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  • 1. Anantharaman, Aparna
    et al.
    Tripathi, Vidisha
    Khan, Abid
    Yoon, Je-Hyun
    Singh, Deepak K.
    Gholamalamdari, Omid
    Guang, Shuomeng
    Ohlson, Johan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Wahlstedt, Helene
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Jantsch, Michael F.
    Conrad, Nicholas K.
    Ma, Jian
    Gorospe, Myriam
    Prasanth, Supriya G.
    Prasanth, Kannanganattu V.
    ADAR2 regulates RNA stability by modifying access of decay-promoting RNA-binding proteins2017In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 45, no 7, p. 4189-4201Article in journal (Refereed)
    Abstract [en]

    Adenosine deaminases acting on RNA (ADARs) catalyze the editing of adenosine residues to inosine (A-to-I) within RNA sequences, mostly in the introns and UTRs (un-translated regions). The significance of editing within non-coding regions of RNA is poorly understood. Here, we demonstrate that association of ADAR2 with RNA stabilizes a subset of transcripts. ADAR2 interacts with and edits the 3' UTR of nuclear-retained Cat2 transcribed nuclear RNA (Ctn RNA). In absence of ADAR2, the abundance and half-life of Ctn RNA are significantly reduced. Furthermore, ADAR2-mediated stabilization of Ctn RNA occurred in an editing-independent manner. Unedited Ctn RNA shows enhanced interaction with the RNA-binding proteins HuR and PARN [Poly(A) specific ribonuclease deadenylase]. HuR and PARN destabilize Ctn RNA in absence of ADAR2, indicating that ADAR2 stabilizes Ctn RNA by antagonizing its degradation by PARN and HuR. Transcriptomic analysis identified other RNAs that are regulated by a similar mechanism. In summary, we identify a regulatory mechanism whereby ADAR2 enhances target RNA stability by limiting the interaction of RNA-destabilizing proteins with their cognate substrates.

  • 2.
    Behm, Mikaela
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Fritzell, Kajsa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Pessa, Heli
    Mackowiak, Sebastian
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Ekdahl, Ylva
    Kang, Wenjing
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Biryukova, Inna
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    von Euler, Anne
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Visa, Neus
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Friedländer, Marc
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Synaptic expression and regulation of miRNA editing in the brainManuscript (preprint) (Other academic)
    Abstract [en]

    In the brain, sophisticated networks of RNA regulatory events tightly control gene expression in order to achieve proper brain function. We and others have previously shown that several miRNAs, encoded within the miR-379-410 cluster, are subjected to A-to-I RNA editing. In the present study we conclude these edited miRNAs to be transcribed as a single long consecutive transcript, however the maturation into functional forms of miRNAs is regulated individually. In seven of the miRNAs, subjected to editing, we analyze how editing relates to miRNA maturation. Of particular interest has been maturation of miR-381-3p and miR-376b-3p, both important for neuronal plasticity, dendrite outgrowth and neuronal homeostasis. Most of the edited miRNAs from the cluster, are highly edited in their unprocessed primary transcript, including miR-381-3p and miR-376b-3p. However, editing in miR-381-3p is almost entirely absent in the mature form, while editing is increased in the mature form of miR-376b-3p compared to the primary transcript. We propose that ADAR1 positively influences the maturation of pri-miR-381 in an editing independent manner. In pri-miR-376b we hypothesize that ADAR1 and ADAR2 competes for editing, and while ADAR2 inhibits miRNA maturation, ADAR1 editing is frequently present in the mature miR-376b-3p. We further show that miR-381-3p and miR-376b-3p regulate the dendritically expressed Pumilio 2 (Pum2) protein. By next generation RNA sequencing (NGS RNA-seq) on purified synaptoneurosomes, we show that miR-381-3p is highly expressed at the synapse, suggesting its functional role in locally regulating Pum2. Furthermore, we identify a set of highly expressed miRNAs at the synapse, which may act locally to target synaptic mRNAs.

  • 3.
    Behm, Mikaela
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Wahlstedt, Helene
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Widmark, Albin
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Eriksson, Maria
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Accumulation of nuclear ADAR2 regulates A-to-I RNA editing during neuronal development2017In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 130, p. 745-753Article in journal (Refereed)
    Abstract [en]

    Adenosine to inosine (A-to-I) RNA editing is important for a functional brain, and most known sites that are subject to selective RNA editing have been found to result in diversified protein isoforms that are involved in neurotransmission. In the absence of the active editing enzymes ADAR1 or ADAR2 (also known as ADAR and ADARB1, respectively), mice fail to survive until adulthood. Nuclear A-to-I editing of neuronal transcripts is regulated during brain development, with low levels of editing in the embryo and a dramatic increase after birth. Yet, little is known about the mechanisms that regulate editing during development. Here, we demonstrate lower levels of ADAR2 in the nucleus of immature neurons than in mature neurons. We show that importin-a4 (encoded by Kpna3), which increases during neuronal maturation, interacts with ADAR2 and contributes to the editing efficiency by bringing it into the nucleus. Moreover, we detect an increased number of interactions between ADAR2 and the nuclear isomerase Pin1 as neurons mature, which contribute to ADAR2 protein stability. Together, these findings explain how the nuclear editing of substrates that are important for neuronal function can increase as the brain develops. 

