Trans and cis factors affecting A-to-I RNA editing efficiency of a noncoding editing target in C. elegans

Washburn, Michael C.; Hundley, Heather A.

doi:10.1261/rna.055079.115

Cited by 13 publications

(13 citation statements)

References 31 publications

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“…Our data indicate that, similar to the function of mammalian RBM47, C. elegans ADR-1 both physically interacts with ADR-2 and promotes stable binding of the complex to RNA to allow ADR-2 to properly edit. However, previous studies have shown that ADR-1 is not required for ADR-2 to edit all adenosines ( 12 , 36 , 61 ) and our RIP studies identified 423 transcripts that associate with ADR-2 in the absence of ADR-1 ( Supplementary Table S3 ). These data suggest that the mode of substrate recognition by ADR-2 differs among various transcripts.…”

Section: Discussionmentioning

confidence: 74%

A protein–protein interaction underlies the molecular basis for substrate recognition by an adenosine-to-inosine RNA-editing enzyme

Rajendren

Manning

Al-Awadi

et al. 2018

Nucleic Acids Research

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Adenosine deaminases that act on RNA (ADARs) convert adenosine to inosine within double-stranded regions of RNA, resulting in increased transcriptomic diversity, as well as protection of cellular double-stranded RNA (dsRNA) from silencing and improper immune activation. The presence of dsRNA-binding domains (dsRBDs) in all ADARs suggests these domains are important for substrate recognition; however, the role of dsRBDs in vivo remains largely unknown. Herein, our studies indicate the Caenorhabditis elegans ADAR enzyme, ADR-2, has low affinity for dsRNA, but interacts with ADR-1, an editing-deficient member of the ADAR family, which has a 100-fold higher affinity for dsRNA. ADR-1 uses one dsRBD to physically interact with ADR-2 and a second dsRBD to bind to dsRNAs, thereby tethering ADR-2 to substrates. ADR-2 interacts with >1200 transcripts in vivo, and ADR-1 is required for 80% of these interactions. Our results identify a novel mode of substrate recognition for ADAR enzymes and indicate that protein–protein interactions can guide substrate recognition for RNA editors.

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Section: Discussionmentioning

confidence: 74%

A protein–protein interaction underlies the molecular basis for substrate recognition by an adenosine-to-inosine RNA-editing enzyme

Rajendren

Manning

Al-Awadi

et al. 2018

Nucleic Acids Research

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“…Despite lacking RNA editing activity, the regulatory role of deaminase-deficient ADARs is conserved in other organisms. The deaminase-deficient ADAR family member in Caenorhabditis elegans, ADR-1, also alters editing levels and has most recently been shown to inhibit RNA editing in the neurons of worms (75,76).…”

Section: Discussionmentioning

confidence: 99%

Adenosine Deaminase That Acts on RNA 3 (ADAR3) Binding to Glutamate Receptor Subunit B Pre-mRNA Inhibits RNA Editing in Glioblastoma

