Article

Modulation of microRNA processing and expression through RNA editing by ADAR deaminases.

The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA.
Nature Structural & Molecular Biology (Impact Factor: 11.63). 02/2006; 13(1):13-21. DOI: 10.1038/nsmb1041
Source: PubMed

ABSTRACT Adenosine deaminases acting on RNA (ADARs) are involved in editing of adenosine residues to inosine in double-stranded RNA (dsRNA). Although this editing recodes and alters functions of several mammalian genes, its most common targets are noncoding repeat sequences, indicating the involvement of this editing system in currently unknown functions other than recoding of protein sequences. Here we show that specific adenosine residues of certain microRNA (miRNA) precursors are edited by ADAR1 and ADAR2. Editing of pri-miR-142, the precursor of miRNA-142, expressed in hematopoietic tissues, resulted in suppression of its processing by Drosha. The edited pri-miR-142 was degraded by Tudor-SN, a component of RISC and also a ribonuclease specific to inosine-containing dsRNAs. Consequently, mature miRNA-142 expression levels increased substantially in ADAR1 null or ADAR2 null mice. Our results demonstrate a new function of RNA editing in the control of miRNA biogenesis.

3 Followers
 · 
181 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Methylation of N6-adenosine (m6A) has been observed in many different classes of RNA, but its prevalence in microRNAs (miRNAs) has not yet been studied. Here we show that a knockdown of the m6A demethylase FTO affects the steady-state levels of several miRNAs. Moreover, RNA immunoprecipitation with an anti-m6A-antibody followed by RNA-seq revealed that a significant fraction of miRNAs contains m6A. By motif searches we have discovered consensus sequences discriminating between methylated and unmethylated miRNAs. The epigenetic modification of an epigenetic modifier as described here adds a new layer to the complexity of the posttranscriptional regulation of gene expression.
    PLoS ONE 02/2015; 10(2):e0118438. DOI:10.1371/journal.pone.0118438 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: RNA editing is a dynamic mechanism for gene regulation attained through the alteration of the sequence of primary RNA transcripts. A-to-I (adenosine-to-inosine) RNA editing, which is catalyzed by members of the adenosine deaminase acting on RNA (ADAR) family of enzymes, is the most common post-transcriptional modification in humans. The ADARs bind double-stranded regions and deaminate adenosine (A) into inosine (I), which in turn is interpreted by the translation and splicing machineries as guanosine (G). In recent years, this modification has been discovered to occur not only in coding RNAs but also in non-coding RNAs (ncRNA), such as microRNAs, small interfering RNAs, transfer RNAs, and long non-coding RNAs. This may have several consequences, such as the creation or disruption of microRNA/mRNA binding sites, and thus affect the biogenesis, stability, and target recognition properties of ncRNAs. The malfunction of the editing machinery is not surprisingly associated with various human diseases, such as neurodegenerative, cardio-vascular, and carcinogenic diseases. Despite the enormous efforts made so far, the real biological function of this phenomenon, as well as the features of the ADAR substrate, in particular in non-coding RNAs, has still not been fully understood. In this work, we focus on the current knowledge of RNA editing on ncRNA molecules and provide a few examples of computational approaches to elucidate its biological function.
    Frontiers in Bioengineering and Biotechnology 04/2015; 3(37). DOI:10.3389/fbioe.2015.00037
  • [Show abstract] [Hide abstract]
    ABSTRACT: MicroRNAs (miRNAs) comprise a class of small, regulatory noncoding RNAs (ncRNAs) with pivotal roles in posttranscriptional gene regulation. Since their initial discovery in 1993, numerous miRNAs have been identified in mammalian genomes, many of which play important roles in diverse cellular processes in development and disease. These small ncRNAs regulate the expression of many protein-coding genes posttranscriptionally, thus adding a substantial complexity to the molecular networks underlying physiological development and disease. In part, this complexity arises from the distinct gene structures, the extensive genomic redundancy, and the complex regulation of the expression and biogenesis of miRNAs. These characteristics contribute to the functional robustness and versatility of miRNAs and provide important clues to the functional significance of these small ncRNAs. The unique structure and function of miRNAs will continue to inspire many to explore the vast noncoding genome and to elucidate the molecular basis for the functional complexity of mammalian genomes. Copyright © 2015, American Association for the Advancement of Science.
    Science Signaling 8(368):re2. DOI:10.1126/scisignal.2005813 · 7.65 Impact Factor

Full-text (2 Sources)

Download
156 Downloads
Available from
May 23, 2014