  • 4.
    Behm, Mikaela
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    RNA Editing: A Contributor to Neuronal Dynamics in the Mammalian Brain2016In: Trends in Genetics, ISSN 0168-9525, E-ISSN 1362-4555, Vol. 32, no 3, p. 165-175Article, review/survey (Refereed)
    Abstract [en]

    Post-transcriptional RNA modification by adenosine to inosine (A-to-I) editing expands the functional output of many important neuronally expressed genes. The mechanism provides flexibility in the proteome by expanding the variety of isoforms, and is a requisite for neuronal function. Indeed, targets for editing include key mediators of synaptic transmission with an overall significant effect on neuronal signaling. In addition, editing influences splice-site choice and miRNA targeting capacity, and thereby regulates neuronal gene expression. Editing efficiency at most of these sites increases during neuronal differentiation and brain maturation in a spatiotemporal manner. This editing-induced dynamics in the transcriptome is essential for normal brain development, and we are only beginning to understand its role in neuronal function. In this review we discuss the impact of RNA editing in the brain, with special emphasis on the physiological consequences for neuronal development and plasticity.

  • 5.
    Daniel, Chammiran
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Behm, Mikaela
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    The role of Alu elements in the cis-regulation of RNA processing2015In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 72, no 21, p. 4063-4076Article, review/survey (Refereed)
    Abstract [en]

    The human genome is under constant invasion by retrotransposable elements. The most successful of these are the Alu elements; with a copy number of over a million, they occupy about 10 % of the entire genome. Interestingly, the vast majority of these Alu insertions are located in gene-rich regions, and one-third of all human genes contains an Alu insertion. Alu sequences are often embedded in gene sequence encoding pre-mRNAs and mature mRNAs, usually as part of their intron or UTRs. Once transcribed, they can regulate gene expression as well as increase the number of RNA isoforms expressed in a tissue or a species. They also regulate the function of other RNAs, like microRNAs, circular RNAs, and potentially long non-coding RNAs. Mechanistically, Alu elements exert their effects by influencing diverse processes, such as RNA editing, exonization, and RNA processing. In so doing, they have undoubtedly had a profound effect on human evolution.

  • 6.
    Daniel, Chammiran
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Lagergren, Jens
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    RNA editing of non-coding RNA and its role in gene regulation2015In: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 117, p. 22-27Article, review/survey (Refereed)
    Abstract [en]

    It has for a long time been known that repetitive elements, particularly Alu sequences in human, are edited by the adenosine deaminases acting on RNA, ADAR, family. The functional interpretation of these events has been even more difficult than that of editing events in coding sequences, but today there is an emerging understanding of their downstream effects. A surprisingly large fraction of the human transcriptome contains inverted Alu repeats, often forming long double stranded structures in RNA transcripts, typically occurring in introns and UTRs of protein coding genes. Alu repeats are also common in other primates, and similar inverted repeats can frequently be found in non-primates, although the latter are less prone to duplex formation. In human, as many as 700,000 Alu elements have been identified as substrates for RNA editing, of which many are edited at several sites. In fact, recent advancements in transcriptome sequencing techniques and bioinformatics have revealed that the human editome comprises at least a hundred million adenosine to inosine (A-to-I) editing sites in Alu sequences. Although substantial additional efforts are required in order to map the editome, already present knowledge provides an excellent starting point for studying cis-regulation of editing. In this review, we will focus on editing of long stem loop structures in the human transcriptome and how it can effect gene expression.

  • 7.
    Daniel, Chammiran
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Silberberg, Gilad
    Behm, Mikaela
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Alu elements shape the primate transcriptome by cis-regulation of RNA editing2014In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 15, no 2, article id R28Article in journal (Refereed)
    Abstract [en]

    Background: RNA editing by adenosine to inosine deamination is a widespread phenomenon, particularly frequent in the human transcriptome, largely due to the presence of inverted Alu repeats and their ability to form double-stranded structures - a requisite for ADAR editing. While several hundred thousand editing sites have been identified within these primate-specific repeats, the function of Alu-editing has yet to be elucidated. Results: We show that inverted Alu repeats, expressed in the primate brain, can induce site-selective editing in cis on sites located several hundred nucleotides from the Alu elements. Furthermore, a computational analysis, based on available RNA-seq data, finds that site-selective editing occurs significantly closer to edited Alu elements than expected. These targets are poorly edited upon deletion of the editing inducers, as well as in homologous transcripts from organisms lacking Alus. Sequences surrounding sites near edited Alus in UTRs, have been subjected to a lesser extent of evolutionary selection than those far from edited Alus, indicating that their editing generally depends on cis-acting Alus. Interestingly, we find an enrichment of primate-specific editing within encoded sequence or the UTRs of zinc finger-containing transcription factors. Conclusions: We propose a model whereby primate-specific editing is induced by adjacent Alu elements that function as recruitment elements for the ADAR editing enzymes. The enrichment of site-selective editing with potentially functional consequences on the expression of transcription factors indicates that editing contributes more profoundly to the transcriptomic regulation and repertoire in primates than previously thought.