Oakes¹,

Anderson

Cohen-Gadol

et al. 2017

Journal of Biological Chemistry

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149

115

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Edited by Charles E. SamuelRNA editing is a cellular process that precisely alters nucleotide sequences, thus regulating gene expression and generating protein diversity. Over 60% of human transcripts undergo adenosine to inosine RNA editing, and editing is required for normal development and proper neuronal function of animals. Editing of one adenosine in the transcript encoding the glutamate receptor subunit B, glutamate receptor ionotropic AMPA 2 (GRIA2), modifies a codon, replacing the genomically encoded glutamine (Q) with arginine (R); thus this editing site is referred to as the Q/R site. Editing at the Q/R site of GRIA2 is essential, and reduced editing of GRIA2 transcripts has been observed in patients suffering from glioblastoma. In glioblastoma, incorporation of unedited GRIA2 subunits leads to a calcium-permeable glutamate receptor, which can promote cell migration and tumor invasion. In this study, we identify adenosine deaminase that acts on RNA 3 (ADAR3) as an important regulator of Q/R site editing, investigate its mode of action, and detect elevated ADAR3 expression in glioblastoma tumors compared with adjacent brain tissue. Overexpression of ADAR3 in astrocyte and astrocytoma cell lines inhibits RNA editing at the Q/R site of GRIA2. Furthermore, the double-stranded RNA binding domains of ADAR3 are required for repression of RNA editing. As the Q/R site of GRIA2 is specifically edited by ADAR2, we suggest that ADAR3 directly competes with ADAR2 for binding to GRIA2 transcript, inhibiting RNA editing, as evidenced by the direct binding of ADAR3 to the GRIA2 pre-mRNA. Finally, we provide evidence that both ADAR2 and ADAR3 expression contributes to the relative level of GRIA2 editing in tumors from patients suffering from glioblastoma.Adenosine deaminases that act on RNA (ADARs) 2 catalyze the hydrolytic deamination of adenosine residues within double-stranded RNA (dsRNA) structures that form by base pairing of nearby complementary sequences (1-3). This RNA editing event creates a non-canonical nucleoside, inosine, which base pairs similarly to guanosine (4). RNA editing affects gene expression through modification of codons to create novel protein isoforms (5). Furthermore, editing can alter microRNA and siRNA binding sites, splice acceptor or splice donor sites, or RNA structure and stability (6 -9). A majority of the targets of RNA editing are found in the nervous system, and RNA editing is critical for maintaining proper neuronal function (10). Furthermore, transcripts encoding proteins involved in neurotransmission are often targets of RNA editing, which alters the protein amino acid sequence and physiological function of these ion channels and receptors (11,12).In mammals, three ADAR proteins, ADAR1, ADAR2, and ADAR3, and two ADAR-like proteins, ADAD1 and ADAD2, have been identified (13-17). The ADAR and ADAR-like protein family members contain several common modular domains that are important for function (18,19). Most strikingly, the human ADAR and ADAR-like proteins contain at least one ds...

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“…The homologous protein in the parasitic nematode Haemonchus contortus is found in excretory and secretory products and is able to bind the interleukin IL2 of its mammalian host ( Wang et al, 2019 ). In C. elegans , the 3’UTR of Y75B8A.8 regulates RNA editing of the ADSR-2 mRNA ( Wheeler et al, 2015 ; Washburn and Hundley, 2016 ). This gene was not known to affect Pn.p cell development.…”

Section: Resultsmentioning

confidence: 99%

“…regulates RNA editing of the ADSR-2 mRNA (Wheeler et al, 2015, Washburn andHundley, 2016). This gene was not known to affect Pn.p cell development.…”

Section: Relations Between the Causative Genes And The Effects On P3mentioning

confidence: 99%

A broad mutational target explains a fast rate of phenotypic evolution

Besnard

Picao-Osorio

Dubois

et al. 2020

eLife

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The rapid evolution of a trait in a clade of organisms can be explained by the sustained action of natural selection or by a high mutational variance, that is the propensity to change under spontaneous mutation. The causes for a high mutational variance are still elusive. In some cases, fast evolution depends on the high mutation rate of one or few loci with short tandem repeats. Here, we report on the fastest evolving cell fate among vulva precursor cells in Caenorhabditis nematodes, that of P3.p. We identify and validate causal mutations underlying P3.p's high mutational variance. We find that these positions do not present any characteristics of a high mutation rate, are scattered across the genome and the corresponding genes belong to distinct biological pathways. Our data indicate that a broad mutational target size is the cause of the high mutational variance and of the corresponding fast phenotypic evolutionary rate.

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Trans and cis factors affecting A-to-I RNA editing efficiency of a noncoding editing target in C. elegans

Cited by 13 publications

References 31 publications

A protein–protein interaction underlies the molecular basis for substrate recognition by an adenosine-to-inosine RNA-editing enzyme

A protein–protein interaction underlies the molecular basis for substrate recognition by an adenosine-to-inosine RNA-editing enzyme

Adenosine Deaminase That Acts on RNA 3 (ADAR3) Binding to Glutamate Receptor Subunit B Pre-mRNA Inhibits RNA Editing in Glioblastoma

A broad mutational target explains a fast rate of phenotypic evolution

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