A-to-I editing of protein coding and noncoding RNAs

Mallela, Arka N.; Nishikura, Kazuko

doi:10.3109/10409238.2012.714350

Cited by 53 publications

(38 citation statements)

References 73 publications

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“…2 F and G and Fig. S5 A and B), revealing the importance of ADAR members in the regulation of both genes, consistent with functions of A-to-I editing in the regulation of noncoding RNA species (14). To gain functional insight into the regulation of PRUNE2 and PCA3, we established sensor/reporter assays in which either PCA3 or the PCA3 antisense sequence (i.e., intron6-PRUNE2) was fused to reporters to generate PCA3-luciferase or intron6-PRUNE2-GFP.…”

Section: Pca3mentioning

confidence: 76%

PRUNE2 is a human prostate cancer suppressor regulated by the intronic long noncoding RNA PCA3

Salameh

Lee

Cardó-Vila

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

234

191

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Prostate cancer antigen 3 (PCA3) is the most specific prostate cancer biomarker but its function remains unknown. Here we identify PRUNE2, a target protein-coding gene variant, which harbors the PCA3 locus, thereby classifying PCA3 as an antisense intronic long noncoding (lnc)RNA. We show that PCA3 controls PRUNE2 levels via a unique regulatory mechanism involving formation of a PRUNE2/PCA3 double-stranded RNA that undergoes adenosine deaminase acting on RNA (ADAR)-dependent adenosine-to-inosine RNA editing. PRUNE2 expression or silencing in prostate cancer cells decreased and increased cell proliferation, respectively. Moreover, PRUNE2 and PCA3 elicited opposite effects on tumor growth in immunodeficient tumor-bearing mice. Coregulation and RNA editing of PRUNE2 and PCA3 were confirmed in human prostate cancer specimens, supporting the medical relevance of our findings. These results establish PCA3 as a dominant-negative oncogene and PRUNE2 as an unrecognized tumor suppressor gene in human prostate cancer, and their regulatory axis represents a unique molecular target for diagnostic and therapeutic intervention.S everal lines of evidence demonstrate that long noncoding RNAs (lncRNAs) are functional in carcinogenesis through regulatory mechanisms such as promoter looping, alternative splicing, antisense gene silencing, transcriptional regulation, and DNA repair, thus potentially serving as tumor markers. A few lncRNA species have emerged as potential prostate cancer biomarkers such as prostate cancer gene expression marker-1 (PCGEM1) and prostate cancer noncoding RNA1 (PRNCR1), which enhance androgen receptor (AR)-dependent gene activation, and prostate cancer-associated ncRNA transcript-1 (PCAT1), which silences BRCA2 via posttranscriptional homologous recombination (1). Notably, the most specific biomarker in human prostate cancer identified to date is an lncRNA, prostate cancer antigen 3 (PCA3, also known as PCA3 DD3 or DD3 PCA3 ), which is up-regulated in human prostate cancer (2). Since its discovery more than 15 y ago, PCA3 has been extensively investigated (3) and has been approved for clinical applications to aid the diagnosis of prostate cancer in both the European Union and the United States. Paradoxically-despite its striking clinical specificity-the inherent cellular role of the lncRNA PCA3 in human prostate cancer, if any, remains completely unknown (1). Here we report a unique biological function for PCA3. Within a single functional genetic unit, we show that PCA3 is an antisense intronic lncRNA that down-regulates an as yet unrecognized tumor suppressor gene, a human homolog of the Drosophila prune gene, PRUNE2, through a process that involves RNA editing mediated by a supramolecular complex containing adenosine deaminase acting on RNA (ADAR) family members. We propose a working model in which PCA3 acts as a dominant-negative oncogene in prostate cancer and show consistent results in therapeutic preclinical models and in patient-derived human samples. Therefore, the molecular interaction of PRUNE2...