  • 8.
    Daniel, Chammiran
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Wahlstedt, Helene
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Ohlson, Johan
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Björk, Petra
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Adenosine-to-Inosine RNA Editing Affects Trafficking of the γ-Aminobutyric Acid Type A (GABAA) Receptor2011In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 286, no 3, p. 2031-2040Article in journal (Refereed)
    Abstract [en]

    Recoding by adenosine-to-inosine RNA editing plays an important role in diversifying proteins involved in neurotransmission. We have previously shown that the Gabra-3 transcript, coding for the α3 subunit of the GABAA receptor is edited in mouse, causing an isoleucine to methionine (I/M) change. Here we show that this editing event is evolutionarily conserved from human to chicken. Analyzing recombinant GABAA receptor subunits expressed in HEK293 cells, our results suggest that editing at the I/M site in α3 has functional consequences on receptor expression. We demonstrate that I/M editing reduces the cell surface and the total number of α3 subunits. The reduction in cell surface levels is independent of the subunit combination as it is observed for α3 in combination with either the β2 or the β3 subunit. Further, an amino acid substitution at the corresponding I/M site in the α1 subunit has a similar effect on cell surface presentation, indicating the importance of this site for receptor trafficking. We show that the I/M editing during brain development is inversely related to the α3 protein abundance. Our results suggest that editing controls trafficking of α3-containing receptors and may therefore facilitate the switch of subunit compositions during development as well as the subcellular distribution of α subunits in the adult brain.

  • 9.
    Daniel, Chammiran
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Widmark, Albin
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Rigardt, Ditte
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Editing inducer elements increases A-to-I editing efficiency in the mammalian transcriptome2017In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 18, article id 195Article in journal (Refereed)
    Abstract [en]

    Background: Adenosine to inosine (A-to-I) RNA editing has been shown to be an essential event that plays a significant role in neuronal function, as well as innate immunity, in mammals. It requires a structure that is largely double-stranded for catalysis but little is known about what determines editing efficiency and specificity in vivo. We have previously shown that some editing sites require adjacent long stem loop structures acting as editing inducer elements (EIEs) for efficient editing. Results: The glutamate receptor subunit A2 is edited at the Q/R site in almost 100% of all transcripts. We show that efficient editing at the Q/R site requires an EIE in the downstream intron, separated by an internal loop. Also, other efficiently edited sites are flanked by conserved, highly structured EIEs and we propose that this is a general requisite for efficient editing, while sites with low levels of editing lack EIEs. This phenomenon is not limited to mRNA, as non-coding primary miRNAs also use EIEs to recruit ADAR to specific sites. Conclusions: We propose a model where two regions of dsRNA are required for efficient editing: first, an RNA stem that recruits ADAR and increases the local concentration of the enzyme, then a shorter, less stable duplex that is ideal for efficient and specific catalysis. This discovery changes the way we define and determine a substrate for A-to-I editing. This will be important in the discovery of novel editing sites, as well as explaining cases of altered editing in relation to disease.

  • 10.
    Daniel, Chammiran
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    RNA editing and its impact on GABAa receptor function2009In: Biochemical Society Transactions, ISSN 0300-5127, E-ISSN 1470-8752, Vol. 37, p. 1399-1403Article in journal (Refereed)
    Abstract [en]

    A-to-I (adenosine-to-inosine) RNA editing catalysed by the ADARs (adenosine deaminases that act on RNA) is a post-transcriptional event that contributes to protein diversity in metazoans. In mammalian neuronal ion channels, editing alters functionally important amino acids and creates receptor subtypes important for the development of the nervous system. The excitatory AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) and kainate glutamate receptors, as well as the inhibitory GABAA [GABA (γ-aminobutyric acid) type A] receptor, are subject to A-to-I RNA editing. Editing affects several features of the receptors, including kinetics, subunit assembly and cell-surface expression. Here, we discuss the regulation of editing during brain maturation and the impact of RNA editing on the expression of different receptor subtypes.

  • 11.
    Ekdahl, Ylva
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Farahani, Hossein Shahrabi
    Behm, Mikaela
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Lagergren, Jens
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    A-to-I editing of microRNAs in the mammalian brain increases during development2012In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 22, no 8, p. 1477-1487Article in journal (Refereed)
    Abstract [en]

    Adenosine-to-inosine (A-to-I) RNA editing targets double-stranded RNA stem-loop structures in the mammalian brain. It has previously been shown that miRNAs are substrates for A-to-I editing. For the first time, we show that for several definitions of edited miRNA, the level of editing increases with development, thereby indicating a regulatory role for editing during brain maturation. We use high-throughput RNA sequencing to determine editing levels in mature miRNA, from the mouse transcriptome, and compare these with the levels of editing in pri-miRNA. We show that increased editing during development gradually changes the proportions of the two miR-376a isoforms, which previously have been shown to have different targets. Several other miRNAs that also are edited in the seed sequence show an increased level of editing through development. By comparing editing of pri-miRNA with editing and expression of the corresponding mature miRNA, we also show an editing-induced developmental regulation of miRNA expression. Taken together, our results imply that RNA editing influences the miRNA repertoire during brain maturation.

  • 12.
    Ensterö, Mats
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Daniel, Chammiran
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Wahlstedt, Helene
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Major, Francois
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Recognition and coupling af A-to-I edited sites are determined by the tertiary structure of the RNA2009In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 37, no 20, p. 6916-6926Article in journal (Refereed)
    Abstract [en]

    Adenosine-to-inosine (A-to-I) editing has been shown to be an important mechanism that increases protein diversity in the brain of organisms from human to fly. The family of ADAR enzymes converts some adenosines of RNA duplexes to inosines through hydrolytic deamination. The adenosine recognition mechanism is still largely unknown. Here, to investigate it, we analyzed a set of selectively edited substrates with a cluster of edited sites. We used a large set of individual transcripts sequenced by the 454 sequencing technique. On average, we analyzed 570 single transcripts per edited region at four different developmental stages from embryogenesis to adulthood. To our knowledge, this is the first time, large-scale sequencing has been used to determine synchronous editing events. We demonstrate that edited sites are only coupled within specific distances from each other. Furthermore, our results show that the coupled sites of editing are positioned on the same side of a helix, indicating that the three-dimensional structure is key in ADAR enzyme substrate recognition. Finally, we propose that editing by the ADAR enzymes is initiated by their attraction to one principal site in the substrate.

