deamination of adenosine that is converted to an inosine creating a dysregulation of the adenosine/inosine (A/I) ratio in the cell. Adenosine to inosine (A-to-I) editing can lead to amino acid recoding events 21 since inosine is recognized as a guanosine. This family includes three enzymes, ADAR1 (UniProtKB P55265), ADAR2 (UniProtKB P78563) and ADAR3 (UniProtKB Q9NS39); also known as ADAR, ADARB1 and ADARB2, respectively 22 .…”

Section: Introductionmentioning

confidence: 99%

Metabolomic and Lipidomic Profiling Identifies The Role of the RNA Editing Pathway in Endometrial Carcinogenesis

Altadill

Dowdy

Gill

et al. 2017

Sci Rep

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Endometrial cancer (EC) remains the most common malignancy of the genital tract among women in developed countries. Although much research has been performed at genomic, transcriptomic and proteomic level, there is still a significant gap in the metabolomic studies of EC. In order to gain insights into altered metabolic pathways in the onset and progression of EC carcinogenesis, we used high resolution mass spectrometry to characterize the metabolomic and lipidomic profile of 39 human EC and 17 healthy endometrial tissue samples. Several pathways including lipids, Kynurenine pathway, endocannabinoids signaling pathway and the RNA editing pathway were found to be dysregulated in EC. The dysregulation of the RNA editing pathway was further investigated in an independent set of 183 human EC tissues and matched controls, using orthogonal approaches. We found that ADAR2 is overexpressed in EC and that the increase in expression positively correlates with the aggressiveness of the tumor. Furthermore, silencing of ADAR2 in three EC cell lines resulted in a decreased proliferation rate, increased apoptosis, and reduced migration capabilities in vitro. Taken together, our results suggest that ADAR2 functions as an oncogene in endometrial carcinogenesis and could be a potential target for improving EC treatment strategies.

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RNA Editing—Systemic Relevance and Clue to Disease Mechanisms?

Cited by 24 publications

References 105 publications

A B–Z junction induced by an A … A mismatch in GAC repeats in the gene for cartilage oligomeric matrix protein promotes binding with the hZαADAR1 protein

A B–Z junction induced by an A … A mismatch in GAC repeats in the gene for cartilage oligomeric matrix protein promotes binding with the hZαADAR1 protein

PacBio-Based Mitochondrial Genome Assembly of Leucaena trichandra (Leguminosae) and an Intrageneric Assessment of Mitochondrial RNA Editing

Metabolomic and Lipidomic Profiling Identifies The Role of the RNA Editing Pathway in Endometrial Carcinogenesis

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