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Section: Pca3mentioning

confidence: 76%

PRUNE2 is a human prostate cancer suppressor regulated by the intronic long noncoding RNA PCA3

Salameh

Lee

Cardó-Vila

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

234

191

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“…Bowtie aligner was used to align the sequences to the miRBase 20, RNAdb, and Deepbase, allowing up to three mismatches (bowtie -v 3 -l 10 -tryhard -a -strata -best -al), whereas alignments to the Rfam were performed allowing for no mismatches (bowtie -v 0 -l 10 -tryhard -a -strata -best -al). The permissive alignment (up to three mismatches) was due to the potential editing of double-stranded small RNA precursor molecules (Heale et al 2009;Mallela and Nishikura 2012).…”

Section: Discussionmentioning

confidence: 99%

Diversity and functional convergence of small noncoding RNAs in male germ cell differentiation and fertilization

García-López

Alonso

Cárdenas

et al. 2015

RNA

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The small noncoding RNAs (sncRNAs) are considered as post-transcriptional key regulators of male germ cell development. In addition to microRNAs (miRNAs) and PIWI-interacting RNAs (piRNAs), other sncRNAs generated from small nucleolar RNAs (snoRNAs), tRNAs, or rRNAs processing may also play important regulatory roles in spermatogenesis. By next-generation sequencing (NGS), we characterized the sncRNA populations detected at three milestone stages in male germ differentiation: primordial germ cells (PGCs), pubertal spermatogonia cells, and mature spermatozoa. To assess their potential transmission through the spermatozoa during fertilization, the sncRNAs of mouse oocytes and zygotes were also analyzed. Both, microRNAs and snoRNA-derived small RNAs are abundantly expressed in PGCs but transiently replaced by piRNAs in spermatozoa and endo-siRNAs in oocytes and zygotes. Exhaustive analysis of miRNA sequence variants also shows an increment of noncanonical microRNA forms along male germ cell differentiation. RNAs-derived from tRNAs and rRNAs interacting with PIWI proteins are not generated by the ping-pong pathway and could be a source of primary piRNAs. Moreover, our results strongly suggest that the small RNAs-derived from tRNAs and rRNAs are interacting with PIWI proteins, and specifically with MILI. Finally, computational analysis revealed their potential involvement in post-transcriptional regulation of mRNA transcripts suggesting functional convergence among different small RNA classes in germ cells and zygotes.

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“…ADARs RNA-specific adenosine deaminases (ADARs) are enzymes involved in the conversion of adenosine (A) to inosine (I) to change the nucleotide sequence of mature RNA species relative to the encoding DNA sequence (A to I RNA-editing) (Gray 2012;Mallela and Nishikura 2012). The molecular effects of the RNA-editing includes alternative splicing, protein sequence alteration, changes in RNA stability and miRNA regulation (Savva et al 2012).…”

Section: Taf15mentioning

confidence: 99%

RNA-binding proteins as molecular links between cancer and neurodegeneration

et al. 2014

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For many years, epidemiological studies have suggested an association between cancer and neurodegenerative disorders-two disease processes that seemingly have little in common. Although these two disease processes share disruptions in a wide range of cellular pathways, including cell survival, cell death and the cell cycle, the end result is very divergent: uncontrolled cell survival and proliferation in cancer and progressive neuronal cell death in neurodegeneration. Despite the clinical data connecting these two disease processes, little is known about the molecular links between them. Among the mechanisms affected in cancer and neurodegenerative diseases, alterations in RNA metabolism are obtaining significant attention given the critical role for RNA transcription, maturation, transport, stability, degradation and translation in normal cellular function. RNA-binding proteins (RBPs) are integral to each stage of RNA metabolism through their participation in the formation of ribonucleoprotein complexes (RNPs). RBPs have a broad range of functions including posttranscriptional regulation of mRNA stability, splicing, editing and translation, mRNA export and localization, mRNA polyadenylation and miRNA biogenesis, ultimately impacting the expression of every single gene in the cell. In this review, we examine the evidence for RBPs as being key a molecular linkages between cancer and neurodegeneration.

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A-to-I editing of protein coding and noncoding RNAs

Cited by 53 publications

References 73 publications

PRUNE2 is a human prostate cancer suppressor regulated by the intronic long noncoding RNA PCA3

PRUNE2 is a human prostate cancer suppressor regulated by the intronic long noncoding RNA PCA3

Diversity and functional convergence of small noncoding RNAs in male germ cell differentiation and fertilization

RNA-binding proteins as molecular links between cancer and neurodegeneration

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