  • 13.
    Ensterö, Mats
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Åkerborg, Örjan
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lundin, Daniel
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Wang, Bei
    Furey, Terrence S
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Lagergren, Jens
    A computational screen for site selective A-to-I editing detects novel sites in neuron specific Hu proteins2010In: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 11, no 6Article in journal (Refereed)
    Abstract [en]

    Background

    Several bioinformatic approaches have previously been used to find novel sites of ADAR mediated A-to-I RNA editing in human. These studies have discovered thousands of genes that are hyper-edited in their non-coding intronic regions, especially in alu retrotransposable elements, but very few substrates that are site-selectively edited in coding regions. Known RNA edited substrates suggest, however, that site selective A-to-I editing is particularly important for normal brain development in mammals.

    Results

    We have compiled a screen that enables the identification of new sites of site-selective editing, primarily in coding sequences. To avoid hyper-edited repeat regions, we applied our screen to the alu-free mouse genome. Focusing on the mouse also facilitated better experimental verification. To identify candidate sites of RNA editing, we first performed an explorative screen based on RNA structure and genomic sequence conservation. We further evaluated the results of the explorative screen by determining which transcripts were enriched for A-G mismatches between the genomic template and the expressed sequence since the editing product, inosine (I), is read as guanosine (G) by the translational machinery. For expressed sequences, we only considered coding regions to focus entirely on re-coding events. Lastly, we refined the results from the explorative screen using a novel scoring scheme based on characteristics for known A-to-I edited sites. The extent of editing in the final candidate genes was verified using total RNA from mouse brain and 454 sequencing.

    Conclusions

    Using this method, we identified and confirmed efficient editing at one site in the Gabra3 gene. Editing was also verified at several other novel sites within candidates predicted to be edited. Five of these sites are situated in genes coding for the neuron-specific RNA binding proteins HuB and HuD.

  • 14. Fong, Nova
    et al.
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Bentley, David L
    Fast ribozyme cleavage releases transcripts from RNA polymerase II and aborts co-transcriptional pre-mRNA processing2009In: Nature Structural & Molecular Biology, ISSN 1545-9993, E-ISSN 1545-9985, Vol. 16, no 9, p. 916-923Article in journal (Refereed)
    Abstract [en]

    Adenosine-to-inosine (A-to-I) editing has been shown to be an important mechanism that increases protein diversity in the brain of organisms from human to fly. The family of ADAR enzymes converts some adenosines of RNA duplexes to inosines through hydrolytic deamination. The adenosine recognition mechanism is still largely unknown. Here, to investigate it, we analyzed a set of selectively edited substrates with a cluster of edited sites. We used a large set of individual transcripts sequenced by the 454 sequencing technique. On average, we analyzed 570 single transcripts per edited region at four different developmental stages from embryogenesis to adulthood. To our knowledge, this is the first time, large-scale sequencing has been used to determine synchronous editing events. We demonstrate that edited sites are only coupled within specific distances from each other. Furthermore, our results show that the coupled sites of editing are positioned on the same side of a helix, indicating that the three-dimensional structure is key in ADAR enzyme substrate recognition. Finally, we propose that editing by the ADAR enzymes is initiated by their attraction to one principal site in the substrate.

  • 15.
    Fritzell, Kajsa
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Xu, Li-Di
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Lagergren, Jens
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    ADARs and editing: The role of A-to-I RNA modification in cancer progression2018In: Seminars in Cell and Developmental Biology, ISSN 1084-9521, E-ISSN 1096-3634, Vol. 79, p. 123-130Article, review/survey (Refereed)
    Abstract [en]

    Cancer arises when pathways that control cell functions such as proliferation and migration are dysregulated to such an extent that cells start to divide uncontrollably and eventually spread throughout the body, ultimately endangering the survival of an affected individual. It is well established that somatic mutations are important in cancer initiation and progression as well as in creation of tumor diversity. Now also modifications of the transcriptome are emerging as a significant force during the transition from normal cell to malignant tumor. Editing of adenosine (A) to inosine (I) in double-stranded RNA, catalyzed by adenosine deaminases acting on RNA (ADARs), is one dynamic modification that in a combinatorial manner can give rise to a very diverse transcriptome. Since the cell interprets inosine as guanosine (G), editing can result in non-synonymous codon changes in transcripts as well as yield alternative splicing, but also affect targeting and disrupt maturation of microRNA. ADAR editing is essential for survival in mammals but its dysregulation can lead to cancer. ADAR1 is for instance overexpressed in, e.g., lung cancer, liver cancer, esophageal cancer and chronic myoelogenous leukemia, which with few exceptions promotes cancer progression. In contrast, ADAR2 is lowly expressed in e.g. glioblastoma, where the lower levels of ADAR2 editing leads to malignant phenotypes. Altogether, RNA editing by the ADAR enzymes is a powerful regulatory mechanism during tumorigenesis. Depending on the cell type, cancer progression seems to mainly be induced by ADAR1 upregulation or ADAR2 downregulation, although in a few cases ADAR1 is instead downregulated. In this review, we discuss how aberrant editing of specific substrates contributes to malignancy.

