Inosine‐specific ribonuclease activity of natural variants of human endonuclease V

Kim, Jung In; Tohashi, Kosuke; Iwai, Shigenori; Kuraoka, Isao

doi:10.1002/1873-3468.12470

Cited by 3 publications

(3 citation statements)

References 36 publications

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“…Because ADAR (adenosine deaminase acting on RNA) and A-to-I RNA editing are prevalent in metazoans (Eisenberg and Levanon, 2018), inosine-specific RNA decay must be necessary. To date, the molecular mechanism for the recognition of RNA instead of DNA and the function of EndoV in mammals remain unresolved (Kim et al, 2016;Nawaz et al, 2016a).…”

Section: Introductionmentioning

confidence: 99%

Evolution of Inosine-Specific Endonuclease V from Bacterial DNase to Eukaryotic RNase

Wu¹,

Samara

Kuraoka

et al. 2019

Molecular Cell

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Endonuclease V (EndoV) cleaves the second phosphodiester bond 3 0 to a deaminated adenosine (inosine). Although highly conserved, EndoV homologs change substrate preference from DNA in bacteria to RNA in eukaryotes. We have characterized EndoV from six different species and determined crystal structures of human EndoV and three EndoV homologs from bacteria to mouse in complex with inosine-containing DNA/RNA hybrid or double-stranded RNA (dsRNA). Inosine recognition is conserved, but changes in several connecting loops in eukaryotic EndoV confer recognition of 3 ribonucleotides upstream and 7 or 8 bp of dsRNA downstream of the cleavage site, and bacterial EndoV binds only 2 or 3 nt flanking the scissile phosphate. In addition to the two canonical metal ions in the active site, a third Mn 2+ that coordinates the nucleophilic water appears necessary for product formation. Comparison of EndoV with its homologs RNase H1 and Argonaute reveals the principles by which these enzymes recognize RNA versus DNA.

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Section: Introductionmentioning

confidence: 99%

Evolution of Inosine-Specific Endonuclease V from Bacterial DNase to Eukaryotic RNase

Wu¹,

Samara

Kuraoka

et al. 2019

Molecular Cell

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“…For example, it is theoretically possible to modulate the overall levels of inosine-containing RNA by regulating ribonuclease V (196, 197). But dysregulation of ribonuclease V has been linked to cancers and psychiatric disorders, indicating the potential hazards (198, 199). This concern can be extended to approaches targeting an individual RNA editase, as mutations of ADAR1 and ADAR2 have been linked to devastating genetic diseases (95, 200).…”

Section: Introductionmentioning

confidence: 99%

The Role of RNA Editing in Cancer Development and Metabolic Disorders

2018

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Numerous human diseases arise from alterations of genetic information, most notably DNA mutations. Thought to be merely the intermediate between DNA and protein, changes in RNA sequence were an afterthought until the discovery of RNA editing 30 years ago. RNA editing alters RNA sequence without altering the sequence or integrity of genomic DNA. The most common RNA editing events are A-to-I changes mediated by adenosine deaminase acting on RNA (ADAR), and C-to-U editing mediated by apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1). Both A-to-I and C-to-U editing were first identified in the context of embryonic development and physiological homeostasis. The role of RNA editing in human disease has only recently started to be understood. In this review, the impact of RNA editing on the development of cancer and metabolic disorders will be examined. Distinctive functions of each RNA editase that regulate either A-to-I or C-to-U editing will be highlighted in addition to pointing out important regulatory mechanisms governing these processes. The potential of developing novel therapeutic approaches through intervention of RNA editing will be explored. As the role of RNA editing in human disease is elucidated, the clinical utility of RNA editing targeted therapies will be needed. This review aims to serve as a bridge of information between past findings and future directions of RNA editing in the context of cancer and metabolic disease.

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“…They differ in the length of the protein coding part of exon 9 and two have two alternative 3’ exons, exons 10a and 10b (Fig 1 and S1 Fig) (NM_173627.4 = hENDOV 282 , NM_001352761.1 = hENDOV 308 and NM_001352760.1 = hENDOV 309 ). Of these, referred to as “full-length” hereafter, the hENDOV 282 isoform is the one that has been used in previous research [11,12,28,29]. It is the default “canonical sequence” in UniProt and the APPRIS [30] principal isoform of the gene.…”

Section: Resultsmentioning

confidence: 99%

Complex alternative splicing of human Endonuclease V mRNA, but evidence for only a single protein isoform

et al. 2019

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Endonuclease V (ENDOV) is a ribonuclease with affinity for inosine which is the deamination product of adenosine. The genomes of most organisms, including human, encode ENDOV homologs, yet knowledge about in vivo functions and gene regulation is sparse. To contribute in this field, we analyzed mRNA and protein expression of human ENDOV (hENDOV). Analyses of public sequence databases revealed numerous hENDOV transcript variants suggesting extensive alternative splicing. Many of the transcripts lacked one or more exons corresponding to conserved regions of the ENDOV core domain, suggesting that these transcripts do not encode for active proteins. Three complete transcripts were found with open reading frames encoding 282, 308 and 309 amino acids, respectively. Recombinant hENDOV 308 and hENDOV 309 share the same cleavage activity as hENDOV 282 which is the variant that has been used in previous studies of hENDOV. However, hENDOV 309 binds inosine-containing RNA with stronger affinity than the other isoforms. Overexpressed GFP-fused isoforms were found in cytoplasm, nucleoli and arsenite induced stress granules in human cells as previously reported for hENDOV 282. RT-qPCR analysis of the 3’-termini showed that hENDOV 308 and hENDOV 309 transcripts are more abundant than hENDOV 282 transcripts in immortalized cell lines, but not in primary cells, suggesting that cells regulate hENDOV mRNA expression. In spite of the presence of all three full-length transcripts, mass spectrometry analyses identified peptides corresponding to the hENDOV 309 isoform only. This result suggests that further studies of human ENDOV should rather encompass the hENDOV 309 isoform.

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Inosine‐specific ribonuclease activity of natural variants of human endonuclease V

Cited by 3 publications

References 36 publications

Evolution of Inosine-Specific Endonuclease V from Bacterial DNase to Eukaryotic RNase

Evolution of Inosine-Specific Endonuclease V from Bacterial DNase to Eukaryotic RNase

The Role of RNA Editing in Cancer Development and Metabolic Disorders

Complex alternative splicing of human Endonuclease V mRNA, but evidence for only a single protein isoform

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