  • 16.
    Fritzell, Kajsa
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Xu, Li-Di
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Otrocka, Magdalena
    Andréasson, Claes
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sensitive ADAR editing reporter in cancer cells enables high-throughput screening of small molecule libraries2019In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 47, no 4, article id e22Article in journal (Refereed)
    Abstract [en]

    Adenosine to inosine editing is common in the human transcriptome and changes of this essential activity is associated with disease. Children with ADAR1 mutations develop fatal Aicardi-Goutieres syndrome characterized by aberrant interferon expression. In contrast, ADAR1 overexpression is associated with increased malignancy of breast, lung and liver cancer. ADAR1 silencing in breast cancer cells leads to increased apoptosis, suggesting an anti-apoptotic function that promotes cancer progression. Yet, suitable high-throughput editing assays are needed to efficiently screen chemical libraries for modifiers of ADAR1 activity. We describe the development of a bioluminescent reporter system that facilitates rapid and accurate determination of endogenous editing activity. The system is based on the highly sensitive and quantitative Nanoluciferase that is conditionally expressed upon reporter-transcript editing. Stably introduced into cancer cell lines, the system reports on elevated endogenous ADAR1 editing activity induced by interferon as well as knockdown of ADAR1 and ADAR2. In a single-well setup we used the reporter in HeLa cells to screen a small molecule library of 33 000 compounds. This yielded a primary hit rate of 0.9% at 70% inhibition of editing. Thus, we provide a key tool for high-throughput identification of modifiers of A-to-I editing activity in cancer cells.

  • 17. Gorodkin, J
    et al.
    Havgaard, J H
    Ensterö, M
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Sawera, M
    Jensen, P
    Öhman, M
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Fredholm, M
    MicroRNA sequence motifs reveal asymmetry between the stem arms2006In: Computational Biology and Chemistry, Vol. 30, p. 249-254Article in journal (Refereed)
  • 18.
    Gowda, Naveen K. C.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kaimal, Jayasankar M.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kityk, Roman
    Daniel, Chammiran
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Liebau, Jobst
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Mayer, Matthias P.
    Andréasson, Claes
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nucleotide exchange factors Fes1 and HspBP1 mimic substrate to release misfolded proteins from Hsp702018In: Nature Structural & Molecular Biology, ISSN 1545-9993, E-ISSN 1545-9985, Vol. 25, no 1, p. 83-+Article in journal (Refereed)
    Abstract [en]

    Protein quality control depends on the tight regulation of interactions between molecular chaperones and polypeptide substrates. Substrate release from the chaperone Hsp70 is triggered by nucleotide-exchange factors (NEFs) that control folding and degradation fates via poorly understood mechanisms. We found that the armadillo-type NEFs budding yeast Fes1 and its human homolog HspBP1 employ flexible N-terminal release domains (RDs) with substrate-mimicking properties to ensure the efficient release of persistent substrates from Hsp70. The RD contacts the substrate-binding domain of the chaperone, competes with peptide substrate for binding and is essential for proper function in yeast and mammalian cells. Thus, the armadillo domain engages Hsp70 to trigger nucleotide exchange, whereas the RD safeguards the release of substrates. Our findings provide fundamental mechanistic insight into the functional specialization of Hsp70 NEFs and have implications for the understanding of proteostasis-related disorders, including Marinesco-Sjögren syndrome.

  • 19.
    Gowda, Naveen Kumar C.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kaimal, Jayasankar Mohanakrishnan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kityk, Roman
    Daniel, Chammiran
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Liebau, Jobst
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Mayer, Matthias P.
    Andréasson, Claes
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Substrate-mimicking domain of nucleotide-exchange factor Fes1/HspBP1 ensures efficient release of persistent substrates from Hsp70Manuscript (preprint) (Other academic)
  • 20. Hart, K
    et al.
    Nyström, B
    Öhman, M
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Nilsson, L
    Molecular dynamics simulations and free energy calculations of base flipping in dsRNA2005In: RNA, Vol. 11, p. 609-618Article in journal (Refereed)
  • 21. Klaue, Y
    et al.
    Källman, Annika M.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Bonin, M
    Nellen, W
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Biochemical analysis and scanning force microscopy reveal productive and non-productive ADAR2 binding to RNA substrates2003In: RNA: A publication of the RNA Society, ISSN 1355-8382, E-ISSN 1469-9001, Vol. 9, no 7, p. 839-846Article in journal (Refereed)
    Abstract [en]

    Scanning force microscopy (SFM) can be used to image biomolecules at high resolution. Here we demonstrate that single-molecule analysis by SFM complements biochemical data on RNA protein binding and can provide information that cannot be obtained by the usual biochemical methods. We have used this method to study the interaction between the RNA editing enzyme ADAR2 and RNA transcripts containing selective and nonselective editing sites. The natural selectively edited R/G site from glutamate receptor subunit B (GluR-B) was inserted into an RNA backbone molecule consisting of a completely double-stranded (ds) central part and incompletely paired ends derived from potato spindle tuber viroid (PSTVd). This molecule was efficiently edited at the R/G site, but promiscuous editing occurred at nonselective sites in the completely double-stranded region. The construct was also used to analyze binding of ADAR2 to wild-type and modified R/G editing sites in relation to binding at other nonselectively edited sites. Editing analysis together with SFM allow us to differentiate between binding and enzymatic activity. ADAR2 has                     been reported to have a general affinity to dsRNA. However, we show that there is a prominent bias for stable binding at sites selectively edited over other edited sites. On the other hand, promiscuous editing at nonselective sites apparently results from transient binding of the enzyme to the substrate. Furthermore, we find distinct sites with nonproductive binding of the enzyme.

  • 22.
    Källman, Annika M.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Sahlin, Margareta
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    ADAR2 A to I editing: site selectivity and editing efficiency are separate events2003In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 31, no 16, p. 4874-4881Article in journal (Refereed)
    Abstract [en]

    ADAR enzymes, adenosine deaminases that act on RNA, form a family of RNA editing enzymes that convert adenosine to inosine within RNA that is completely or largely double‐stranded. Site‐selective A→I editing has been detected at specific sites within  a few tructured pre‐mRNAs of metazoans. We have analyzed the editing selectivity of ADAR enzymes and have chosen to study the naturally edited R/G site in the pre‐mRNA of the glutamate receptor subunit B (GluR‐B). A comparison of editing by ADAR1 and ADAR2 revealed differences in the specificity of editing. Our results show that ADAR2 selectively edits the R/G site, while ADAR1 edits more promiscuously at several other adenosines in the double‐stranded stem. To further understand the mechanism of selective ADAR2 editing we have investigated the importance of internal loops in the RNA substrate. We have found that the immediate structure surrounding the editing site is important. A purine opposite to the editing site has a negative on both selectivity and efficiency of editing. More distant internal loops in the substrate were found to have minor effects on site selectivity, while efficiency of editing was found to be influenced. Finally, changes in the RNA structure that affected editing did not alter the binding abilities of ADAR2. Overall these findings suggest that binding and catalysis are independent events.                 

  • 23. Laurencikiene, J
    et al.
    Källman, A M
    Fong, N
    Bentley, D L
    Öhman, M
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    RNA editing and alternative splicing: the importance of co-transcriptional coordination2006In: EMBO Reports, Vol. 7, no 3, p. 303-307Article in journal (Other academic)
  • 24. Mannion, Niamh M.
    et al.
    Greenwood, Sam M.
    Young, Robert
    Cox, Sarah
    Brindle, James
    Read, David
    Nellaker, Christoffer
    Vesely, Cornelia
    Ponting, Chris P.
    McLaughlin, Paul J.
    Jantsch, Michael F.
    Dorin, Julia
    Adams, Ian R.
    Scadden, A. D. J.
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Keegan, Liam P.
    O'Connell, Mary A.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Cambridge, England.
    The RNA-Editing Enzyme ADAR1 Controls Innate Immune Responses to RNA2014In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 9, no 4, p. 1482-1494Article in journal (Refereed)
    Abstract [en]

    The ADAR RNA-editing enzymes deaminate adenosine bases to inosines in cellular RNAs. Aberrant interferon expression occurs in patients in whom ADAR1 mutations cause Aicardi-Goutieres syndrome (AGS) or dystonia arising from striatal neurodegeneration. Adar1 mutant mouse embryos show aberrant interferon induction and die by embryonic day E12.5. We demonstrate that Adar1 embryonic lethality is rescued to live birth in Adar1; Mavs double mutants in which the antiviral interferon induction response to cytoplasmic double-stranded RNA (dsRNA) is prevented. Aberrant immune responses in Adar1 mutant mouse embryo fibroblasts are dramatically reduced by restoring the expression of editing-active cytoplasmic ADARs. We propose that inosine in cellular RNA inhibits antiviral inflammatory and interferon responses by altering RLR interactions. Transfecting dsRNA oligonucleotides containing inosine-uracil base pairs into Adar1 mutant mouse embryo fibroblasts reduces the aberrant innate immune response. ADAR1 mutations causing AGS affect the activity of the interferon-inducible cytoplasmic isoform more severely than the nuclear isoform.

  • 25. Navon, Ruth
    et al.
    Silberberg, Gilad
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Lundin, Daniel
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    A Comprehensive Survey of RNA Editing In Psychiatric Disorders Reveals Multiple Novel Editing Sites in Coding Regions2011Conference paper (Refereed)
  • 26.
    Ohlson, Johan
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    A method for finding sites of selective adenosine deamination2007In: Methods in Enzymology, ISSN 0076-6879, E-ISSN 1557-7988, Vol. 424, p. 289-300Article, review/survey (Refereed)
    Abstract [en]

    Single sites of selective adenosine (A) to inosine (1) RNA editing with functional consequences on the proteome are rarely found in mammals. Here we describe a method that can be used to detect novel site-selective A-to-I editing in various tissues as well as species. The method utilizes immunoprecipitation of intrinsic RNA-protein complexes to extract substrates subjected to site-selective in vivo editing. We show that known single sites of A-to-I editing are enriched utilizing an antibody against the ADAR2 protein. We propose that this method is suitable for identification of novel substrates subjected to site-selective A-to-I editing.

  • 27. Ring, Henrik
    et al.
    Boije, Henrik
    Daniel, Chammiran
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Ohlson, Johan
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Increased A-to-I RNA editing of the transcript for GABAA receptor subunit α3 during chick retinal development2010In: Visual Neuroscience, ISSN 0952-5238, E-ISSN 1469-8714, Vol. 27, no 5-6, p. 149-157Article in journal (Refereed)
  • 28. Rybak-Wolf, Agnieszka
    et al.
    Stottmeister, Christin
    Glazar, Petar
    Jens, Marvin
    Pino, Natalia
    Giusti, Sebastian
    Hanan, Mor
    Behm, Mikaela
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Bartok, Osnat
    Ashwal-Fluss, Reut
    Herzog, Margareta
    Schreyer, Luisa
    Papavasileiou, Panagiotis
    Ivanov, Andranik
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Refojo, Damian
    Kadener, Sebastian
    Rajewsky, Nikolaus
    Circular RNAs in the Mammalian Brain Are Highly Abundant, Conserved, and Dynamically Expressed2015In: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 58, no 5, p. 870-885Article in journal (Refereed)
    Abstract [en]

    Circular RNAs (circRNAs) are an endogenous class of animal RNAs. Despite their abundance, their function and expression in the nervous system are unknown. Therefore, we sequenced RNA from different brain regions, primary neurons, isolated synapses, as well as during neuronal differentiation. Using these and other available data, we discovered and analyzed thousands of neuronal human and mouse circRNAs. circRNAs were extraordinarily enriched in the mammalian brain, well conserved in sequence, often expressed as circRNAs in both human and mouse, and sometimes even detected in Drosophila brains. circRNAs were overall upregulated during neuronal differentiation, highly enriched in synapses, and often differentially expressed compared to their mRNA isoforms. circRNA expression correlated negatively with expression of the RNA-editing enzyme ADAR1. Knockdown of ADAR1 induced elevated circRNA expression. Together, we provide a circRNA brain expression atlas and evidence for important circRNA functions and values as biomarkers.

  • 29.
    Silberberg, Gilad
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Lundin, Daniel
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Navon, Ruth
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Deregulation of the A-to-I RNA editing mechanism in psychiatric disorders2012In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 21, no 2, p. 311-321Article in journal (Refereed)
    Abstract [en]

    Schizophrenia and bipolar disorder (BPD) are common neurodevelopmental disorders, characterized by various life-crippling symptoms and high suicide rates. Multiple studies support a strong genetic involvement in the etiology of these disorders, although patterns of inheritance are variable and complex. Adenosine-to-inosine RNA editing is a cellular mechanism, which has been implicated in mental disorders and suicide. To examine the involvement of altered RNA editing in these disorders, we: (i) quantified the mRNA levels of the adenosine deaminase acting on RNA (ADAR) editing enzymes by real-time quantitative polymerase chain reaction, and (ii) measured the editing levels in transcripts of several neuroreceptors using 454 high-throughput sequencing, in dorsolateral-prefrontal cortices of schizophrenics, BPD patients and controls. Increased expression of specific ADAR2 variants with diminished catalytic activity was observed in schizophrenia. Our results also indicate that the I/V editing site in the glutamate receptor, ionotropic kainate 2 (GRIK2) transcript is under-edited in BPD (type I) patients (45.8 versus 53.9%, P = 0.023). GRIK2 has been implicated in mood disorders, and editing of its I/V site can modulate Ca(+2) permeability of the channel, consistent with numerous observations of elevated intracellular Ca(+2) levels in BPD patients. Our findings may therefore, at least partly, explain a molecular mechanism underlying the disorder. In addition, an intriguing correlation was found between editing events on separate exons of GRIK2. Finally, multiple novel editing sites were detected near previously known sites, albeit most with very low editing rates. This supports the hypothesis raised previously regarding the existence of wide-spread low-level 'background' editing as a mechanism that enhances adaptation and evolvability.

  • 30.
    Silberberg, Gilad
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    The edited transcriptome: novel high throughput approaches to detect nucleotide deamination2011In: Current Opinion in Genetics and Development, ISSN 0959-437X, E-ISSN 1879-0380, Vol. 21, no 4, p. 401-406Article, review/survey (Refereed)
    Abstract [en]

    RNA editing is emerging as a wide-spread phenomenon both in coding and non-coding RNA regions. While the mechanisms underlying many of these post-transcriptional modifications have not been elucidated, RNA editing by nucleotide deamination has been known for over two decades as a mechanism to generate base substitutions. With the recently growing use of high throughput sequencing technologies, knowledge about the frequency and diversity of RNA nucleotide substitutions has vastly increased. In this review we will highlight recent findings within this field, and illustrate how novel technologies have made it possible to detect and measure the efficiency of editing in an unprecedented accuracy and robustness. Future prospects for the detection of important transcriptome variations will also be discussed.

  • 31.
    Wahlstedt, Helene
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Daniel, Chammiran
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Ensterö, Mats
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Large-scale mRNA sequencing determines global regulation of RNA editing during brain development2009In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 19, p. 978-986Article in journal (Refereed)
    Abstract [en]

    RNA editing by adenosine deamination has been shown to generate multiple isoforms of several neural receptors, often with profound effects on receptor function. However, little is known about the regulation of editing activity during development. We have developed a large-scale RNA sequencing protocol to determine adenosine-to-inosine (A-to-I) editing frequencies in the coding region of genes in the mammalian brain. Using the 454 Life Sciences (Roche) Amplicon Sequencing technology, we were able to determine even low levels of editing with high accuracy. The efficiency of editing for 28 different sites was analyzed during the development of the mouse brain from embryogenesis to adulthood. We show that, with few exceptions, the editing efficiency is low during embryogenesis, increasing gradually at different rates up to the adult mouse. The variation in editing gave receptors like HTR2C and GABAA (gamma-aminobutyric acid type A) a different set of protein isoforms during development from those in the adult animal. Furthermore, we show that this regulation of editing activity cannot be explained by an altered expression of the ADAR proteins but, rather, by the presence of a regulatory network that controls the editing activity during development.

  • 32.
    Wahlstedt, Helene
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Site-selective versus promiscuous A-to-I editing2011In: Wiley Interdiscip Reviews - RNA, ISSN 1757-7012, Vol. 2, no 6, p. 761-771Article, review/survey (Refereed)
    Abstract [en]

    RNA editing by adenosine deamination is acting on polymerase II derived transcripts in all metazoans. Adenosine-to-inosine (A-to-I) editing is mediated by the adenosine deaminase that acts on RNA (ADAR) enzymes. Two types of adenosine to inosine (A-to-I) RNA editing have been defined: site selective and hyper-editing. Typically, in site selectively edited substrates, one or a few A-to-I sites are edited in double-stranded RNA structures, frequently interrupted by single-stranded bulges and loops. Hyper-editing occurs in long stretches of duplex RNA where multiple adenosines are subjected to deamination. In this review, recent findings on editing within noncoding RNA as well as examples of site selective editing within coding regions are presented. We discuss how these two editing events have evolved and the structural differences between a site selective and hyper-edited substrate.

  • 33.
    Witman, Nevin M.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Behm, Mikaela
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Morrison, Jamie I.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    ADAR-Related Activation of Adenosine-to-Inosine RNA Editing During Regeneration2013In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 22, no 16, p. 2254-2267Article in journal (Refereed)
    Abstract [en]

    Urodele amphibians possess an amazing regenerative capacity that requires the activation of cellular plasticity in differentiated cells and progenitor/stem cells. Many aspects of regeneration in Urodele amphibians recapitulate development, making it unlikely that gene regulatory pathways which are essential for development are mutually exclusive from those necessary for regeneration. One such post-transcriptional gene regulatory pathway, which has been previously shown to be essential for functional metazoan development, is RNA editing. RNA editing catalyses discrete nucleotide changes in RNA transcripts, creating a molecular diversity that could create an enticing connection to the activated cellular plasticity found in newts during regeneration. To assess whether RNA editing occurs during regeneration, we demonstrated that GABRA3 and ADAR2 mRNA transcripts are edited in uninjured and regenerating tissues. Full open-reading frame sequences for ADAR1 and ADAR2, two enzymes responsible for adenosine-to-inosine RNA editing, were cloned from newt brain cDNA and exhibited a strong resemblance to ADAR (adenosine deaminase, RNA-specific) enzymes discovered in mammals. We demonstrated that ADAR1 and ADAR2 mRNA expression levels are differentially expressed during different phases of regeneration in multiple tissues, whereas protein expression levels remain unaltered. In addition, we have characterized a fascinating nucleocytoplasmic shuttling of ADAR1 in a variety of different cell types during regeneration, which could provide a mechanism for controlling RNA editing, without altering translational output of the editing enzyme. The link between RNA editing and regeneration provides further insights into how lower organisms, such as the newt, can activate essential molecular pathways via the discrete alteration of RNA sequences.

  • 34.
    Xu, Li-Di
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    ADAR1 Editing and its Role in Cancer2019In: Genes & Genetic Systems, ISSN 1341-7568, E-ISSN 1880-5779, Vol. 10, no 1, article id 12Article, review/survey (Refereed)
    Abstract [en]

    It is well established that somatic mutations and escape of immune disruption are two essential factors in cancer initiation and progression. With an increasing number of second-generation sequencing data, transcriptomic modifications, so called RNA mutations, are emerging as significant forces that drive the transition from normal cell to malignant tumor, as well as providing tumor diversity to escape an immune attack. Editing of adenosine to inosine (A-to-I) in double-stranded RNA, catalyzed by adenosine deaminases acting on RNA (ADARs), is one dynamic modification that in a combinatorial manner can give rise to a very diverse transcriptome. Since the cell interprets inosine as guanosine (G), A-to-I editing can result in non-synonymous codon changes in transcripts as well as yield alternative splicing, but also affect targeting and disrupt maturation of microRNAs. ADAR-mediated RNA editing is essential for survival in mammals, however, its dysregulation causes aberrant editing of its targets that may lead to cancer. ADAR1 is commonly overexpressed, for instance in breast, lung, liver and esophageal cancer as well as in chronic myelogenous leukemia, where it promotes cancer progression. It is well known that ADAR1 regulates type I interferon (IFN) and its induced gene signature, which are known to operate as a significant barrier to tumor formation and progression. Adding to the complexity, ADAR1 expression is also regulated by IFN. In this review, we discussed the regulatory mechanisms of ADAR1 during tumorigenesis through aberrant editing of specific substrates. Additionally, we hypothesized that elevated ADAR1 levels play a role in suppressing an innate immunity response in cancer cells.

  • 35.
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    A to I editing as a co-transcriptional RNA processing event2008In: RNA and DNA editing: mechanisms and their impact on biological systems, John Wiley & Sons, NJ , 2008Chapter in book (Refereed)
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